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.

The coactivator LXXLL nuclear receptor recognition motif

Abstract: Nuclear receptors require coactivator binding in order to activate transcription of their cognate target genes. Ligands regulate nuclear receptor (NR)-mediated recruitment of coactivators by binding to the ligand-binding domain of the receptor and inducing a conformational change allowing for recognition of a specific motif contained within the coactivator protein. This motif is known as the NR box or LXXLL (where L is leucine and X is any amino acid) domain. Here, we review the discovery of the domain as well as its characterization.

The cost of relapse and the predictors of relapse in the treatment of schizophrenia.

Abstract: To assess the direct cost of relapse and the predictors of relapse during the treatment of patients with schizophrenia in the United States. Data were drawn from a prospective, observational, noninterventional study of schizophrenia in the United States (US-SCAP) conducted between 7/1997 and 9/2003. Patients with and without relapse in the prior 6 months were compared on total direct mental health costs and cost components in the following year using propensity score matching method. Baseline predictors of subsequent relapse were also assessed. Of 1,557 participants with eligible data, 310 (20%) relapsed during the 6 months prior to the 1-year study period. Costs for patients with prior relapse were about 3 times the costs for patients without prior relapse. Relapse was associated with higher costs for inpatient services as well as for outpatient services and medication. Patients with prior relapse were younger and had onset of illness at earlier ages, poorer medication adherence, more severe symptoms, a higher prevalence of substance use disorder, and worse functional status. Inpatient costs for patients with a relapse during both the prior 6 months and the follow-up year were 5 times the costs for patients with relapse during the follow-up year only. Prior relapse was a robust predictor of subsequent relapse, above and beyond information about patients' functioning and symptom levels. Despite the historical decline in utilization of psychiatric inpatient services, relapse remains an important predictor of subsequent relapse and treatment costs for persons with schizophrenia.

A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia.

Abstract: The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.

γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease

Abstract: The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.

A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia.

Abstract: Background: An intramuscular (IM) formulation of olanzapine has been developed because there are no rapidacting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia. Methods: Recently hospitalized acutely agitated patients with schizophrenia (N=270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection. Results: Olanzapine exhibited a dose-response relationship for reduction in agitation (F1,179=14.4; P.001). Mean PANSS-EC reductions 2 hours after the first injection of olanzapine (2.5 mg=�5.5; 5.0 mg=�8.1; 7.5 mg=�8.7; 10.0 mg=�9.4) were superior to those with placebo (�2.9; P=.01 vs olanzapine at 2.5 mg; P.001 for each other olanzapine dose) but not with haloperidol (�7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event, or for clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with 2.5 (P=.03), 5.0 (P=.03), or 7.5 mg (P=.01) of IM olanzapine (0%) or with placebo (0%) (P=.01). Conclusions: Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile. Arch Gen Psychiatry. 2002;59:441-448