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 & Agonist. The organization has 17826 authors who have published 22835 publications receiving 946714 citations. The organization is also known as: Eli Lily.

Subgroup identification based on differential effect search—A recursive partitioning method for establishing response to treatment in patient subpopulations

Abstract: We propose a novel recursive partitioning method for identifying subgroups of subjects with enhanced treatment effects based on a differential effect search algorithm. The idea is to build a collection of subgroups by recursively partitioning a database into two subgroups at each parent group, such that the treatment effect within one of the two subgroups is maximized compared with the other subgroup. The process of data splitting continues until a predefined stopping condition has been satisfied. The method is similar to 'interaction tree' approaches that allow incorporation of a treatment-by-split interaction in the splitting criterion. However, unlike other tree-based methods, this method searches only within specific regions of the covariate space and generates multiple subgroups of potential interest. We develop this method and provide guidance on key topics of interest that include generating multiple promising subgroups using different splitting criteria, choosing optimal values of complexity parameters via cross-validation, and addressing Type I error rate inflation inherent in data mining applications using a resampling-based method. We evaluate the operating characteristics of the procedure using a simulation study and illustrate the method with a clinical trial example.

Model of complications of NIDDM. I. Model construction and assumptions

Abstract: OBJECTIVE To develop a model of NIDDM for analyzing prevention strategies for NIDDM. RESEARCH DESIGN AND METHODS A Markov type model with Monte Carlo techniques was used. Age, sex, and ethnicity of cohort was based on U.S. data. Incidence rates of complications were also based on community and population studies. RESULTS Nonproliferative retinopathy, proliferative retinopathy, and macular edema are predicted in 79, 19, and 52%, respectively, of people with NIDDM; 19% are predicted to develop legal blindness. Microalbuminuria, gross proteinuria, and end-stage renal disease related to diabetes are predicted in 53, 40, and 17%, respectively. Symptomatic sensorimotor neuropathy and lower-extremity amputation are predicted in 31 and 17%, respectively. Cardiovascular disease is predicted in 39%. Higher rates of complications (1.1−3.0×) are predicted in minority populations. Predicted average life expectancy is 17 years after diagnosis. CONCLUSIONS A probabilistic model of NIDDM predicts the vascular complications of NIDDM in a cohort representative of the incident cases of diabetes in the U.S. before age 75 years. Predictions of complications and mortality are consistent with the known epidemiology of NIDDM. The model is suitable for evaluating the effect of preventive interventions on the natural history of NIDDM.

Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells.

Abstract: P-glycoprotein (Pgp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells, and it plays a major role in causing multidrug resistance (MDR). Confocal microscopy was used to study in vitro and in vivo drug accumulation, net uptake and efflux, and MDR modulation by P-glycoprotein inhibitors in MDR1-transduced human MDA-MB-435mdr (MDR) cancer cells. The MDR cells were approximately 9-fold more resistant to the anticancer drug doxorubicin than their parental wild-type MDA-MB-435wt (WT) cells. Doxorubicin accumulation in the MDR cells was only 19% of that in the WT cells. The net uptake of doxorubicin in the nuclei of the MDR cells was 2-fold lower than that in the nuclei of the WT cells. Pgp inhibitors verapamil, cyclosporine A, or PSC833 increased doxorubicin accumulation in the MDR cells up to 79%, and it reversed drug resistance in these cells. In living animals, doxorubicin accumulation in MDA-MB-435mdr xenograft tumors was 68% of that in the wild-type tumors. Administration of verapamil, cyclosporine A, or PSC833 before doxorubicin treatment of the animals increased doxorubicin accumulation in the MDR tumors up to 94%. These studies have added direct in vitro and in vivo information on the capacity of the transporter protein Pgp to efflux doxorubicin and on the reversal of MDR by Pgp inhibitors in resistant cancer cells.

Mesial Temporal Lobe Epilepsy: Pathogenesis, Induced Rodent Models and Lesions

Abstract: Mesial temporal lobe epilepsy (MTLE), the most common epilepsy in adults, is generally intractable and is suspected to be the result of recurrent excitation or inhibition circuitry. Recurrent excitation and the development of seizures have been associated with aberrant mossy fiber sprouting in the hippocampus. Of the animal models developed to investigate the pathogenesis of MTLE, post-status epilepticus models have received the greatest acceptance because they are characterized by a latency period, the development of spontaneous motor seizures, and a spectrum of lesions like those of MTLE. Among post-status epilepticus models, induction of systemic kainic acid or pilocarpine-induced epilepsy is less labor-intensive than electrical-stimulation models and these models mirror the clinicopathologic features of MTLE more closely than do kindling, tetanus toxin, hyperthermia, post-traumatic, and perinatal hypoxia/ischemia models. Unfortunately, spontaneous motor seizures do not develop in kindling or adult hyp...

Efficacy and Safety of Dulaglutide Monotherapy Versus Metformin in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-3)

Abstract: OBJECTIVE Compare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A 1c (HbA 1c ) at 26 weeks. RESEARCH DESIGN AND METHODS This 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients ( N = 807) had HbA 1c ≥6.5% (≥48 mmol/mol) and ≤9.5% (≤80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTS At 26 weeks, changes from baseline HbA 1c (least squares [LS] mean ± SE) were: dulaglutide 1.5 mg, −0.78 ± 0.06% (−8.5 ± 0.70 mmol/mol); dulaglutide 0.75 mg, −0.71 ± 0.06% (−7.8 ± 0.70 mmol/mol); and metformin, −0.56 ± 0.06% (−6.1 ± 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): −0.22% (−2.4 mmol/mol) and −0.15% (−1.6 mmol/mol) (one-sided P 1c targets P CONCLUSIONS Dulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.