Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Mutations in GBA1, the gene encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.

Relevance of Biochemical Deep Phenotyping for a Personalised Approach to Parkinson's Disease.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the nigrostriatal tract. The identification of disease-modifying therapies is the Holy Grail of PD research, but to date no drug has been approved as such a therapy. A possible reason is the remarkable phenotypic heterogeneity of PD patients, which can generate confusion in the interpretation of results or even mask the efficacy of a therapeutic intervention. This heterogeneity should be taken into account in clinical trials, stratifying patients by their expected response to drugs designed to engage selected molecular targets. In this setting, stratification methods (clinical and genetic) should be supported by biochemical phenotyping of PD patients, in line with the deep phenotyping concept. Collection, from single patients, of a range of biological samples would streamline the generation of these profiles. Several studies have proposed biochemical characterisations of patient cohorts based on analysis of blood, cerebrospinal fluid, urine, stool, saliva and skin biopsy samples, with extracellular vesicles attracting increasing interest as a source of biomarkers. In this review we report and critically discuss major studies that used a biochemical approach to stratify their PD cohorts. The analyte most studied is α-synuclein, while other studies have focused on neurofilament light chain, lysosomal proteins, inflammasome-related proteins, LRRK2 and the urinary proteome. At present, stratification of PD patients, while promising, is still a nascent approach. Deep phenotyping of patients will allow clinical researchers to identify homogeneous subgroups for the investigation of tailored disease-modifying therapies, enhancing the chances of therapeutic success.

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing.

INTRODUCTION: The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio. METHODS: Release profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h. RESULTS: In IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 µg/cm2/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose. CONCLUSIONS: CL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.

Challenges in the Development of Intravenous Neurokinin-1 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose-Finding, Phase 1 Study of Intravenous Fosnetupitant.

Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK1 RA]) and palonosetron (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1 RA water solubility, preventing the occurrence of hypersensitivity and infusion-site reactions associated with these products. In this phase 1 study, subjects received a 30-minute placebo or fosnetupitant (17.6-353 mg) infusion and an oral NEPA or placebo capsule, with 2-sequence crossover treatment for fosnetupitant 118- to 353-mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300-mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler-identified infusion-site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment-related AEs did not increase with ascending fosnetupitant doses. The most common treatment-related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235-mg dose was equivalent, in terms of netupitant exposure, to 300-mg oral netupitant. The safety profile of a single fosnetupitant 235-mg infusion was similar to that of single-dose oral NEPA.

Early Development of a Virtual Coach for Healthy Coping Interventions in Type 2 Diabetes Mellitus: Validation Study.

BACKGROUND: Mobile health solutions aimed at monitoring tasks among people with diabetes mellitus (DM) have been broadly applied. However, virtual coaches (VCs), embedded or not in mobile health, are considered valuable means of improving patients' health-related quality of life and ensuring adherence to self-care recommendations in diabetes management. Despite the growing need for effective, healthy coping digital interventions to support patients' self-care and self-management, the design of psychological digital interventions that are acceptable, usable, and engaging for the target users still represents the main challenge, especially from a psychosocial perspective. OBJECTIVE: This study primarily aims to test VC interventions based on psychoeducational and counseling approaches to support and promote healthy coping behaviors in adults with DM. As a preliminary study, university students have participated in it and have played the standardized patients' (SPs) role with the aim of improving the quality of the intervention protocol in terms of user acceptability, experience, and engagement. The accuracy of users' role-playing is further analyzed. METHODS: This preliminary study is based on the Obesity-Related Behavioral Intervention Trial model, with a specific focus on its early phases. The healthy coping intervention protocol was initially designed together with a team of psychologists following the main guidelines and recommendations for psychoeducational interventions for healthy coping in the context of DM. The protocol was refined with the support of 3 experts in the design of behavioral intervention technologies for mental health and well-being, who role-played 3 SPs' profiles receiving the virtual coaching intervention in a Wizard of Oz setting via WhatsApp. A refined version of the healthy coping protocol was then iteratively tested with a sample of 18 university students (mean age 23.61, SD 1.975 years) in a slightly different Wizard of Oz evaluation setting. Participants provided quantitative and qualitative postintervention feedback by reporting their experiences with the VC. Clustering techniques on the logged interactions and dialogs between the VC and users were collected and analyzed to identify additional refinements for future VC development. RESULTS: Both quantitative and qualitative analyses showed that the digital healthy coping intervention was perceived as supportive, motivating, and able to trigger self-reflection on coping strategies. Analyses of the logged dialogs showed that most of the participants accurately played the SPs' profile assigned, confirming the validity and usefulness of this testing approach in preliminary assessments of behavioral digital interventions and protocols. CONCLUSIONS: This study outlined an original approach to the early development and iterative testing of digital healthy coping interventions for type 2 DM. Indeed, the intervention was well-accepted and proved its effectiveness in the definition and refinement of the initial protocol and of the user experience with a VC before directly involving real patients in its subsequent use and testing.

