Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration-QTc modeling.

PURPOSE: To investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). PARTICIPANTS AND METHODS: In two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01-0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. RESULTS: Twenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3-1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21-0.24 L/kg). Total recovery of gadolinium in urine amounted to 82-95 % (Study 1) and 96-99 % (Study 2) of the dose administered. Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration-QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. CONCLUSION: Gadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Bioequivalence Evaluation Between Acarbose and Metformin Fixed-Dose Combination and Corresponding Individual Components in Healthy Chinese Male and Female Subjects.

Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design. Pharmacodynamic parameters of serum glucose ratio between treatment day and baseline (ratio of maximum concentration [Cmax ], day 1/Cmax , day -1 and ratio of area under the concentration-time curve [AUC] from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1) were used as the primary variables to evaluate BE of acarbose. Pharmacokinetic parameters Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC were used to evaluate BE of metformin. The results showed that the 90% confidence intervals of the ratios of all primary target variables including ratio of Cmax , day 1/Cmax , day -1 and ratio of AUC from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1 for acarbose, and Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC for metformin all fell within the acceptance limits of 0.8 to 1.25. Thus, BE between 50-mg acarbose and 500-mg metformin as an FDC and loose combination was established. Furthermore, different kinds of exploratory pharmacodynamic parameters (based on either serum glucose or insulin) including several newly proposed parameters were also investigated for acarbose BE evaluation in this study, and inconsistent results were observed.

Positive association between musclin and insulin resistance in obesity: evidence of a human study and an animal experiment.

BACKGROUND: Musclin is a novel skeletal muscle-derived secretory factor considered to be a potent regulator of the glucose metabolism and therefore may contribute to the pathogenesis of obesity and insulin resistance (IR). METHODS: To test this hypothesis, we examined the plasma musclin levels in overweight/obese subjects and lean controls. Rats on a high fat diet (HFD) were used as the annimal model of obesity. Radioimmunoassay and western blot were used to determine musclin levels in plasma and skeletal muscle. RESULTS: According to radioimmunoassays,the overweight/obese subjects exhibited elevated musclin plasma levels compared with the lean controls (89.49 ± 19.00 ng/L vs 80.39 ± 16.35 ng/L, P < 0.01). The musclin levels were positively correlated with triglyceride, fasting plasma glucose, and homeostasis model assessment of IR levels. These observations were confirmed with a high-fat diet(HFD) rat model. HFD rats also exhibited increased musclin immunoreactivity in plasma (P < 0.01) and in skeletal muscle (P < 0.05), as well as increased musclin mRNA levels in skeletal muscle (P < 0.01). Musclin incubation significantly inhibited muscles 3H-2-DG uptake in the normal diet(ND) group (P < 0.01). The protein expression of glucose transporter type 4 was significantly down regulated by 30% (P < 0.05) in the ND group after soleusmuscle was incubated with musclin compared with the control. Musclin incubation also increased the protein levels of glucose-regulated protein (GRP)78 and GRP94 by 146.8 and 54% (both P < 0.05), respectively, in ND rats. CONCLUSIONS: Our data support the hypothesis that musclin has a strong relationship with obesity-associated IR by impairing the glucose metabolism and, at least in part, through causing endoplasmic reticulum stress.

Increased circulating levels of musclin in newly diagnosed type 2 diabetic patients.

BACKGROUND: Musclin is a newly identified skeletal muscle-derived secretory factor, which has been recently characterized as a stimulator that induces insulin resistance in mice. However, the pathophysiological role of musclin in humans remains poorly understood. The aim of this study was to explore the potential correlations between musclin plasma levels and various metabolic parameters in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In this hospital-based study, plasma samples were collected from the enrolled individuals, including 38 newly diagnosed, treatment-naive type 2 diabetes mellitus patients and 41 age- and gender-matched control subjects. Plasma musclin levels were examined by radioimmunoassay. RESULTS: Compared with the control group, musclin plasma levels were significantly higher in untreated type 2 diabetes mellitus patients. Musclin levels in the plasma of newly diagnosed type 2 diabetes mellitus patients were positively correlated with fasting plasma glucose, haemoglobin A1c, serum insulin, triglycerides and homeostasis model assessment of insulin resistance. Furthermore, multivariate logistic regression analysis showed that the level of musclin was associated with the presence of type 2 diabetes mellitus. Receiver operating characteristic curve analysis yielded an area under the curve for musclin of 0.718 in type 2 diabetes mellitus. CONCLUSION: The circulating concentration of musclin was significantly increased in type 2 diabetes mellitus patients. Our results suggest that musclin has a strong relationship with insulin resistance in type 2 diabetes mellitus.

Cortistatin Inhibits NLRP3 Inflammasome Activation of Cardiac Fibroblasts During Sepsis.

