Showing papers on "Growth hormone secretagogue published in 2008"
TL;DR: It is suggested that ghrelin has potent anti-inflammatory properties through modulation of secretion of both pro-inflammatory and anti- inflammatory cytokines from LPS-stimulated macrophages through distinct signaling cascades.
217 citations
TL;DR: Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.
Abstract: Background: In animals, insulin-like growth factor-1 (IGF-1) increases clearance of β-amyloid, a pathologic hallmark of Alzheimer disease (AD), from the CNS. Serum IGF-1 level decreases with age, and shows a further decrease in AD. We examined whether the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, slows the rate of progression of symptoms in patients with AD. Methods: A double-blind, multicenter study was conducted in which 563 patients with mild to moderate AD were randomized to receive MK-677 25 mg or placebo daily for 12 months. Efficacy measures were mean change from baseline at month 12 on the Clinician9s Interview Based Impression of Change with caregiver input (CIBIC-plus), the cognitive subscale of the Alzheimer9s Disease Assessment Scale (ADAS-Cog), Alzheimer9s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating-sum of boxes (CDR-sob). Results: A total of 416 patients completed treatment and assessments at 12 months. Administration of MK-677 25 mg resulted in a 60.1% increase in serum IGF-1 levels at 6 weeks and a 72.9% increase at 12 months. In mixed-effects models that included treatment, time (month), randomization strata (baseline MMSE score ≤20 vs >20), and interaction of treatment-by-time, there were no significant differences between the treatment groups on the CIBIC-plus or the mean change from baseline scores on the ADAS-Cog, ADCS-ADL, or CDR-sob scores over 12 months. Conclusion: Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.
88 citations
TL;DR: Results of a stepwise regression statistical analysis showed that both preprandial ghrelin concentration and energy balance were significant predictors of prandial GH increase over baseline, suggesting Adaptations to negative energy balance in lactating dairy cattle likely include enhanced gh Relin secretion and greater GH response to ghrelIn.
74 citations
TL;DR: Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic signals to hypothalamic nuclei involved in the regulation of energy homeostasis.
Abstract: Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders.
61 citations
TL;DR: Surprisingly, variations in receptor density were not identified in any of these binding sites upon a change in nutritional status, despite relevant alterations in plasma ghrelin levels being identified, which could indicate that peripheral gh Relin is unlikely to be the major source of ghrelIn that acts in many hypothalamic sites.
48 citations
German Cancer Research Center1, International Agency for Research on Cancer2, Aarhus University Hospital3, French Institute of Health and Medical Research4, National and Kapodistrian University of Athens5, Harvard University6, Imperial College London7, Andalusian School of Public Health8, Utrecht University9, Umeå University10, University of Cambridge11, University of Oxford12
TL;DR: Evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk is observed, however, these associations might also be due to chance findings and further large studies are needed to confirm these results.
Abstract: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case-control study on 1359 breast cancer cases and 2389 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition, to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with anthropometric measures, circulating insulin growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 and breast cancer risk. Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes. A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele (odds ratio: 1.2; 95% confidence interval: 1.0-1.4; P = 0.02). The GHRL single-nucleotide polymorphism rs375577 was associated with a 5% increase in IGF-I levels (P = 0.01). A number of GHRL and GHSR polymorphisms were associated with body mass index (BMI) and height (P between <0.01 and 0.04). The false-positive report probability (FPRP) approach suggests that these results are noteworthy (FPRP < 0.20). The results presented here add to a growing body of evidence that GHRL variations are associated with BMI. Furthermore, we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk. These associations, however, might also be due to chance findings and further large studies are needed to confirm our results.
45 citations
TL;DR: The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl gh Relin does not potently share these functions.