A Virtual Coach (Motibot) for Supporting Healthy Coping Strategies Among Adults With Diabetes: Proof-of-Concept Study.

BACKGROUND: Motivation is a core component of diabetes self-management because it allows adults with diabetes mellitus (DM) to adhere to clinical recommendations. In this context, virtual coaches (VCs) have assumed a central role in supporting and treating common barriers related to adherence. However, most of them are mainly focused on medical and physical purposes, such as the monitoring of blood glucose levels or following a healthy diet. OBJECTIVE: This proof-of-concept study aims to evaluate the preliminary efficacy of a VC intervention for psychosocial support before and after the intervention and at follow-up. The intent of this VC is to motivate adults with type 1 DM and type 2 DM to adopt and cultivate healthy coping strategies to reduce symptoms of depression, anxiety, perceived stress, and diabetes-related emotional distress, while also improving their well-being. METHODS: A total of 13 Italian adults with DM (18-51 years) interacted with a VC, called Motibot (motivational bot) using the Telegram messaging app. The interaction covered 12 sessions, each lasting 10 to 20 minutes, during which the user could dialogue with the VC by inputting text or tapping an option on their smartphone screen. Motibot is developed within the transtheoretical model of change to deliver the most appropriate psychoeducational intervention based on the user's motivation to change. RESULTS: Results showed that over the 12 sessions, there were no significant changes before and after the intervention and at follow-up regarding psychosocial factors. However, most users showed a downward trend over the 3 time periods in depression and anxiety symptoms, thereby presenting good psychological well-being and no diabetes-related emotional distress. In addition, users felt motivated, involved, encouraged, emotionally understood, and stimulated by Motibot during the interaction. Indeed, the analyses of semistructured interviews, using a text mining approach, showed that most users reported a perceived reduction in anxiety, depression, and/or stress symptoms. Moreover, users indicated the usefulness of Motibot in supporting and motivating them to find a mindful moment for themselves and to reflect on their own emotions. CONCLUSIONS: Motibot was well accepted by users, particularly because of the inclusion of mindfulness practices, which motivated them to adopt healthy coping skills. To this extent, Motibot provided psychosocial support for adults with DM, particularly for those with mild and moderate symptoms, whereas those with severe symptoms may benefit more from face-to-face psychotherapy.

Neuroprotective and Symptomatic Effects of Cannabidiol in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.

Potential therapeutic effects of polyphenols in Parkinson's disease: in vivo and in vitro pre-clinical studies.

Parkinson's disease is a neurodegenerative disorder characterized by a combination of severe motor and non-motor symptoms. Over the years, several factors have been discovered to play a role in the pathogenesis of this disease, in particular, neuroinflammation and oxidative stress. To date, the pharmacological treatments used in Parkinson's disease are exclusively symptomatic. For this reason, in recent years, the research has been directed towards the discovery and study of new natural molecules to develop potential neuroprotective therapies against Parkinson's disease. In this context, natural polyphenols have raised much attention for their important anti-inflammatory and antioxidant properties, but also for their ability to modulate protein misfolding. In this review, we propose to summarize the relevant in vivo and in vitro studies concerning the potential therapeutic role of natural polyphenols in Parkinson's disease.

The brain-penetrating, orally bioavailable, ghrelin receptor agonist HM01 ameliorates motion-induced emesis in Suncus murinus (house musk shrew).

BACKGROUND AND PURPOSE: HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02. EXPERIMENTAL APPROACH: The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed. KEY RESULTS: HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion-induced emesis by 67.6%. Motion increased c-Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c-Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c-Fos in the PVH. Both compounds antagonized the motion-induced increases in c-Fos expression in the MVe. CONCLUSIONS AND IMPLICATIONS: HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.

