Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

Life cycle greenhouse gas emissions of anesthetic drugs.

BACKGROUND: Anesthesiologists must consider the entire life cycle of drugs in order to include environmental impacts into clinical decisions. In the present study we used life cycle assessment to examine the climate change impacts of 5 anesthetic drugs: sevoflurane, desflurane, isoflurane, nitrous oxide, and propofol. METHODS: A full cradle-to-grave approach was used, encompassing resource extraction, drug manufacturing, transport to health care facilities, drug delivery to the patient, and disposal or emission to the environment. At each stage of the life cycle, energy, material inputs, and emissions were considered, as well as use-specific impacts of each drug. The 4 inhalation anesthetics are greenhouse gases (GHGs), and so life cycle GHG emissions include waste anesthetic gases vented to the atmosphere and emissions (largely carbon dioxide) that arise from other life cycle stages. RESULTS: Desflurane accounts for the largest life cycle GHG impact among the anesthetic drugs considered here: 15 times that of isoflurane and 20 times that of sevoflurane on a per MAC-hour basis when administered in an O(2)/air admixture. GHG emissions increase significantly for all drugs when administered in an N(2)O/O(2) admixture. For all of the inhalation anesthetics, GHG impacts are dominated by uncontrolled emissions of waste anesthetic gases. GHG impacts of propofol are comparatively quite small, nearly 4 orders of magnitude lower than those of desflurane or nitrous oxide. Unlike the inhaled drugs, the GHG impacts of propofol primarily stem from the electricity required for the syringe pump and not from drug production or direct release to the environment. DISCUSSION: Our results reiterate previous published data on the GHG effects of these inhaled drugs, while providing a life cycle context. There are several practical environmental impact mitigation strategies. Desflurane and nitrous oxide should be restricted to cases where they may reduce morbidity and mortality over alternative drugs. Clinicians should avoid unnecessarily high fresh gas flow rates for all inhaled drugs. There are waste anesthetic gas capturing systems, and even in advance of reprocessed gas applications, strong consideration should be given to their use. From our results it appears likely that techniques other than inhalation anesthetics, such as total i.v. anesthesia, neuraxial, or peripheral nerve blocks, would be least harmful to the environment.

A real-world, multi-site, observational study of infusion time and treatment satisfaction with rheumatoid arthritis patients treated with intravenous golimumab or infliximab.

OBJECTIVES: To assess real-world infusion times for golimumab (GLM-IV) and infliximab (IFX) for rheumatoid arthritis (RA) patients and factors associated with treatment satisfaction. METHODS: An observational study assessed infusion time including: clinic visit duration, RA medication preparation and infusion time, and infusion process time. Satisfaction was assessed by a modified Treatment Satisfaction Questionnaire for Medication (patient) and study-specific questionnaires (patient and clinic personnel). Comparative statistical testing for patient data utilized analysis of variance for continuous measures, and Fisher's exact or Chi-square test for categorical measures. Multivariate analysis was performed for the primary time endpoints and patient satisfaction. RESULTS: One hundred and fifty patients were enrolled from six US sites (72 GLM-IV, 78 IFX). The majority of patients were female (80.0%) and Caucasian (88.7%). GLM-IV required fewer vials per infusion (3.7) compared to IFX (4.9; p = .0001). Clinic visit duration (minutes) was shorter for GLM-IV (65.1) compared to IFX (153.1; p < .0001), as was total infusion time for RA medication (32.8 GLM-IV, 119.5 IFX; p < .0001) and infusion process times (45.8 GLM-IV, 134.1 IFX; p < .0001). Patients treated with GLM-IV reported higher satisfaction ratings with infusion time (p < .0001) and total visit time (p = .0003). Clinic personnel reported higher satisfaction with GLM-IV than IFX specific to medication preparation time, ease of mixing RA medication, frequency of patients requiring pre-medication, and infusion time. LIMITATIONS: Findings may not be representative of care delivery for all RA infusion practices or RA patients. CONCLUSIONS: Shorter overall clinic visit duration, infusion process, and RA medication infusion times were observed for GLM-IV compared to IFX. A shorter duration in infusion time was associated with higher patient and clinic personnel satisfaction ratings.

'Cytology-on-a-chip' based sensors for monitoring of potentially malignant oral lesions.

UNLABELLED: Despite significant advances in surgical procedures and treatment, long-term prognosis for patients with oral cancer remains poor, with survival rates among the lowest of major cancers. Better methods are desperately needed to identify potential malignancies early when treatments are more effective. OBJECTIVE: To develop robust classification models from cytology-on-a-chip measurements that mirror diagnostic performance of gold standard approach involving tissue biopsy. MATERIALS AND METHODS: Measurements were recorded from 714 prospectively recruited patients with suspicious lesions across 6 diagnostic categories (each confirmed by tissue biopsy -histopathology) using a powerful new 'cytology-on-a-chip' approach capable of executing high content analysis at a single cell level. Over 200 cellular features related to biomarker expression, nuclear parameters and cellular morphology were recorded per cell. By cataloging an average of 2000 cells per patient, these efforts resulted in nearly 13 million indexed objects. RESULTS: Binary "low-risk"/"high-risk" models yielded AUC values of 0.88 and 0.84 for training and validation models, respectively, with an accompanying difference in sensitivity+specificity of 6.2%. In terms of accuracy, this model accurately predicted the correct diagnosis approximately 70% of the time, compared to the 69% initial agreement rate of the pool of expert pathologists. Key parameters identified in these models included cell circularity, Ki67 and EGFR expression, nuclear-cytoplasmic ratio, nuclear area, and cell area. CONCLUSIONS: This chip-based approach yields objective data that can be leveraged for diagnosis and management of patients with PMOL as well as uncovering new molecular-level insights behind cytological differences across the OED spectrum.