Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.

AIMS: Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg-1 min-1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. RESULTS: Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion. CONCLUSIONS: These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.

Developing long-acting growth hormone formulations.

Daily recombinant growth hormone (GH) restores normal growth and body composition in GH-deficient children and adults; however, daily injections are inconvenient and can be distressing for some children. On top of this compliance is a problem in up to 75% of children. Developing long-acting GH formulations has proved challenging, and questions remain regarding safety and efficacy. In this review, we focus on the rationale for generating long-acting GH agonists and the technologies being developed to deliver prolonged exposure to GH.

Clinical review: The human experience with ghrelin administration.

CONTEXT: Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. EVIDENCE ACQUISITION: PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. EVIDENCE SYNTHESIS: Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. CONCLUSIONS: Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation.

[Optimization of the medical treatment for acromegaly]. / Optimización del tratamiento médico de la acromegalia.

Somatostatin analogues are the cornerstone in the first-line and adjuvant (postsurgical) therapy in patients with acromegaly. These drugs highly effectively decrease serum concentrations of growth hormone (GH) and insulin-like growth factor type I (IGF-I), as well as pituitary adenoma size. However, in approximately one third of patients response to these agents is unsatisfactory. The optimization of the medical therapy for acromegaly can be accomplished by modifying the dose or the interval of administration of somatostatin analogues or by combining other pharmacological agents. Increasing the dose or frequency of administration is followed by an additional decrease in GH and IGF-I levels in a significant percentage of patients. These changes are not accompanied by a relevant increase in the number or severity of adverse events. Combined treatment with somatostatin analogues and pegvisomant has been shown to significantly reduce serum IGF-I levels in patients with inadequate control of disease activity. The addition of cabergoline to somatostatin analogue therapy is accompanied by a further decrease in IGF-I levels that is independent of serum prolactin concentrations.

Possible usefulness of growth hormone/insulin-like growth factor-I axis in Alzheimer's disease treatment.

Alzheimer's disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. Neuropathological analysis of AD-affected brains reveals extensive atrophy due to neuronal loss, and accumulation of neurofibrillary tangles and neuritic plaques, surrounded by a tract of neuroinflammation and loss of neurons. Recently, emerging evidence supports the concept that AD is also a disorder of metabolic degeneration. Taken together, the neurochemical changes in the brain from patients with AD indicate multiple disturbances and it seems likely that the changes are secondary to more fundamental changes into the brain. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing and the possibility that the GH/ IGF-I axis is involved in cognitive deficits has been recognized for several years. The IGF-I is a potent neurotrophic as well neuroprotective factor found in the brain with a wide range of actions in both central and peripheral nervous system. IGF-I is a critical promoter of brain development and neuronal survival and plays a role in neuronal rescue during degenerative diseases. The investigations of GH releasing stimulation tests especially to GHRH in AD are equivocal and in some cases contradictory. When a cholinesterase inhibitor as rivastigmine, a drug for AD, is acutely administered the area under the curve of the GH response to GHRH doubled, showing that rivastigmine is a powerful drug to enhance GH release. Starting with a more accurate diagnosis not of the clinical syndrome, but of underlying molecular defects, that may eventually lead to a personalized, more effective treatment. Hence, the development of novel therapeutic approaches is urgently needed.

Epidermal growth factor receptor signalling mediates growth hormone-induced growth of chondrocytes from sex hormone-inhibited adolescent rats.

1. Growth hormone (GH) has been demonstrated to overcome the inappropriate deceleration of growth rate in children with central precocious puberty treated with gonadotropin-releasing hormone analogue (GnRHa). However, the underlying mechanisms remain largely unclear. In the present study, we investigated the potential involvement of the epidermal growth factor receptor (EGFR) pathway in the growth promotion by GH using in vitro cultured growth plate chondrocytes isolated from adolescent rats treated with GnRHa. 2. Chondrocytes were stimulated with GH in the presence or absence of the Janus tyrosine kinase (JAK) 2 inhibitor AG490 (1, 10 and 100 nmol/L), the EGFR kinase inhibitor AG1478 (0.1, 1 and 10 nmol/L), U0126 (an inhibitor of extracellular signal-regulated kinase (Erk) activation; 10 µmol/L) or a neutralizing antibody against epidermal growth factor (EGF Ab; 0.1, 1 and 10 µg/mL). The proliferation of chondrocytes was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and immunostaining for proliferating cell nuclear antigen (PCNA). Phosphorylation of Erk1/2 and EGFR was detected by western-blotting. Intracellular mRNA and extracellular protein levels of EGF were detected using reverse transcription-polymerase chain reaction and ELISA, respectively. 3. Growth hormone promoted the proliferation of chondrocytes, which was correlated with increased phosphorylation of Erk1/2 and EGFR and enhanced expression of EGF. Pretreatment with AG490, AG1478, U0126 or EGF Ab completely or partially inhibited the proliferation of chondrocytes and activation of Erk1/2 and EGFR. Pretreatment with AG490, AG1478, or U0126 partially inhibited the expression of EGF. 4. The findings indicate that GH promotes chondrocyte proliferation by activating EGFR signalling.

Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification.

High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.

Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty.