Neuroprotective effects of lignan 7-hydroxymatairesinol (HMR/lignan) in a rodent model of Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNc). The proinflammatory response can occur early in the disease, contributing to nigrostriatal degeneration. Identification of the new molecules, which are able to slow down the degenerative process associated with PD, represents one of the main interests. Recently, natural polyphenols, especially lignans, have raised attention for their anti-inflammatory, antioxidant, and estrogenic activity at a peripheral level. The aim of this study was to evaluate the central effects of chronic treatment with lignan 7-hydroxymatairesinol (HMR/lignan) on neurodegenerative, neuroinflammatory processes and motor deficits induced by a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats to evaluate the potential neuroprotective properties of this compound. METHODS: Sprague-Dawley male rats underwent lignan (10 mg/kg) or vehicle treatment (oral) for 4 wk starting from the day of 6-OHDA injection. The degree of nigrostriatal damage was evaluated by immunohistochemistry. Moreover, we performed a quantitative and qualitative assessment of neuroinflammatory process, including phenotypic polarization of microglia and astrocytes. The motor performance was assessed by behavioral tests. RESULTS: We demonstrated that chronic treatment with HMR/lignan was able to slow down the progression of degeneration of striatal dopaminergic terminals in a rat model of PD, with a consequent improvement in motor performance. Nevertheless, the anti-inflammatory effect of HMR/lignan observed in SNc was not sufficient to protect dopaminergic cells bodies. CONCLUSION: These results suggest intriguing properties of HMR/lignan at neuroprotective and symptomatic levels in the context of PD.

Development and biochemical characterization of a mouse model of Parkinson's disease bearing defective glucocerebrosidase activity.

GBA1 gene encodes for the lysosomal membrane protein glucocerebrosidase (GCase). GBA1 heterozygous mutations profoundly impair GCase activity and are currently recognized as an important risk factor for the development of Parkinson's disease (PD). Deficits in lysosomal degradation pathways may contribute to pathological α-synuclein accumulation, thereby favoring dopaminergic neuron degeneration and associated microglial activation. However, the precise mechanisms by which GCase deficiency may influence PD onset and progression remain unclear. In this work we used conduritol-ß-epoxide (CBE), a potent inhibitor of GCase, to induce a partial, systemic defect of GCase activity comparable to that associated with heterozygous GBA1 mutations, in mice. Chronic (28 days) administration of CBE (50 mg/kg, i.p.) was combined with administration of a classic PD-like inducing neurotoxin, such as MPTP (30 mg/kg, i.p. for 5 days). The aim was to investigate whether a pre-existing GCase defect may influence the effects of MPTP in terms of nigrostriatal damage, microglia activation and α-synuclein accumulation. Pre-treatment with CBE had tendency to enhance MPTP-induced neurodegeneration in striatum and caused significant increase of total α-synuclein expression in substantia nigra. Microglia was remarkably activated by CBE alone, without further increases when combined with MPTP. Overall, we propose this model as an additional tool to study pathophysiological processes of PD in the presence of GCase defects.

A Comparison of the Central versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics.

The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral effects on ghrelin receptors within the enteric nervous system and via the ghrelin receptor on the vagus nerve, which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects to the overall prokinetic effect of ghrelin agonists requires further investigation. Here, we investigated the central versus peripheral prokinetic effect of ghrelin by using two novel ghrelin agonists: HM01 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-methyl-N-[1,3,3-trimethyl-(4R)-piperidyl]-urea HCL) with high brain penetration compared with HM02 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-hydroxy-N-(1-methyl-4-piperidinyl)-urea), a more peripherally acting ghrelin agonist. The pharmacokinetic profiles of both ghrelin agonists were evaluated after intravenous and oral administration in rats. The efficacy of HM01 and HM02 was assessed in a rat model of postoperative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Pharmacokinetic results in our models confirmed that HM01, but not HM02, was a brain-penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delayed upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01, but not HM02, significantly increased the weight of fecal pellets. Our findings suggest that, in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit through a peripheral site of action. However, in the defecation assay, our data suggest that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders.

Corrigendum: Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew).

[This corrects the article DOI: 10.3389/fphar.2018.00869.].

Rational Design, Synthesis, and Pharmacological Characterization of Novel Ghrelin Receptor Inverse Agonists as Potential Treatment against Obesity-Related Metabolic Diseases.

A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic and pharmacokinetic properties. The structure-activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability, and notable brain penetration in rat ( F = 27%, B/ P ratio = 1.9). First in vivo studies demonstrated effective reduction of food intake after oral or parenteral administration to mouse (78% at 1 h and 38% at 8 h, respectively). Further preclinical studies are needed to evaluate the most suited mode of administration with the aim of promoting a first central-acting ghrelin inverse agonist molecule to development, which would represent a significant step toward therapeutic agents to treat metabolic disorders related to obesity, such as type 2 diabetes mellitus.

Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew).

Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of GHS-R1A has broad inhibitory anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating GHS-R1A mimetic, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), to reduce emesis induced by a variety of emetic challenges. HM01 (1 to 30 mg/kg, p.o.) antagonized emesis induced by cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against emesis induced by nicotine (5 mg/kg, s.c.) and copper sulfate (120 mg/kg by intragastric gavage). In other experiments, HM01 (3 mg/kg, p.o.) enhanced the anti-emetic control of a regimen of palonosetron (0.01 mg/kg, p.o.) alone and palonosetron (0.01 mg/kg p.o.) plus netupitant (1 mg/kg, p.o.). HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in nicotine-treated animals, and it shortened the latency to drink in animals treated with cisplatin. These data indicate that brain-penetrating GHS-R1A agonists may have use alone and/or in combination with standard anti-emetic regimens for the treatment of chemotherapy-induced nausea and vomiting and motion sickness. Highlights: - The novel orally bioavailable brain-penetrating GHS-R1A agonist, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), antagonizes motion- and cisplatin-induced emesis.- HM01 did not reduce emesis induced by nicotine or by intragastric copper sulfate.- HM01 has positive effects on food consumption after treatment with nicotine.- HM01 has synergistic effects against cisplatin when combined with palonosetron and palonosetron/netupitant regimens.- It is suggested that GHS-R1A agonists may be protective against chemotherapy-induced nausea and vomiting in combination with traditional anti-emetics and against motion-induced emesis.

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.

Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease.

AIMS: Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2. MATERIALS AND METHODS: In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids. RESULTS: Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice. CONCLUSIONS: Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus.

Profile of Antiemetic Activity of Netupitant Alone or in Combination with Palonosetron and Dexamethasone in Ferrets and Suncus murinus (House Musk Shrew).

BACKGROUND AND AIMS: Chemotherapy-induced acute and delayed emesis involves the activation of multiple pathways, with 5-hydroxytryptamine (5-HT; serotonin) playing a major role in the initial response. Substance P tachykinin NK1 receptor antagonists can reduce emesis induced by disparate emetic challenges and therefore have a clinical utility as broad inhibitory anti-emetic drugs. In the present studies, we investigate the broad inhibitory anti-emetic profile of a relatively new NK1 receptor antagonist, netupitant, alone or in combination with the long acting 5-HT3 receptor antagonist, palonosetron, for a potential to reduce emesis in ferrets and shrews. MATERIALS AND METHODS: Ferrets were pretreated with netupitant and/or palonosetron, and then administered apomorphine (0.125 mg/kg, s.c.), morphine (0.5 mg/kg, s.c.), ipecacuanha (1.2 mg/kg, p.o.), copper sulfate (100 mg/kg, intragastric), or cisplatin (5-10 mg/kg, i.p.); in other studies netupitant was administered to Suncus murinus before motion (4 cm horizontal displacement, 2 Hz for 10 min). RESULTS: Netupitant (3 mg/kg, p.o.) abolished apomorphine-, morphine-, ipecacuanha- and copper sulfate-induced emesis. Lower doses of netupitant (0.03-0.3 mg/kg, p.o.) dose-dependently reduced cisplatin (10 mg/kg, i.p.)-induced emesis in an acute (8 h) model, and motion-induced emesis in S. murinus. In a ferret cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis model, netupitant administered once at 3 mg/kg, p.o., abolished the first 24 h response and reduced the 24-72 h response by 94.6%; the reduction was markedly superior to the effect of a three times per day administration of ondansetron (1 mg/kg, i.p.). A single administration of netupitant (1 mg/kg, p.o.) plus palonosetron (0.1 mg/kg, p.o.) combined with dexamethasone (1 mg/kg, i.p., once per day), also significantly antagonized cisplatin-induced acute and delayed emesis and was comparable with a once-daily regimen of ondansetron (1 mg/kg, p.o.) plus aprepitant (1 mg/kg, p.o.) in combination with dexamethasone (1 mg/kg, i.p.). CONCLUSION: In conclusion, netupitant has potent and long lasting anti-emetic activity against a number of emetic challenges indicating broad inhibitory properties. The convenience of protection afforded by the single dosing of netupitant together with palonosetron was demonstrated and also is known to provide an advantage over other therapeutic strategies to control emesis in man.