Showing papers by "Eli Lilly and Company published in 2010"

How to improve R&D productivity: the pharmaceutical industry's grand challenge

Abstract: The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.

Membrane transporters in drug development.

Abstract: Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

Abstract: Content Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes. Objective To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. Data Sources and Study Selection A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained. Data Extraction Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype. Results Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P Conclusion Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

Alzheimer's disease: strategies for disease modification

Abstract: Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide - a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis - are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.

The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

Abstract: Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A 1C ) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A 1C 1C 7.0-7.9%) glucose control. Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l ( Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. Trial registration NCT00000620.

The Microarray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models

Abstract: Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18).

Abstract: An 18F-labeled PET amyloid-β (Aβ) imaging agent could facilitate the clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer disease (AD) pathology. Here we present the results of a clinical trial with (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45 or flobetapir F 18). Methods: An open-label, multicenter brain imaging, metabolism, and safety study of 18F-AV-45 was performed on 16 patients with AD (Mini-Mental State Examination score, 19.3 ± 3.1; mean age ± SD, 75.8 ± 9.2 y) and 16 cognitively healthy controls (HCs) (Mini-Mental State Examination score, 29.8 ± 0.45; mean age ± SD, 72.5 ± 11.6 y). Dynamic PET was performed over a period of approximately 90 min after injection of the tracer (370 MBq [10 mCi]). Standardized uptake values and cortical-to-cerebellum standardized uptake value ratios (SUVRs) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps for a subset of subjects. Results: Valid PET data were available for 11 AD patients and 15 HCs. 18F-AV-45 accumulated in cortical regions expected to be high in Aβ deposition (e.g., precuneus and frontal and temporal cortices) in AD patients; minimal accumulation of the tracer was seen in cortical regions of HCs. The cortical-to-cerebellar SUVRs in AD patients showed continual substantial increases through 30 min after administration, reaching a plateau within 50 min. The 10-min period from 50 to 60 min after administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 ± 0.175 for patients with AD versus 1.25 ± 0.177 for HCs. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r = 0.58–0.88, P

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan

Abstract: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients. Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m−2 plus gemcitabine 1000 mg m−2 on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m−2 on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks. A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and γ-GTP increase (29.3%/35.7%). Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.

The Alzheimer's Disease Neuroimaging Initiative: Progress report and future plans

Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid beta (Abeta) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of Abeta and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD.

LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis a phase I randomized, double-blind, placebo-controlled, proof-of-concept study

Abstract: Objective We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin-17 (anti–IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). Methods This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. Results Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. Conclusion LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

Meta-Analysis of Genome-Wide Association Studies of Attention- Deficit/Hyperactivity Disorder

Abstract: Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

Teriparatide for Acceleration of Fracture Repair in Humans: A Prospective, Randomized, Double-Blind Study of 102 Postmenopausal Women With Distal Radial Fractures

Abstract: Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 mu g dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 mu g (n = 34) or teriparatide 40 mu g (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparaticle 40 mu g versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparaticle 20 1 and 40 mu g, respectively (overall p = .015). There was no significant difference between the teriparaticle 40 mu g versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparaticle 40 1 versus 20 mu g (p = .053); however, the time to healing was shorter in teriparaticle 20 mu g than placebo (p = .006). The primary hypothesis that teriparatide 40 jug would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparaticle 20 mu g compared with placebo still may suggest that fracture repair can be accelerated by teriparaticle, but this result should be interpreted with caution and warrants further study.

The slow (<1 Hz) rhythm of non-REM sleep: a dialogue between three cardinal oscillators

Abstract: The slow (<1 Hz) rhythm, the most important electroencephalogram (EEG) signature of non–rapid eye movement (NREM) sleep, is generally viewed as originating exclusively from neocortical networks. Here we argue that the full manifestation of this fundamental sleep oscillation in a corticothalamic module requires the dynamic interaction of three cardinal oscillators: one predominantly synaptically based cortical oscillator and two intrinsic, conditional thalamic oscillators. The functional implications of this hypothesis are discussed in relation to other EEG features of NREM sleep, with respect to coordinating activities in local and distant neuronal assemblies and in the context of facilitating cellular and network plasticity during slow-wave sleep.

HMGB1 release and redox regulates autophagy and apoptosis in cancer cells.

Abstract: The functional relationship and cross-regulation between autophagy and apoptosis is complex. In this study we show that the high-mobility group box 1 protein (HMGB1) is a redox-sensitive regulator of the balance between autophagy and apoptosis. In cancer cells, anticancer agents enhanced autophagy and apoptosis, as well as HMGB1 release. HMGB1 release may be a prosurvival signal for residual cells after various cytotoxic cancer treatments. Diminished HMGB1 by short hairpin RNA transfection or inhibition of HMGB1 release by ethyl pyruvate or other small molecules led predominantly to apoptosis and decreased autophagy in stressed cancer cells. In this setting, reducible HMGB1 binds to the receptor for advanced glycation end products (RAGEs), but not to Toll-like receptor 4, induces Beclin1-dependent autophagy and promotes tumor resistance to alkylators (melphalan), tubulin disrupting agents (paclitaxel), DNA crosslinkers (ultraviolet light) and DNA intercalators (oxaliplatin or adriamycin). On the contrary, oxidized HMGB1 increases the cytotoxicity of these agents and induces apoptosis mediated by the caspase-9/-3 intrinsic pathway. HMGB1 release, as well as its redox state, thus links autophagy and apoptosis, representing a suitable target when coupled with conventional tumor treatments.

Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia.

