Eli Lilly and Company

About: Eli Lilly and Company is a company organization based out in Indianapolis, Indiana, United States. It is known for research contribution in the topics: Population & Receptor. The organization has 17826 authors who have published 22835 publications receiving 946714 citations. The organization is also known as: Eli Lily.

Therapeutic angiogenesis in cardiovascular disease

Abstract: Despite considerable progress in the management of ischaemic cardiovascular disease during the past three decades, there remains a significant population of patients who are not served well by current treatment approaches. Stimulating revascularization in ischaemic regions is an attractive novel therapeutic strategy, and several angiogenic agents anticipated to have the potential to achieve this goal have been clinically evaluated in recent years. However, as yet none have shown sufficient efficacy to be approved. Here, we consider the key findings from the completed clinical trials of therapeutic angiogenesis in cardiovascular disease, and discuss possible changes to the way in which such agents are developed that could improve the chances of success.

Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

Abstract: SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms

Abstract: Contributors Jean-Marc Aiache, Nobuo Aoyagi, Dennis Bashaw, Cynthia Brown, William Brown, Diane Burgess, John Crison, Patrick DeLuca, Ruzica Djerki, Jennifer Dressman, Thomas Foster, Kirsti Gjellan, Vivian Gray, Ajaz Hussain, Tom Ingallinera, James Klancke, Johannes Kraemer, Henning Kristensen, Kofi Kumi, Christian Leuner, Jobst Limberg, Petra Loos, Lenny Margulis, Patrick Marroum, Helga Moeller, Bernd Mueller, Martin Mueller-Zsigmondy, Ngozi Okafo, Larry Ouderkirk, Shravan Parsi, Saeed Qureshi, Joseph Robinson, Vinod Shah, Martin Siewert, Ramana Uppoor, and Roger Williams. Aventis, Frankfurt, Germany JW Goethe University, Frankfurt, Germany Eli Lilly and Company, Indianapolis, IN Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD Universite d'Auvergne, Clermont-Ferrand Cedex, France National Institute of Health Sciences, Division of Drugs, Tokyo, Japan US Pharmacopeia, Rockville, MD University of Connecticut, Storrs Mansfield, CT Pfizer, Inc, La Jolla, CA University of Kentucky, Lexington, KY Novartis Pharma, Basel, Switzerland AstraZeneca, Sodertalje, Sweden V.A. Gray Consulting, Inc, Hockessin, DE AAI International, Charleston, SC CIMA Laboratories, Inc, Minneapolis, MN Laboratory and Quality Services, Eschborn, Germany University of Copenhagen, Denmark Bundesinstitut fur Arzneimittel, Bonn, Germany Aventis Pharmaceuticals, Bridgewater, NJ Pfizer, Groton, CT Zentrallaboratorium Deutscher Apotheker, Eschborn, Germany Kiel University, Kiel, Germany Alza Corporation, Mountain View, CA DPT Laboratories, Ltd, San Antonio, TX Health Protection Branch, Ottawa, Canada University of Wisconsin, WI

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity

Abstract: Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as ‘tau propagation’ and may explain the stereotypic progression of tau pathology in the brains of Alzheimer’s disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity

Abstract: Expression of eukaryotic translation initiation factor 4E (eIF4E) is commonly elevated in human and experimental cancers, promoting angiogenesis and tumor growth. Elevated eIF4E levels selectively increase translation of growth factors important in malignancy (e.g., VEGF, cyclin D1) and is thereby an attractive anticancer therapeutic target. Yet to date, no eIF4E-specific therapy has been developed. Herein we report development of eIF4E-specific antisense oligonucleotides (ASOs) designed to have the necessary tissue stability and nuclease resistance required for systemic anticancer therapy. In mammalian cultured cells, these ASOs specifically targeted the eIF4E mRNA for destruction, repressing expression of eIF4E-regulated proteins (e.g., VEGF, cyclin D1, survivin, c-myc, Bcl-2), inducing apoptosis, and preventing endothelial cells from forming vessel-like structures. Most importantly, intravenous ASO administration selectively and significantly reduced eIF4E expression in human tumor xenografts, significantly suppressing tumor growth. Because these ASOs also target murine eIF4E, we assessed the impact of eIF4E reduction in normal tissues. Despite reducing eIF4E levels by 80% in mouse liver, eIF4E-specific ASO administration did not affect body weight, organ weight, or liver transaminase levels, thereby providing the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissues. These data have prompted eIF4E-specific ASO clinical trials for the treatment of human cancers.