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.

Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease

Abstract: Aims The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmaco ...

Depressive Signs and Symptoms in Schizophrenia: A Prospective Blinded Trial of Olanzapine and Haloperidol

Abstract: Background Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression. Methods This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D 2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period. Results At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, ≥16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol ( P =.001). Furthermore, the response rate for the group receiving olanzapine (≥50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher ( P =.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment ( P Conclusions Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non–D 2 -mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.

Rules for identifying potentially reactive or promiscuous compounds.

Abstract: This article describes a set of 275 rules, developed over an 18-year period, used to identify compounds that may interfere with biological assays, allowing their removal from screening sets. Reasons for rejection include reactivity (e.g., acyl halides), interference with assay measurements (fluorescence, absorbance, quenching), activities that damage proteins (oxidizers, detergents), instability (e.g., latent aldehydes), and lack of druggability (e.g., compounds lacking both oxygen and nitrogen). The structural queries were profiled for frequency of occurrence in druglike and nondruglike compound sets and were extensively reviewed by a panel of experienced medicinal chemists. As a means of profiling the rules and as a filter in its own right, an index of biological promiscuity was developed. The 584 gene targets with screening data at Lilly were assigned to 17 subfamilies, and the number of subfamilies at which a compound was active was used as a promiscuity index. For certain compounds, promiscuous activ...

Three-Dimensional Quantitative Structure-Activity Relationship for Inhibition of Human Ether-a-Go-Go-Related Gene Potassium Channel

Abstract: The protein product of the human ether-a-go-go gene (hERG) is a potassium channel that when inhibited by some drugs may lead to cardiac arrhythmia. Previously, a three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore model was constructed using Catalyst with in vitro inhibition data for antipsychotic agents. The rationale of the current study was to use a combination of in vitro and in silico technologies to further test the pharmacophore model and qualitatively predict whether molecules are likely to inhibit this potassium channel. These predictions were assessed with the experimental data using the Spearman's rho rank correlation. The antipsychotic-based hERG inhibitor model produced a statistically significant Spearman's rho of 0.71 for 11 molecules. In addition, 15 molecules from the literature were used as a further test set and were also well ranked by the same model with a statistically significant Spearman's rho value of 0.76. A Catalyst General hERG pharmacophore model was generated with these literature molecules, which contained four hydrophobic features and one positive ionizable feature. Linear regression of log-transformed observed versus predicted IC(50) values for this training set resulted in an r(2) value of 0.90. The model based on literature data was evaluated with the in vitro data generated for the original 22 molecules (including the antipsychotics) and illustrated a significant Spearman's rho of 0.77. Thus, the Catalyst 3D-QSAR approach provides useful qualitative predictions for test set molecules. The model based on literature data therefore provides a potentially valuable tool for discovery chemistry as future molecules may be synthesized that are less likely to inhibit hERG based on information provided by a pharmacophore for the inhibition of this potassium channel.

Factors associated with women's decisions to seek treatment for urinary incontinence.

Abstract: Background: Urinary incontinence is a highly prevalent and burdensome condition among women. However, fewer than half of women with symptoms talk to a physician about incontinence, and the determinants of treatment seeking are not well understood. Design: A two-stage cross-sectional survey of adult U.S. women; 45,000 households participating in NFO Worldgroup survey research received a questionnaire to identify adults with incontinence. Based on stratified random sampling of identified incontinent women, 2310 women received a detailed questionnaire. Results: Among 1970 women with urinary incontinence symptoms, 38% had initiated a conversation with a physician about incontinence. In multivariate logistic regression analysis, some of the factors associated significantly with treatment seeking were symptom duration >3 years (OR 2.33, 95% CI 1.57-3.45), having a history of a noticeable accident (OR 1.41, 95% CI 1.06-1.87), worse disease-specific quality of life scores (OR 1.89, 95% CI 1.32-2.70), not being em...