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 epidemiology, economic burden, and pharmacological treatment of chronic low back pain in France, Germany, Italy, Spain and the UK: a literature-based review.

Abstract: Objective: This study's objective was to review the literature on the epidemiological and economic burden and treatment of chronic low back pain (CLBP) in France, Germany, Italy, Spain and the UK. Methods: A literature search was conducted for 1997 – 2007, focusing on CLBP burden and treatment in the countries of interest. Results: The literature search yielded 1552 articles; 23 sources were included in this review. General population prevalence estimates for CLBP were available for two countries: 5.91% (Italy) and 6.3 – 11.1% (UK). Resource utilization estimates were available for Germany, Italy, Spain and the UK. Patients visited general practitioners and osteopaths. Annual direct costs of low back pain were available only for Germany: > € 7000 per person. Work absenteeism accounted for 75% of the total per-patient cost of low back pain in Germany. The five identified treatment guidelines recommended a multimodal approach. Recommended pharmacotherapies included NSAIDs, muscle relaxants, analgesics and a...

Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia.

Abstract: Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M 4 subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M 4 receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M 4 receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D 432 ) in the third extracellular loop of the human M 4 receptor to be critical for selectivity and agonist potentiation by LY2033298. Importantly, LY2033298 was active in animal models predictive of clinical antipsychotic drug efficacy indicating its potential use as a first-in-class, selective, allosteric muscarinic antipsychotic agent.

Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.

Abstract: A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA2 complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA2.