The melanocortin receptors and their accessory proteins.

The five melanocortin receptors (MCRs) named MC1R-MC5R have diverse physiological roles encompassing pigmentation, steroidogenesis, energy homeostasis and feeding behavior as well as exocrine function. Since their identification almost 20 years ago much has been learnt about these receptors. As well as interacting with their endogenous ligands the melanocortin peptides, there is now a growing list of important peptides that can modulate the way these receptors signal, acting as agonists, antagonists, and inverse agonists. The discovery of melanocortin 2 receptor accessory proteins as a novel accessory factor to the MCRs provides further insight into the regulation of these important G protein-coupled receptor

Quinolones modulate ghrelin receptor signaling: potential for a novel small molecule scaffold in the treatment of cachexia

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.Irish Research Council for Science and Technology (IRCSET)Science Foundation Ireland (SFI/12/IP/1315)Science Foundation Ireland (SFI/12/RC/2275)Science Foundation Ireland (SFI/12/RC/2273)Universidad de Sevill

Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms

Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts

Inhaled corticosteroids versus long-acting beta -agonists for chronic obstructive pulmonary disease (Review).

Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear

Anticholinergic therapy for acute asthma in children.

Inhaled anticholinergics as single agent bronchodilators (or in combination with beta(2)-agonists) are one of the several medications available for the treatment of acute asthma in children

Treatment of type 2 diabetes by free fatty acid receptor agonists

Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programmes within industry and academia aimed at improving the safety and effectiveness of these potential treatments

Guideline on management of the acute asthma attack in children by Italian Society of Pediatrics.

BACKGROUND: Acute asthma attack is a frequent condition in children. It is one of the most common reasons for emergency department (ED) visit and hospitalization. Appropriate care is fundamental, considering both the high prevalence of asthma in children, and its life-threatening risks. Italian Society of Pediatrics recently issued a guideline on the management of acute asthma attack in children over age 2, in ambulatory and emergency department settings. METHODS: The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was adopted. A literature search was performed using the Cochrane Library and Medline/PubMed databases, retrieving studies in English or Italian and including children over age 2 year. RESULTS: Inhaled ß2 agonists are the first line drugs for acute asthma attack in children. Ipratropium bromide should be added in moderate/severe attacks. Early use of systemic steroids is associated with reduced risk of ED visits and hospitalization. High doses of inhaled steroids should not replace systemic steroids. Aminophylline use should be avoided in mild/moderate attacks. Weak evidence supports its use in life-threatening attacks. Epinephrine should not be used in the treatment of acute asthma for its lower cost / benefit ratio, compared to β2 agonists. Intravenous magnesium solphate could be used in children with severe attacks and/or forced expiratory volume1 (FEV1) lower than 60% predicted, unresponsive to initial inhaled therapy. Heliox could be administered in life-threatening attacks. Leukotriene receptor antagonists are not recommended. CONCLUSIONS: This Guideline is expected to be a useful resource in managing acute asthma attacks in children over age 2