Abstract: Obesity is a chronic, costly, and globally prevalent condition, with excess caloric intake a suspected etiologic factor. Nonsurgical treatments are modestly efficacious, and weight loss maintenance is hampered by anti-famine homeostatic mechanisms. Ghrelin, a gastric hormone linked to meal initiation, energy expenditure, and fuel partitioning, is hypothesized to facilitate weight gain and impede weight loss. Unique among known animal peptides, the serine-3 residue of ghrelin is posttranslationally acylated with an n-octanoic acid, a modification important for the peptide's active blood-brain transport and growth hormone secretagogue receptor-1 agonist activity. Pharmacological degradation of ghrelin would be hypothesized to reduce ghrelin's biological effects. To study endogenous ghrelin's role in appetite and energy expenditure, we generated antibodies that hydrolyze the octanoyl moiety of ghrelin to form des-acyl ghrelin. The most proficient antibody catalyst, GHR-11E11, was found to display a second-order rate constant of 18 M−1·s−1 for the hydrolysis of ghrelin to des-acyl ghrelin. I.v. administration of GHR-11E11 (50 mg/kg) maintained a greater metabolic rate in fasting C57BL/6J mice as compared with mice receiving a control antibody and suppressed 6-h refeeding after 24 h of food deprivation. Indirect respiratory measures of metabolism after refeeding and relative fuel substrate utilization were unaffected. The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl ghrelin does not potently share these functions. Catalytic anti-ghrelin antibodies might thereby adjunctively aid consolidation of caloric restriction-induced weight loss and might also be therapeutically relevant to Prader–Willi syndrome, characterized after infancy by hyperghrelinemia, hyperphagia, and obesity. hormone inactivation obesity neuropeptides
45 citations
TL;DR: Elevated ghrelin levels in uraemic patients despite poor appetite are observed, but the underlying reasons remain unclear.
Abstract: Background. Patients with renal insufficiency often suffer from cachexia and growth retardation due to low appetite and increased resting metabolic rate. The neuroendocrine hormone ghrelin, a growth hormone secretagogue, enhances food intake, but its role in the development of a cachectic state in renal insufficiency is unclear. Objective. The aim of our study was to investigate the plasma concentration of total ghrelin and other hormones involved in appetite regulation in children with preterminal chronic renal failure (CRF, n = 24), children undergoing dialysis (n = 19), children after renal transplantation (RTx, n = 59) and healthy controls (n = 10). Results. Total ghrelin was significantly elevated in CRF patients(1370 ±182pg/ml;mean ±SEM)whencompared tocontrolsubjects(682 ±106pg/ml;P =0.016)orpatients followingRTx(859 ±51pg/ml;P =0.002).Furthermore,a negative correlation between glomerular filtration rate and total ghrelin was observed in CRF and transplant recipients (r =0.36,P =0.0006).BMISDS(standarddeviationscore) is lower in CRF patients compared to the other groups (P < 0.0001). Leptin, adiponectin, blood glucose, insulin, IGF-I, IGFBP-3 and growth hormone concentrations did not differ among groups. Conclusions. We observed elevated ghrelin levels in uraemic patients despite poor appetite, but the underlying reasons remain unclear. Normal ghrelin levels can be re-achieved following RTx.
36 citations
TL;DR: It is suggested that ghrelin inhibited both the proliferation and apoptosis of rat VSMCs, which is probably mediated by the growth hormone secretagogue receptor type 1a receptor, while the latter effect may be mediated through other receptors.
Abstract: To evaluate the possible role of ghrelin in the development of atherosclerosis, its effects on tumor necrosis factor (TNF)-alpha-induced proliferation and apoptosis of vascular smooth muscle cells (VSMCs) were investigated. Rat VSMCs were pretreated with different concentrations of ghrelin and then with TNF-alpha. VSMC proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry method. Apoptosis was detected using propidium iodide and Annexin-V labeling method. Exogenous ghrelin (10-1000 ng/ml) significantly inhibited TNF-alpha-induced proliferation of VSMCs in a concentration-dependent manner. Treatment with 1000 ng/ml ghrelin was most effective at inhibiting VSMC proliferation rate and the expression of proliferating cell nuclear antigen. However, treatment with des-acyl ghrelin affected neither proliferation nor PCNA expression. In contrast, TNF-alpha-induced apoptosis of VSMCs was inhibited by both ghrelin and des-acyl ghrelin in concentration-dependent manners, with maximal inhibition observed for both compounds at 1000 ng/ml. Taken together, our results suggested that ghrelin inhibited both the proliferation and apoptosis of rat VSMCs. Furthermore, the former effect is probably mediated by the growth hormone secretagogue receptor type 1a receptor, while the latter effect may be mediated through other receptors.
