Combination therapy with anamorelin and a myostatin inhibitor is advantageous for cancer cachexia in a mouse model.

Cancer cachexia is a multifactorial disease that causes continuous skeletal muscle wasting. Thereby, it seems to be a key determinant of cancer-related death. Although anamorelin, a ghrelin receptor agonist, has been approved in Japan for the treatment of cachexia, few medical treatments for cancer cachexia are currently available. Myostatin (MSTN)/growth differentiation factor 8, which belongs to the transforming growth factor-ß family, is a negative regulator of skeletal muscle mass, and inhibition of MSTN signaling is expected to be a therapeutic target for muscle-wasting diseases. Indeed, we have reported that peptide-2, an MSTN-inhibiting peptide from the MSTN prodomain, alleviates muscle wasting due to cancer cachexia. Herein, we evaluated the therapeutic benefit of myostatin inhibitory D-peptide-35 (MID-35), whose stability and activity were more improved than those of peptide-2 in cancer cachexia model mice. The biologic effects of MID-35 were better than those of peptide-2. Intramuscular administration of MID-35 effectively alleviated skeletal muscle atrophy in cachexia model mice, and the combination therapy of MID-35 with anamorelin increased food intake and maximized grip strength, resulting in longer survival. Our results suggest that this combination might be a novel therapeutic tool to suppress muscle wasting in cancer cachexia.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral ß1 receptors.

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic ß1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.

Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.

Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome.

Anamorelin hydrochloride is an orally active ghrelin receptor agonist in development by Helsinn, for the treatment of non-small-cell lung cancer (NSCLC) cachexia. In preclinical and clinical studies, the potent affinity of anamorelin for the ghrelin receptor is associated with significant appetite-enhancing activity and resultant improvements in body weight, lean body mass, and handgrip strength compared with placebo. The accompanying stimulatory effects on growth hormone and IGF-1 are not associated with tumor growth, and overall survival in patients with cancer is not compromised. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. The findings of ongoing Phase III studies are needed to confirm the significant potential of anamorelin to treat NSCLC cachexia.

Linaclotida en el tratamiento de pacientes con síndrome del intestino irritable con estreñimiento: análisis de una oportunidad / Linaclotide in the treatment of patients with irritable bowel syndrome and constipation - analysis of an opportunity

La linaclotida es un secretagogo que asocia un efecto combinado sobre el dolor visceral. La European Medicines Agency ha aprobado su indicación en el tratamiento sintomático en adultos del síndrome del intestino irritable con estreñimiento moderado o grave. El objetivo de esta revisión es analizar el marco clínico de aplicación de linaclotida en nuestro medio, las características del fármaco, su desarrollo preclínico y los estudios clínicos que apoyan su uso, con el fin de establecer los correspondientes juicios de validez y aplicabilidad clínica. Los resultados indican que el único efecto adverso, no grave, del fármaco es la diarrea. En cuanto a su eficacia, linaclotida presenta consistentemente favorables y significativas diferencias de riesgo absolutas frente a placebo en todas las variables resultado objetivas marcadas por las agencias reguladoras, con una respuesta combinada a dolor y estreñimiento entre el 12,6% y el 22,8%, según la variable y el ensayo considerados. Esta respuesta es sostenida y vinculada al fármaco, pues desaparece tras su retirada. Se concluye que linaclotida presenta un perfil de seguridad y eficacia que justifica, desde una perspectiva clínica, su uso en pacientes que cumplan criterios de síndrome del intestino irritable con estreñimiento con sintomatología de intensidad significativa que no pueda resolverse con otros tratamientos menos específicos. En ausencia de reglas de predicción de respuesta se recomienda que, si tras un periodo de prueba el paciente no responde, debe considerarse que no es candidato a tratamiento con linaclotida, reservando indicación y continuidad del tratamiento solo a los respondedores objetivos (AU)

Linaclotide is a secretagogue that provides a combined effect on visceral pain. The European Medicines Agency has authorized its indication for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation in adults. The purpose of this review is to discuss the clinical framework for linaclotide use in our setting, the drug’s characteristics and pre-clinical development, and the clinical studies supporting its use in order to establish relevant views regarding its validity and clinical applicability. The results suggest that the only —nonsevere— adverse effect associated with this drug is diarrhea. As regards effectiveness, linaclotide consistently shows favorable, significant differences in absolute risk versus placebo for all objective outcome variables described by regulatory agencies, with a combined pain and constipation response between 12.6% and 22.8% according to the variable and trial under consideration. This response is sustained and drug-related, as it goes away upon discontinuation. To conclude, linaclotide has a safety and efficacy profile that, from a clinical perspective, warrants its use for patients meeting irritable bowel syndrome and constipation criteria, with significant symptoms that cannot be relieved with other less specific measures. In the absence of predictive rules for response, it is recommended that, should the patient fail to respond, he or she should be considered not eligible for linaclotide therapy, and both indication and treatment continuity should be reserved for objective responders alone (AU)

[Ghrelin and growth hormone secretagogues (GHS): modulation of growth hormone secretion and therapeutic applications]. / Ghrelina e secretagogos do hormônio de crescimento (GHS): modulação da secreção do hormônio de crescimento e perspectivas terapêuticas.

Growth hormone-releasing hormone (GHRH) and somatostatin modulate growth hormone (GH) secretion. A third mechanism was discovered in the last decade, involving the action of growth hormone secretagogues (GHS). Ghrelin, the endogenous ligand of the GHS-receptor, is an acylated peptide mainly produced by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GHRH, activating multiple interdependent intracellular pathways. However, its main site of action is the hypothalamus. In the current paper it is reviewed the available data on the discovery of this peptide, the mechanisms of action and possible physiological roles of the GHS and ghrelin on GH secretion, and finally, the possible therapeutic applications of these compounds.

Ghrelina e secretagogos do hormônio de crescimento (GHS): modulação da secreção do hormônio de crescimento e perspectivas terapêuticas: [revisão] / Ghrelin and growth hormone secretagogues (GHS): modulation of growth hormone secretion and therapeutic applications: [review]

A secreção do hormônio de crescimento (GH) é modulada pelo hormônio liberador de hormônio de crescimento (GHRH) e pela somatostatina. Na última década foi descoberto um terceiro mecanismo de controle, envolvendo os secretagogos de GH (GHS). A ghrelina, o ligante endógeno do receptor dos GHS, é um peptídeo acilado produzido no estômago, que também é sintetizado no hipotálamo. Este peptídeo é capaz de liberar GH, além de aumentar a ingesta alimentar. A ghrelina endógena parece amplificar o padrão básico de secreção de GH, ampliando a resposta do somatotrofo ao GHRH, estimulando múltiplas vias intracelulares interdependentes. Entretanto, seu local de atuação predominante é o hipotálamo. Neste trabalho, será apresentada revisão sobre a descoberta da ghrelina, os mecanismos de ação e o possível papel fisiológico dos GHS e da ghrelina na secreção de GH e, finalmente, as possíveis aplicações terapêuticas destes compostos.

Growth hormone-releasing hormone (GHRH) and somatostatin modulate growth hormone (GH) secretion. A third mechanism was discovered in the last decade, involving the action of growth hormone secretagogues (GHS). Ghrelin, the endogenous ligand of the GHS-receptor, is an acylated peptide mainly produced by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GHRH, activating multiple interdependent intracellular pathways. However, its main site of action is the hypothalamus. In the current paper it is reviewed the available data on the discovery of this peptide, the mechanisms of action and possible physiological roles of the GHS and ghrelin on GH secretion, and finally, the possible therapeutic applications of these compounds.