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma

Asthma patients who continue to experience symptoms despite being on regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) or anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS.ObjectivesWe compared the efficacy and safety profile of adding either daily LABA or LTRA in adults and children with asthma who remain symptomatic on ICS.Search strategyWe searched the Cochrane Airways Group Specialised Register (up to and including March 2010). We consulted reference lists of all included studies and contacted authors and pharmaceutical manufacturers for other published or unpublished studies.Selection criteriaWe included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS and where a fixed dose of a long-acting beta2-agonist or leukotriene agent was added for a minimum of 28 days.Data collection and analysisTwo authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design, where necessary.Main resultsWe included 17 RCTs (7032 participants), of which 16 recruited adults and adolescents (6850) and one recruited children aged 6 to 17 years (182). Participants demonstrated substantial reversibility to short-acting beta-agonist at baseline. The studies were at a low risk of bias. The risk of exacerbations requiring systemic corticosteroids was lower with the combination of LABA and ICS compared with LTRA and ICS, from 11% to 9% (RR 0.83, 95% CI 0.71 to 0.97; six studies, 5571 adults). The number needed to treat (NNT) with LABA compared to LTRA to prevent one exacerbation over 48 weeks was 38 (95% CI 22 to 244). The choice of LTRA did not significantly affect the results. The effect appeared stronger in the trials using a single device to administer ICS and LABA compared to those using two devices. In the absence of data from the paediatric trial and the clinical homogeneity of studies, we could not perform subgroup analyses. The addition to ICS of LABA compared to LTRA was associated with a statistically greater improvement from baseline in several of the secondary outcomes, including lung function, functional status measures and quality of life. Serious adverse events were more common with LABA than LTRA, although the estimate was imprecise (RR 1.35, 95% CI 1.00 to 1.82), and the NNT to harm for one additional patient to suffer a serious adverse event on LABA over 48 weeks was 78 (95% CI 33 to infinity). The risk of withdrawal for any reason in adults was significantly lower with LABA and ICS compared to LTRA and ICS (RR 0.84, 95% CI 0.74 to 0.96).Authors' conclusionsIn adults with asthma that is inadequately controlled on low doses of inhaled steroids and showing significant reversibility with beta2-agonists, LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest. There is some evidence of increased risk of SAEs with LABA. The findings support the use of a single inhaler for the delivery of LABA and inhaled corticosteroids. We are unable to draw conclusions about which treatment is better as add-on therapy for children.PLAIN LANGUAGE SUMMARYWhat are the effects of long-acting beta2-agonists compared with anti-leukotrienes when added to inhaled steroids?People who continue to experience asthma symptoms despite regularly taking inhaled corticosteroids are a challenge for management. It is not clear whether the addition of a long-acting beta2-agonist (LABA) such as formoterol or salmeterol would provide more benefit in comparison with an oral anti-leukotriene agent (LTRA), for example zafirlukast or montelukast.Seventeen trials (16 in adults and one in children) were included in this review and were of good quality. We found that the addition of a LABA provides significantly greater protection against exacerbations requiring oral steroids when compared with a LTRA for adults. Based on the results of our analyses, approximately 38 adults (with a range of between 22 and 244) would need to be treated with a LABA rather than a LTRA for 48 weeks to prevent one experiencing an exacerbation needing a course of oral steroids. The trial on children did not contribute data on the main outcome and therefore we could not draw any conclusions for children.LABAs also led to a greater improvement in lung function, improvement in symptoms, use of rescue medication, quality of life and symptoms compared to the use of LTRAs. The magnitude of the improvements was modest. Serious adverse events were more frequent with LABA than with LTRAs although this result was imprecise. Based on our analyses, around 78 people would need to be treated for 48 weeks with a LABA rather than a LTRA for one of them to experience a serious adverse event. However, due to the lack of precision around our result, the true number could be between 33 and infinity. There are currently insufficient data to draw any conclusions about the effects of these drugs in children

Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor.

The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR. We further show that positive allosteric modulators of µ-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell-free, signal transduction-independent and is generally applicable to GPCRs

A meta-analysis and systematic review of randomized controlled trials with degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer

Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced prostate cancer (PC). This comparison was performed either in terms of biochemical or oncological or safety profiles. To this end we, carried out a systematic review and meta-analysis of the literature.We selected only studies directly and prospectively analyzing the two treatments in the same population (randomized phase III studies). We followed the Preferred Reporting Items for Systematic Reviews and meta-analyses process for reporting studies.After we eliminated studies according to the exclusion criteria, 9 publications were considered relevant to this review. These articles described 5 clinical trials that were eligible for inclusion. The follow-up duration in all trials did not exceed 364 days. This meta-analysis and review comprised a total of 1719 men, 1061 randomized to degarelix versus 658 to GnRH agonists treatment for advanced PC. Oncological results were evaluated only in 1 trial (CS21:408 cases) and they were not the primary endpoints of the study. Treatment emerging adverse events were reported in 61.4% and 58.8% of patients in the degarelix and GnRH agonists group, respectively (odds ratio, OR = 1.17; 95% confidence interval, 95% CI: 0.78-1.77, P > 0.1). Treatment related severe cardiovascular side effects were reported (trial CS21-30-35) in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26-1.14, P > 0.1).Our analysis evidences relevant limitations in particular for the comparative evaluation of the efficacy and the oncological results related to degarelix