GLP-1(28-36)amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?

Meng-Wong Taing,1,2 Felicity J Rose,1,3 Jonathan P Whitehead11Metabolic Medicine, Mater Research Institute, University of Queensland, 2School of Pharmacy, University of Queensland, Brisbane, QLD, Australia; 3University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, AustraliaAbstract: The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36)amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP) and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin-based therapies to promote pancreatitis and pancreatic and thyroid cancers. The effects ascribed to the nonapeptide make it a potential contributor to such outcomes, raising additional questions about its therapeutic suitability. Notwithstanding, the nonapeptide, like other GLP-1 metabolites, appears to be biologically active. Increasing understanding of such noncanonical GLP-1 activities should help to improve future incretin-based therapeutics.Keywords: diabetes, incretins, metabolites, insulinotropis

Why aren't Australian pharmacists supplying naloxone? Findings from a qualitative study

Background: Opioid overdose is a significant public health issue among people who use pharmaceutical opioids and/or heroin. One response to reducing overdose deaths is to expand public access to naloxone. The Australian Therapeutic Goods Administration down-scheduled naloxone from prescription only (S4)to pharmacist only over-the-counter (OTC, schedule 3)in February 2016. There is little research examining pharmacists’ perspectives or experiences of this change. Methods: Thirty-seven semi-structured interviews with Australian community pharmacists were conducted in 2016–2017 to investigate pharmacists’ attitudes to and experiences of OTC naloxone. Transcripts were thematically analysed, guided by a broad interest in facilitators and barriers to OTC supply. Results: Around half of the pharmacists were aware of the down-scheduling and only two had provided OTC naloxone. Core barriers to pharmacist provision of OTC naloxone included limited understanding of opioid overdose, confusion about the role and responsibilities of pharmacists in providing OTC naloxone, concerns about business, stigma related to people who inject drugs (PWID)and system-level challenges. Conclusion: Pharmacy provision of OTC naloxone offers an important opportunity to reduce overdose mortality. Our study suggests this opportunity is yet to be realised and highlights several individual- and structural-level impediments hindering the expansion of public access to naloxone via community pharmacies. There is a need to develop strategies to improve pharmacists’ knowledge of OTC naloxone and opioid overdose as well as to address other logistical and cultural barriers that limit naloxone provision in pharmacy settings. These need to be addressed at the individual level (training)as well as the system level (information, regulation and supply)

β-Nitroso-o-Quinone Methides: Potent Intermediates in Organic Chemistry and Biology : The impact of the NO group on their Structure and Reactivity Profile: a Theoretical Insight

The structure and reactivity profile of prototype o-quinone methides 1, 2 and their ß-nitroso analogues 6-9 have been investigated by means of DFT and MP2 calculations. These highly reactive unstable species are generated by oxidative dearomatization of their precursor oximes. The destabilization of their structure is more pronounced in the ß-nitroso congeners 7-9. There is only a weak π conjugation across the nitrosoalkene arm. The latter gives rise to E and Z conformations and causes some distortion on the ring -frame while the π-frame is weakly perturbed. The Z conformation is the most stable in all structures. Their geometry is also affected by the o-quinone ring and the 1,2-(7 and 8) and 2,3-(9) isomer pattern. The stability of these conformations is rationalized in terms of ortho- or peri- ring formations. The impact of their geometry profile on their reactivity pattern has been studied by means of reactivity descriptors such as Fukui function f(r), chemical potential and hardness, HOMO and LUMO energies and their separation (HOMO-LUMO gap) as well as aromaticity indices such as HOMA and out-of-plane deformability. All descriptors consistently demonstrate that the reactivity is dominated by an intramolecular ortho or peri-cyclization mode to fused 1,2-oxazoles or 1,2-oxazines, respectively. Intermolecular primary reactions can occur at the quinone alkene bond or that of the nitrosoalkene arm.Peer reviewe