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Spurlino J.C.,Johnson and Johnson Pharmaceutical Research and Development
Methods in Enzymology

Abstract We screen for fragments using X-ray crystallography as the primary screen. There are several unique features in our screening methodology. As a result of using X-ray diffraction as our primary screen, we do not use affinity data to bias our data collection or design in progressing hits toward a lead. Another difference in our methodology is that we choose to group our compounds as shape-similar groups. We also screen in a first pass mode without recollecting failed diffraction experiments. This method of screening results in an average loss of 510% of the data sets for the primary screen. The remaining data sets offer enough information to successfully advance three to five scaffolds into the secondary library design. We do not deconvolute the wells which show evidence of fragment binding by repeating the soaks with single compounds. Instead, evaluation of the possible fragments is done by refinement and examination of the resulting electron density difference maps. These methods allow us to complete the initial screen of a primary library of fragments in less than 3 months. A secondary library of fragments is designed using the base structures with electron density envelopes from the successful fragment hits of the primary library. Chemistry is chosen to probe interactions with the target and push the observed binding pocket limits in order to more clearly define the plasticity and range of possible extensions to the scaffolds chosen. The secondary library compounds are also screened in shape-similar groupings of five that are chosen without the knowledge of binding affinity. Our approach is a completely orthogonal one from traditional high-throughput screening in finding novel compounds. © 2011 Elsevier Inc. Source

Salter R.,Johnson and Johnson Pharmaceutical Research and Development
Journal of Labelled Compounds and Radiopharmaceuticals

Rapid and efficient iridium-mediated hydrogen-tritium exchange labeling of pharmaceutical compounds is a key methodology in the life sciences industry. A review of the development and use of iridium(I) phosphine systems for ortho-directed isotopic exchange is described to provide the reader with a comprehensive introduction to the area and to serve as a starting point for experimental investigators. Examples of useful catalyst systems and their application to different substrates types as well as potential areas for further development are discussed. Copyright © 2010 John Wiley & Sons, Ltd. Source

Wallace M.,University of California at San Diego | Thipphawong J.,Johnson and Johnson Pharmaceutical Research and Development
Pain Medicine

Objective: To investigate the efficacy, safety, and impact on quality of life of long-term administration of OROS hydromorphone ER (8-128 mg) in patients with chronic low back pain. Design: A total of 113 adults with chronic low back pain who completed a 6-week open-label study were enrolled in this 6-month extension study. Outcome Measures: The primary end point was the daily pain relief rating obtained during monthly study visits. Secondary end points included Investigator and Patient Global Evaluations, Brief Pain Inventory scores obtained at monthly study visits, and quality-of-life measures (Medical Outcomes Study Questionnaire and 36-Item Short-Form Health Survey score) obtained at monthly intervals. Results: Mean ± SD change from baseline in pain relief with OROS hydromorphone ER for the Month 6 visit was 0.9 ± 2.55 (P = 0.0007) and for the last assessment of the extension study was 0.9 ± 2.53 (P = 0.0002). At the Month 6 visit, 81.3% of investigators and 71.0% of patients rated their satisfaction of pain relief with OROS hydromorphone ER treatment as good, very good, or excellent. Changes on the 36-item Short Form Health Survey, a quality-of-life measure, were statistically significant for the physical composite scores for all extension phase time points, including Month 6 (2.1 ± 5.34; P < 0.0001) and the last assessment (2.4 ± 5.56; P < 0.0001) and mental composite scores for all extension phase time points, including Month 6 (3.3 ± 9.52; P = 0.0006) and the last assessment (3.1 ± 9.5; P = 0.0008). Treatment with OROS hydromorphone ER also resulted in significant improvement in sleep disturbances. Adverse events included gastrointestinal and central nervous system symptoms. Conclusions: The results support the long-term use of OROS hydromorphone ER in managing chronic moderate to severe low back pain. © 2010 American Academy of Pain Medicine. Source

Ryan P.,Johnson and Johnson Pharmaceutical Research and Development
Statistical Methods in Medical Research

Observational healthcare databases offer significant potential for generating evidence about the effects of medical products. Recent US and international efforts attempt to coordinate analysis activities across observational data networks for active drug safety surveillance and comparative effectiveness research. Several statistical challenges exist that require further research to inform the appropriate use of observational data for identifying and evaluating temporal relationships between medical product exposures and outcomes. This review highlights current work across the areas of data quality, methods development, and performance evaluation that promise to contribute to our understanding of best practices for observational analyses moving forward. © 2011 The Author(s). Source

Zorych I.,Columbia University | Madigan D.,Columbia University | Ryan P.,Johnson and Johnson Pharmaceutical Research and Development | Bate A.,Pfizer
Statistical Methods in Medical Research

Data mining disproportionality methods (PRR, ROR, EBGM, IC, etc.) are commonly used to identify drug safety signals in spontaneous report system (SRS) databases. Newer data sources such as longitudinal observational databases (LOD) provide time-stamped patient-level information and overcome some of the SRS limitations such as an absence of the denominator, total number of patients who consume a drug, and limited temporal information. Application of the disproportionality methods to LODs has not been widely explored. The scale of the LOD data provides an interesting computational challenge. Larger health claims databases contain information on more than 50 million patients and each patient has records for up to 10 years. In this article we systematically explore the application of commonly used disproportionality methods to simulated and real LOD data. © 2011 The Author(s). Source

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