36 citations
TL;DR: The immunocytochemical and electrophysiological results suggest that systemic and central administration of MK‐0677 activates a population of neurons in the arcuate nucleus of the male rat, consistent with an action of neurons involved in the regulation of GH release.
Abstract: There is accumulating evidence that the hypothalamic arcuate nucleus plays an important role in mediating the effects of growth hormone secretagogues on growth hormone (GH) release from the anterior pituitary gland. One such nonpeptidyl secretagogue, MK-0677, has been shown to directly stimulate growth hormone release from isolated pituitary cells but its central actions remain to be established. Therefore, in the present study, we have employed both immunocytochemical and in vivo electrophysiological techniques to examine the effects of MK-0677 within the hypothalamic arcuate nucleus of the male rat. In conscious male rats, both central and systemic injection of MK-0677 induced fos-like immunoreactivity specifically within the arcuate nucleus indicating selective neuronal activation of neurons within this region. MK-0677 induced-activation was generally confined close to the wall of the third ventricle, whereas systemic injection of the peptide secretagogue, GHRP-6, also induced fos-like immunoreactivity in more lateral regions of the nucleus. In urethane anaesthetized rats, intravenous injection of MK-0677 increased the electrical activity of a population of antidromically identified (i.e. neuroendocrine) arcuate neurons with a similar electrophysiological profile to cells excited by GHRP-6. The activity of neuroendocrine arcuate neurons excited by MK-0677 injection could be attenuated by a subsequent systemic injection of somatostatin. However, the activity of neuroendocrine arcuate neurons unaffected by MK-0677 injection and the activity of non-neuroendocrine arcuate neurons was unaltered by somatostatin injection. Taken together, the immunocytochemical and electrophysiological results suggest that systemic and central administration of MK-0677 activates a population of neurons in the arcuate nucleus. Furthermore, the inhibitory effects of somatostatin on MK-0677-induced excitation of these neuroendocrine cells is consistent with an action of neurons involved in the regulation of GH release.
26 citations
TL;DR: This review summarizes the current understanding of the effects of ghrelin on cell differentiation and tissue development, with an emphasis on the lineage determination of mesenchymal stem cells.
Abstract: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is a gastric hormone that has been found to have a wide variety of biological functions. This review summarizes our current understanding of the effects of ghrelin on cell differentiation and tissue development, with an emphasis on the lineage determination of mesenchymal stem cells.
TL;DR: The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 and the ortho position of the benzyl moiety was found to be favorable for introduction of substituents.
TL;DR: A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Patent•
10 Apr 2008
TL;DR: In this paper, the authors proposed methods of treating or preventing emesis and improving a subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Abstract: The present invention relates to methods of treating or preventing emesis and improving a subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
TL;DR: The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved and the incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency.
Patent•
08 Feb 2008
TL;DR: In this article, a method of treating cell proliferative disorders by administering to a subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof is described.
Abstract: The present invention relates to a method of treating cell proliferative disorders by administering to a subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
TL;DR: Injections or infusions of growth hormonereleasing hormone (GHRH) and parenteral or oral administration of a ghrelin-mimetic growth hormone secretagogue (GHS) have been shown to restore levels of growth hormones in older persons to those of young adults, indicating that the aging pituitary is capable of enhanced growth hormone secretion if appropriate stimuli are supplied and suggesting that older adults with relative growth hormone deficiency might also benefit from growth hormone stimulation.
Abstract: In this issue, Nass and colleagues report that at 1 year, an oral ghrelin mimetic increased pulsatile growth hormone secretion and morning insulin-like growth factor I concentration to that in heal...
Patent•
11 Mar 2008
TL;DR: Using a growth protein secretion promoter and a milk-derived basic protein fraction, which is based on the promotion of secretion of ghrelin, which has a growth hormone secretion promoting action, comprising a milk derived Basic Protein fraction as an active ingredient as discussed by the authors.