OBJECTIVE: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). DESIGN AND PATIENTS: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height sd score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n=17) or no treatment (n=15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. RESULTS: FH was not different between treatment and control groups. Treated children had a larger height gain (FH-PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P<0.05). FH was higher than PAH0 in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. CONCLUSION: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age.

Impurity profile tracking for active pharmaceutical ingredients: case reports.

Tracking the impurity profile of an active pharmaceutical ingredient (API) is a very important task for all stages of drug development. A systematic approach for tracking impurity profile of API is described. Various real pharmaceutical applications are presented through successful examples of impurity profile tracking for three different novel APIs. These include MK-0969, an M3 antagonist; MK-0677, an oral-active growth hormone secretagogue and API-A, a cathepsin K inhibitor. A general strategy including selection of a reversed phase high performance liquid chromatographic (RP-HPLC) impurity profile method based on screening various stationary phases and changing the pH of the mobile phase and elucidation of impurity structures through the utilization of LC-MS, preparative-LC and NMR is demonstrated. A series of studies were conducted on the peak purity check by using the LC-UV diode-array and LC-MS detections. The advantages and disadvantages of each technique in the evaluation of peak purity are discussed.

The KIGS experience with the addition of gonadotropin-releasing hormone agonists to growth hormone (GH) treatment of children with idiopathic GH deficiency.

Although recombinant techniques have enabled the production of limitless amounts of human growth hormone (GH), and clinical methods for diagnosis and treatment have been greatly enhanced, the mean final heights of children with idiopathic GH deficiency (IGHD) treated with GH remain in the range of -1.3 standard deviation scores (SDS) below normal height. One of the methods used to increase height outcomes is to delay the onset and progression of puberty to allow for a longer 'pre-pubertal' growth phase. We reviewed the KIGS (Pharmacia International Growth Database) data of patients with IGHD who had been treated with gonadotropin-releasing hormone agonists (GnRHa) in order to see if a greater gain in height could be achieved by altering the tempo of pubertal maturation. Near-final height data were analysed in 39 adolescents (out of a total of 249) who had received GH + GnRHa therapy and were compared with similar data from 1,893 patients with IGHD treated with GH alone. The total change in height SDS in boys who received GH alone was +1.6, in contrast to +1.1 in GH + GnRHa-treated boys; the total change in height SDS in girls who received GH alone was +1.4 in contrast to +1.1 in girls treated with GH + GnRHa. The near final height SDS in girls treated with GH + GnRHa was 1.0 below the mid-parental target height (MPH), whereas there was only a -0.5 SDS difference in girls treated with GH. Approximation to the MPH did not differ in boys between the two treatment groups. These data suggest that the attainment of a substantial height SDS by manipulating the tempo of puberty is limited, but that optimizing growth during the pre-pubertal phase is a more important factor.

Acute administration of nutritionally sourced tryptophan increases fear recognition.

RATIONALE: The serotonin precursor tryptophan (TRP) has been widely used as a nutritional supplement and antidepressant. Recently, however, the use of TRP has been severely restricted due to its association with the eosinophilic myalgic syndrome, an autoimmune disorder probably caused by ingestion of a contaminant produced in certain TRP manufacturing processes. OBJECTIVES: To determine the bioavailability of a nutritional source of TRP obtained from milk protein and to assess whether administration of this material produced neuroendocrine and neuropsychological effects consistent with increased brain serotonin activity. METHODS: We studied 24 healthy subjects who ingested approximately 1.8 g of nutritionally-sourced TRP or placebo in a double-blind, parallel group, design. We carried out venous sampling for amino acid and hormone estimation and performed a test of emotional processing using a facial expression recognition task. RESULTS: The nutritionally-sourced TRP caused a substantial increase in the availability of TRP in plasma. Relative to placebo the TRP material produced some evidence of an increase in plasma cortisol, and enhanced the perception of fearful and happy facial expressions. CONCLUSIONS: A nutritional source of TRP increased the availability of TRP for brain serotonin synthesis and produced endocrine and neuropsychological changes consistent with increased brain serotonin function. The effect of TRP on emotional processing may be relevant to its reported activity in primate studies of social behaviour.

Growth hormone secretagogues: mechanism of action and use in aging.

GH secretagogues present a tool for furthering our understanding of the control of GH secretion, as well as a unique therapeutic opportunity. These compounds activate the receptors of a putative endogenous ligand in the hypothalamus and pituitary. Acting as functional somatostatin antagonists, GH secretagogues potentiate the actions of GHRH on GH secretion, enhancing pulsatile GH secretion. The clinical target of the elderly population presents significant challenges to drug development. Age-related musculoskeletal impairment as a result of muscle wasting (sarcopenia) is not well recognized as a clinical syndrome. In addition, given the inherent day to day variability in function in the "frail" target population as well as the presence of a host of concomitant conditions, the appropriate patient population to be studied remains to be defined, and demonstration of clinically meaningful efficacy may be difficult. It is not clear whether it will be useful to restore to young levels the activity of the GHIGF-I axis in aging. Nevertheless, if beneficial effects on strength, similar to those demonstrated with GH79 can be shown, GH secretagogues could provide a well-tolerated clinical approach for treating or preventing sarcopenia, and perhaps, even forestall the inevitability of age-associated decline in function and independence. Such efficacy would have a great social impact.