BACKGROUND: Cortistatin is a recently discovered neuropeptide that has emerged as a potential endogenous antiinflammatory peptide. As a clinical syndrome, sepsis occurs when an infection becomes amplified, leading to organ dysfunction or risk for secondary infection. Human septic shock involves excessive inflammatory cytokine production. Interleukin (IL) 1ß is one of these cytokines, and it plays a pivotal role in sepsis-induced myocardial dysfunction. The aim of the present study is to evaluate whether cortistatin inhibits nucleotide-binding oligomerization domain-like receptor with a pyrin-domain 3 (NLRP3) inflammasome/caspase-1/IL-1ß pathway in cardiac fibroblasts (CFs) and whether this role can subsequently affect myocardial injury. METHODS AND RESULTS: To test these processes, a murine model of cecal ligation and puncture in vivo and lipopolysaccharide-induced cardiac fibroblasts were used in vitro. We found that pretreatment with cortistatin inhibited NLRP3-mediated ASC pyroptosome formation, caspase-1 activation, and IL-1ß secretion. Additionally cortistatin inhibits proinflammatory pathways (nuclear factor κB and pro-IL-1ß). CONCLUSIONS: This work provided the first evidence of cortistatin as a new immunomodulatory factor with the capacity to deactivate NLRP3 inflammasome activity and to protect against the myocardial injury induced by sepsis. This study has important implications for the design of new strategies to control NLRP3-related diseases.

Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase.

Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), is a cardioprotective peptide. In our previous work, we have revealed that ghrelin could protect heart against ischemia/reperfusion (I/R) injury by inhibiting endoplasmic reticulum stress (ERS), which contributes to many heart diseases. In current study, using both in vivo and in vitro models, we investigated how ghrelin inhibits myocardial ERS. In the in vivo rat heart injury model induced by isoproterenol (ISO), we found that exogenous ghrelin could alleviate heart dysfunction, reduce myocardial injury and apoptosis and inhibit the excessive myocardial ERS induced by ISO. More importantly, the activation of AMP-activated protein kinase (AMPK) was observed. To explore the role of AMPK activation in ERS inhibition by ghrelin, we set up two in vitro ERS models by exposing cultured rat cardiomyocytes to tunicamycin(Tm) or dithiothreitol (DTT). In both models, compared with Tm or DTT treatment alone, pre-incubation cardiomyocytes with ghrelin significantly activated AMPK, reversed the upregulation of the ERS markers, C/EBP-homologous protein (CHOP) and cleaved caspase-12, and reduced apoptosis of cardiomyocytes. Further, we found that the ERS inhibitory and anti-apoptotic actions induced by ghrelin were blocked by an AMPK inhibitor. To investigate how ghrelin activates AMPK, selective antagonist of GHS-R1a and inhibitor of Ca(2+)/Calmodulin-dependent protein kinase kinase (CaMKK) were added, respectively, before ghrelin pre-incubation, and we found that AMPK activation was prevented and the ERS inhibitory and anti-apoptotic actions of ghrelin were blocked. In conclusion, ghrelin could protect heart against ERS-induced injury and apoptosis, at least partially through a GHS-R1a/CaMKK/AMPK pathway.

Angiotensin-(1-7) inhibits vascular calcification in rats.

Angiotensin-(1-7) [Ang-(1-7)] is a new bioactive heptapeptide in the renin-angiotensin-aldosterone system (RAAS) with potent protective effects in cardiovascular diseases, opposing many actions of angiotensin II (Ang II) mediated by Ang II type 1 (AT1) receptor. It is produced mainly by the activity of angiotensin-converting enzyme 2 (ACE2) and acts through the Mas receptor. However, the role of Ang-(1-7) in vascular calcification (VC) is still unclear. In this study, we investigated the protective effects of Ang-(1-7) on VC in an in vivo rat VC model induced by vitamin D3 plus nicotine. The levels of ACE2 and the Mas receptor, as well as ACE, AT1 receptor, Ang II type 2 receptor and angiotensinogen, were significantly increased in calcified aortas, and Ang-(1-7) reversed the increased levels. Ang-(1-7) restored the reduced expression of lineage markers, including smooth muscle (SM) α-actin, SM22α, calponin and smoothelin, in vascular smooth muscle cells (VSMCs) and retarded the osteogenic transition of VSMCs by decreasing the expression of bone-associated proteins. It reduced alkaline phosphatase activity and calcium deposition in VC and alleviated the hemodynamic disorders of rats with VC. We provide the first in vivo evidence that Ang-(1-7) can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs, at least in part by decreasing levels of the ACE/Ang II/AT1 axis. The increased expression of ACE2 and the Mas receptor in calcified aortas suggests the involvement of the ACE2/Ang-(1-7)/Mas axis during VC. Ang-(1-7) might be an efficient endogenous vasoprotective factor for VC.