Abstract: Using a growth protein secretion promoter and a milk-derived basic protein fraction, which is based on the promotion of secretion of ghrelin, which has a growth hormone secretion promoting action, comprising a milk-derived basic protein fraction as an active ingredient A method of promoting ghrelin secretion. This growth hormone secretagogue can be taken on a daily basis and is safe even if taken for a long time.
Patent•
10 Apr 2008
TL;DR: In this paper, the authors proposed methods of treating or preventing emesis and improving a subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Abstract: The present invention relates to methods of treating or preventing emesis and improving a subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Patent•
03 Jul 2008
TL;DR: In this paper, the growth hormone secretagogue contains a lactobacillus fermentation product of soya milk as an active component, which can be used as a functional food having a growth hormone secretion promoting activity by adding the fermentation product to an arbitrary food or drink.
Abstract: PROBLEM TO BE SOLVED: To provide a growth hormone secretagogue useful for the health maintenance and improvement such as the increase in the muscle bulk, the springiness of the skin and the bone density, and to provide a functional food or drink containing the agent. SOLUTION: The growth hormone secretagogue contains a lactobacillus fermentation product of soya milk as an active component. The fermentation product is obtained by adding lactic bacteria belonging to the genus Lactobacillus, Leuconostoc or Pediococcus to soya milk and collecting the fermentation product. The lactobacillus fermentation product of soya milk is usable as a functional food having a growth hormone secretion promoting activity by adding the fermentation product to an arbitrary food or drink. COPYRIGHT: (C)2008,JPO&INPIT
Patent•
08 Feb 2008
TL;DR: In this article, the authors describe the intermediates of conformationally defined macrocyclic compounds that bind to and/or are functional modulators of the ghrelin (growth hormone secretagogue) receptor including GHS-R1a and subtypes, isoforms and variants thereof.
Abstract: The present invention relates to intermediates of conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the ghrelin (growth hormone secretagogue) receptor including GHS-R1a and subtypes, isoforms and/or variants thereof and the use of these interemdaites to prepare said macrocyclic compounds.
TL;DR: There is not a relation between plasma ghrelin levels and H. pylori infection, as in Turkey the prevalence of the strains that cause atrophic gastritis is lower and differences in studied populations can also affect results.
01 Jun 2008
TL;DR: A review of the literature regarding the effects of ghrelin on energy balance can be found in this paper, where the authors discuss both food intake and energy expenditure in relation to Ghrelin.
Abstract: Introduction The discovery of ghrelin, a 28 amino-acid peptide hormone, has generated a substantial amount of attention for a number of reasons. Initially, ghrelin was heralded as the long sought endogenous ligand for the orphan growth hormone secretagogue receptors (GHS-Rs). Indeed, like growth hormone secretagogues (GHS), ghrelin targeted these receptors to potently increase the release of growth hormone (GH) both in vitro and in vivo. Soon, however, it became evident that ghrelin was implicated in a variety of physiological processes that include cell proliferation, metabolism, cell protection, reproduction, etc. Of these, the effects of ghrelin on food intake and metabolism have had the biggest impact; unlike other peripheral signals associated with energy balance, ghrelin increases appetite and leads to the accumulation of body fat. Indeed, the stimulatory effects of ghrelin on food intake and its apparent opposite relation to the anorectic hormone, leptin, have been proposed as the ying/yang model for hormonal regulation of energy balance. Nevertheless, the more is known about ghrelin, the more it becomes obvious that ghrelin produces its metabolic effects via a multitude of central and peripheral mechanisms that work in parallel to modulate the effects of ghrelin in energy regulation. This chapter will review the literature regarding the effects of ghrelin on energy balance. Energy balance implies the regulation of both food intake and energy expenditure, therefore we will discuss both topics in relation to ghrelin. A description of the possible central routes of ghrelin actions on energy balance within the brain will follow.
Patent•
10 Apr 2008
TL;DR: In this article, a method of treating or preventing vomiting and improving the subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue promoting compound or a pharmaceutically acceptable salt, hydrate or solvate thereof was proposed.
Abstract: The present invention relates to a method of treating or preventing vomiting and improving the subject's ASAS score by administering to the subject an effective amount of a growth hormone secretagogue promoting compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.