Calderon Hart (santaprint3)

WIN55,212-2 had a similar pattern as 2-arachidonylglycerol (reference). The other agonists displayed bias towards internalisation compared to cAMP inhibition. However, only Δ9 -tetrahydrocannabinol and BAY59,3074 demonstrated bias in the pERK-cAMP pathway comparison. Furthermore, all the agonists exhibited little preference between internalisation and pERK. CONCLUSION AND IMPLICATIONS This is the first joint kinetic assessment of biased agonism at a GPCR (e.g., CB1 receptor) under non-equilibrium conditions. Kinetic modelling is a natural method to handle time-varying data when traditional equilibria are not present and enables quantification of ligand bias. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Type 2 diabetes is one of the most severe chronic diseases and is becoming an increasingly serious public health trouble worldwide. There are several glucagon-like peptide-1 receptor agonists (GLP-1RAs) were developed to treat the type 2 diabetes. However, most of them are injectable form, which immensely reduce the tolerance of patients and increase the risk of infection. Here, we designed a novel orally available GLP-1RA with only replacing the amino acids in exendin-4, named oral hypoglycemic peptide 2 (OHP2), and investigated the pharmacokinetic profiles, therapeutic effects and absorption mechanism of it. EXPERIMENTAL APPROACH Healthy Wistar rats were applied for pharmacokinetic research. Diabetic db/db mice were administrated with OHP2 for 8 weeks to evaluate the effects on hyperglycemia, dyslipidemia, basal metabolism, tissue injury. Moreover, the endocytosis and transcytosis mechanism of OHP2 were explored by using the Caco-2 cell monolayer model. KEY RESULTS The absolute bioavailability of OHP2 at 1.31% revealed the orally available of it. In db/db mice, OHP2 exhibits great potential in glucose-lowing and weight loss by oral administration in a dosage dependent manner. this website OHP2 also alleviates hyperlipidemia, ameliorates the energy metabolism, and promotes tissue repair in diabetic mice. Furthermore, we found that the uptake of OHP2 is dependent on caveolae-mediated transcytosis rather than GLP-1R-mediated endocytosis. CONCLUSIONS AND IMPLICATIONS Our findings indicated that OHP2 could be used as a potential oral candidate for the treatment of type 2 diabetes and the uncovered transcytosis mechanism could help us to develop absorption enhancers of OHP2 in the future. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor (H3R) inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo H3R occupancy of BF2.649 using positron emission tomography (PET) brain imaging with the H3R antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 hours after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in 9 brain regions of interest with the 2 tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS Pitolisant 40 mg promoted 84±7% (x̅±SD) occupancy of H3R. The drug was well -tolerated and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS The administration of pitolisant 40 mg produces a high occupancy of H3R and may bea new tool for the treatment of various central nervous system disorders that are associated with H3R mechanisms. This article is protected by copyright. All rights reserved.We are presenting the difficulties we encountered with the female patient with previously diagnosed primary pigmented nodular adrenal disease (PPNAD) and conflicting