20 research outputs found
Murine Hyperglycemic Vasculopathy and Cardiomyopathy: Whole-Genome Gene Expression Analysis Predicts Cellular Targets and Regulatory Networks Influenced by Mannose Binding Lectin
Hyperglycemia, in the absence of type 1 or 2 diabetes, is an independent risk factor for cardiovascular disease. We have previously demonstrated a central role for mannose binding lectin (MBL)-mediated cardiac dysfunction in acute hyperglycemic mice. In this study, we applied whole-genome microarray data analysis to investigate MBL’s role in systematic gene expression changes. The data predict possible intracellular events taking place in multiple cellular compartments such as enhanced insulin signaling pathway sensitivity, promoted mitochondrial respiratory function, improved cellular energy expenditure and protein quality control, improved cytoskeleton structure, and facilitated intracellular trafficking, all of which may contribute to the organismal health of MBL null mice against acute hyperglycemia. Our data show a tight association between gene expression profile and tissue function which might be a very useful tool in predicting cellular targets and regulatory networks connected with in vivo observations, providing clues for further mechanistic studies
ECMO for COVID-19 patients in Europe and Israel
Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO
support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed
on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients
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The Role of Complement in Ischemic Heart Disease in Type 2 Diabetes Mellitus
The mechanisms responsible for the enhanced inflammatory response in type 2 diabetes (T2DM) and its contribution to the severe ischemia/reperfusion (I/R) injury observed in the T2DM heart are unclear. I/R is associated with an acute inflammatory response recognized by reactive oxidant production, complement activation, and leukocyte-endothelial cell adhesion, among others. Complement activation plays an important role in the inflammatory response and is involved in the manifestation of I/R injury in the non-diabetic heart, and is a potent chemoattractant for circulating neutrophils (PMNs). The purpose of this dissertation research was to test the hypothesis that the complement system, predominantly the lectin pathway, is a significant contributor to the excessive response of the Zucker Diabetic Fatty (ZDF), a rat model of T2DM, to myocardial I/R injury. Following 30min of coronary artery occlusion and 120min of reperfusion we measured C3 deposition, PMN accumulation, PMN CD11b expression, and ICAM-1 expression. We found significantly more C3 deposition, PMN accumulation, ICAM-1 and PMN CD11b expression in diabetic samples compared to non-diabetic samples. To elucidate a role for complement system activation, we treated animals with FUT-175, a broad complement inhibitor. In vivo, FUT-175 treatment significantly decreased complement deposition (66%), PMN accumulation (59%), and infarct size (55%) compared to untreated animals in both non-diabetic Sprague-Dawley and diabetic ZDF rats. To specifically examine the role of the lectin pathway, we selectively inhibited rat MBL-A prior to myocardial I/R in ZDF rats. Anti-MBL treatment significantly decreased infarct size, C3 deposition and PMN accumulation in the ZDF post-ischemic left ventricle (LV). Genomic analysis revealed that gene expression of the pro-inflammatory cytokines IL-6 and IL-1α was enhanced in the ZDF heart following reperfusion, and quantitative RT-PCR results confirmed IL-6 upregulation. We found significantly increased complement C5a receptor (CD88) expression on diabetic neutrophils prior to ischemia, suggesting that diabetic PMNs are "primed" to respond to complement activation. Taken together, these results provide evidence that 1) the ZDF rat is a good model for chronic inflammation in the setting of T2DM, 2) lectin pathway activation plays a significant role in the inflammatory response to I/R injury in the ZDF heart, and 3) anti-complement therapy may be particularly cardio-protective in T2DM
Systematic Evaluation of Wajima Superposition (Css-MRT) in the Estimation of Human Intravenous Pharmacokinetic Profile
Synopsis
The prediction of human pharmacokinetics became an integral part of drug development as it helps the planning stage of clinical development, such as the projection of efficacious human dose or optimal dosing paradigm. The objective of this paper is to systematically examine the application of the Wajima’s superposition on a set of 57 compounds, with a balanced representation of metabolically and renally eliminated compounds and diverse chemical space with a wide variety of lipophilicity as well as ionization characters (acid/base). The present work also aims at offering some guidance, and at exploring caveats which may be encountered during the application toward the generation of predicted human i.v. PK profiles
A novel diclofenac-hydrogel conjugate system for intraarticular sustained release: Development of 2-pyridylamino-substituted 1-phenylethanol (PAPE) and its derivatives as tunable traceless linkers
A local sustained-release drug delivery system, or depot, for intra-articular injection offers the opportunity to release a therapeutic agent directly to the joint with limited need for reinjection. A successful system would provide more consistent efficacy and minimize systemic side effects. In this paper, we explore the potential use of diclofenac, a non-steroidal anti-inflammatory drug, for use in a polymer-conjugate depot system. During the course of our exploration it was determined that “conventional ester” conjugates of diclofenac were not appropriate as upon incubation in buffer (pH 7.4) or in bovine synovial fluid, a considerable amount of undesired diclofenac-lactam was released. Thus we developed a novel linker system for diclofenac in order to minimize the production of the lactam. This new linker enables a diclofenac conjugate system with tunable release rates and minimizes the production of undesired lactam side-products
Design and Discovery of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (LXH254), A selective, efficacious, well-tolerated RAF inhibitor targeting RAS mutant cancers: The path to the clinic
RAS and BRAF oncogenes are mutated in more than one-third of human cancers and exquisite dependency on CRAF, MEK1/2 and ERK1/2 has been demonstrated in preclinical models of RAS mutant cancer. Direct pharmacological inhibition of RAS has remained elusive and efforts to target CRAF have been challenging due to the nature of the RAF signaling complex downstream of activated RAS and the poor overall kinase selectivity profile of putative RAF inhibitors such as sorafenib and RAF265. Herein, we describe 15 (LXH254), a selective B/C RAF inhibitor, which has been developed through a hypothesis-driven approach focusing on drug-like properties. We have previously disclosed the discovery of 3 (RAF709), a preclinical tool compound which was potent, selective, efficacious, and well-tolerated in preclinical models, but the high intrinsic clearance [HLM Cl(int) = 94] precluded further development.X The high clearance of 3 by HLM prompted the medicinal chemistry team to further investigate close analogs as well as novel scaffolds. While keeping drug-like properties in mind, the team identified multiple cell-potent scaffolds with low-to-moderate human clearance and progressed them into in-vivo pharmacology studies. Unexpectedly, the majority of novel scaffolds caused significant body weight loss in mice for unknown reasons, with the 2-pyridine series emerging as the only scaffold which was not plagued by this problem. A structure-based approach led to the realization that an alcohol side-chain in the 2-position of the pyridine could interact with the DFG loop and significantly improve cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition of CYP3A4 (TDI) led to the discovery of 15, which had favorable PK and proved to be efficacious in multiple xenograft models such as Calu-6 (KRASQ61K),with a favorable therapeutic index. Due to its excellent in vitro/ in vivo properties, it has progressed through preclinical toxicology studies and now being tested as a single agent and as a combination partner in phase 1 clinical trial