Generation and Characterization of Highly Constitutive Active Histamine H3 Receptors

ABSTRACT Constitutive activation of G-protein-coupled receptors is a well recognized phenomenon, and G-protein-coupled receptor antagonists have been found to possess inverse agonist activity. Constitutive activation of histamine H3 receptor is recently documented in in vivo as well as in recombinant receptor systems in vitro. Several H3 antagonists have been shown to act as inverse agonists and such profiles of H3 antagonists have been implicated in their pharmacological functions. Here we report the construction and characterization of a highly constitutive active H3 receptor (MT6), in which the 357 alanine residue was converted to lysine (A357K). We generated a series of mutated H3 receptors and their functions were examined in human embryonic kidney (HEK) 293 cells. Among them, induced mutation at the amino acid 357 position (A357K) showed a dramatically enhanced response to thioperamide-induced cAMP accumulation compared with the cells expressing wildtype (WT) H3 receptors, suggesting that the mutation rendered receptors to high constitutive activity. We further characterized by ligand binding assays using membrane fractions, and K i values of imetit (agonist) and proxyfan (partial agonist) against the MT6 receptors were lower compared with those observed in WT H3 receptors. In contrast, H3 antagonists (thioperamide, ciproxifan, and GT2016) with inverse agonism displayed increased K i values against the MT6 receptors (2.5-to 5.8-fold), demonstrating more a prominent effect of inverse agonists to the constitutive active receptor. Taken together, these data suggested that A357K mutation in the H3 receptor increased the population of active state receptors that preferably binds to agonists than inverse agonists, which could be termed as a constitutively active mutant of H3 receptor

Retrospective analysis of medical costs and resource utilization for severe hypoglycemic events in patients with type 2 diabetes in Japan

Abstract Aims/Introduction The present study aimed to describe hospital utilization and examine actual medical costs for severe hypoglycemic events in patients with type 2 diabetes mellitus in Japan. Materials and Methods Medical resource utilization associated with severe hypoglycemia was evaluated using a receipt database of acute‐care hospitals in Japan. Patients with type 2 diabetes treated with antihyperglycemic agents were included. Severe hypoglycemic events were identified and divided into two groups: with or without hospitalization. Total and attributable medical costs per event were calculated based on the actual medical treatment after severe hypoglycemic events. Attributable costs were estimated from the receipt codes directly associated with the treatment of severe hypoglycemia. Results In the hospitalized patients, the median length of hospital stay was 11 days, and the median total and attributable medical costs were ¥402,081 and ¥302,341, respectively. The majority of the hospitalized patients underwent a radiographic examination and general blood tests. Apart from the hospitalization costs, the costs associated with diagnosis accounted for 29.6% of the total medical costs. In the outpatients, 60.6% visited hospitals only once for the severe hypoglycemic event, whereas 11.4% visited hospitals daily for a week after the severe hypoglycemic event. The mean number of hospital visits of the outpatient after a severe hypoglycemic event was 2.7 ± 2.6 days. The median total and attributable medical costs were ¥265,432 and ¥4,628, respectively. Conclusions Significant medical resources are used for the treatment of severe hypoglycemic events of patients with type 2 diabetes in Japan

Factors Associated with Prescriptions for an Orexin Receptor Antagonist Among Japanese Patients with Insomnia: Analysis of a Nationwide Japanese Claims Database

Abstract Background Few studies have examined the prescribing patterns of orexin receptor antagonists (ORAs) in the real-world clinical setting in Japan. Objective We sought to analyze the factors associated with ORA prescriptions for patients with insomnia in Japan. Methods Outpatients (aged ≥ 20 to < 75 years old) prescribed one or more hypnotic for insomnia between April 1, 2018 and March 31, 2020 with continuous enrollment for ≥ 12 months were extracted from the JMDC Claims Database. We performed multivariable logistic regression to identify factors (patient demographics and psychiatric comorbidities) associated with ORA prescription in new or non-new users of hypnotics (patients without or with hypnotics prescription history, respectively). Results Of 58,907 new users, 11,589 (19.7%) were prescribed ORA at the index date. Male sex (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.12–1.22) and presence of bipolar disorders (OR 1.36, 95% CI 1.20–1.55) were associated with greater odds of ORA prescription. Among 88,611 non-new users, 15,504 (17.5%) were prescribed ORA at the index date. Younger age and several psychiatric comorbidities, such as neurocognitive disorders (OR 1.64, 95% CI 1.15–2.35), substance use disorders (OR 1.19, 95% CI 1.05–1.35), bipolar disorders (OR 1.14, 95% CI 1.07–1.22), schizophrenia spectrum disorders (OR 1.07, 95% CI 1.01–1.14), and anxiety disorders (OR 1.05, 95% CI 1.00–1.10), were associated with greater odds of ORA prescription. Conclusion This is the first study to determine the factors associated with ORA prescriptions in Japan. Our findings could help guide appropriate insomnia treatment using ORAs