Abstract: To assess baseline predictors and consequences of antipsychotic adherence during the long-term treatment of schizophrenia outpatients, data were taken from the 3-year, prospective, observational, European Schizophrenia Outpatients Health Outcomes (SOHO) study, in which outpatients starting or changing antipsychotics were assessed every 6 months. Physician-rated adherence was dichotomized as adherence/non-adherence. Regression models tested for predictors of adherence during follow-up, and associations between adherence and outcome measures. Of the 6731 patients analysed, 71.2% were adherent and 28.8% were non-adherent over 3 years. The strongest predictor of adherence was adherence in the month before baseline assessment. Other baseline predictors of adherence included initial treatment for schizophrenia and greater social activities. Baseline predictors of non-adherence were alcohol dependence and substance abuse in the previous month, hospitalization in the previous 6 months, independent housing and the presence of hostility. Non-adherence was significantly associated with an increased risk of relapse, hospitalization and suicide attempts. In conclusion, non-adherence is common but can partly be predicted. This may allow strategies to improve adherence to be targeted to high-risk patients. Also, reversal of some risk factors may improve adherence. Non-adherence is associated with a range of poorer long-term outcomes, with clinical and economic implications.

Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans.

Abstract: Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA). Knowledge of the CYP-dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the pharmacokinetics of and pharmacodynamic response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to thienopyridine antiplatelet therapy with prasugrel. Current literature shows that greater ADP-mediated IPA is associated with significantly better clinical outcomes for patients with acute coronary syndrome.

Psychosocial adjustment of siblings of children with cancer: a systematic review.

Abstract: Objectives: To promote a broader understanding of the psychosocial impact of childhood cancer on siblings, a systematic review was undertaken. Directions for future research are proposed and clinical strategies are suggested for addressing the needs of these children. Methods: Searches of Medline, PsycINFO and CINAHL revealed 65 relevant qualitative, quantitative, or mixed methods' papers published between 1997 and 2008. These papers were rated for scientific merit and findings were extracted for summary. Results: Siblings of children with cancer do not experience elevated mean rates of psychiatric disorders, but a significant subset experiences post-traumatic stress symptoms, negative emotional reactions (e.g. shock, fear, worry, sadness, helplessness, anger, and guilt), and poor quality of life in emotional, family, and social domains. In general, distress is greater closer to time of diagnosis. School difficulties are also evident within 2 years of diagnosis. Qualitative studies reveal family-level themes such as loss of attention and status as well as positive outcomes including increased sibling maturity and empathy. Conclusions: Research regarding siblings of children with cancer continues to be methodologically limited. The conclusions of qualitative and quantitative studies differ considerably. We propose a research agenda to propel this field forward including greater attention to alterations in normative development (as opposed to psychiatric conditions), development of more appropriate quantitative measures, examination of potential moderators of adaptation, and use of prospective longitudinal designs. Siblings of children with cancer are a psychosocially at-risk group and should be provided with appropriate supportive services. Copyright © 2009 John Wiley & Sons, Ltd.

Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium

Abstract: The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

Abstract: There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

Abstract: Objective: In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP-1 receptor agonist exenatide once weekly (exenatide QW; 2mg) was compared to exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from exenatide BID to exenatide QW after 30 weeks. Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. Results: Patients continuing exenatide QW maintained A1C improvements through 52 weeks (−2.0% [−2.1 to −1.8%]; LS mean [95% CI]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C 40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. ClinicalTrials.gov identifier: NCT00308139

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects

Abstract: Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.

Hplc For Pharmaceutical Scientists

Abstract: PREFACE CONTRIBUTORS PART I HPLC THEORY AND PRACTICE 1 Introduction (Yuri Kazakevich and Rosario LoBrutto) 11 Chromatography in the Pharmaceutical World 12 Chromatographic Process 13 Classification 14 History of Discovery and Early Development (1903-1933) 15 General Separation Process 16 Types of HPLC 17 HPLC Descriptors (Vr, k, N, etc) 2 HPLC Theory (Yuri Kazakevich) 21 Introduction 22 Basic Chromatographic Descriptors 23 Efficiency 24 Resolution 25 HPLC Retention 26 Retention Mechanism 27 General Column Mass Balance 28 Partitioning Model 29 Adsorption Model 210 Total and Excess Adsorption 211 Mass Balance in Adsorption Model 212 Adsorption of the Eluent Components 213 Void Volume Considerations 214 Thermodynamic Relationships 215 Adsorption-Partitioning Retention Mechanism 216 Secondary Equilibria 217 Gradient Elution Principles 218 Types of Analyte Interactions with the Stationary Phase 219 Conclusion 3 Stationary Phases (Yuri Kazakevich and Rosario LoBrutto) 31 Introduction 32 Type of Packing Material (Porous, Nonporous, Monolithic) 33 Base Material (Silica, Zirconia, Alumina, Polymers) 34 Geometry 35 Adsorbent Surface Chemistry 36 Surface of Chemically Modified Material 37 Polymer-Based Adsorbents 38 Stationary Phases for Chiral Separations 39 Columns 4 Reversed-Phase HPLC (Rosario LoBrutto and Yuri Kazakevich) 41 Introduction 42 Retention in Reversed-Phase HPLC 43 Stationary Phases for RPLC 44 Mobile Phases for RPLC 45 pH Effect on HPLC Separations 46 Effect of Organic Eluent Composition on Analyte Ionization 47 Synergistic Effect of pH, Organic Eluent, and Temperature on Ionizable Analyte Retention and Selectivity 48 Examples of Applying pH Shift and Analyte pKa Shift Rules 49 Effect of Temperature on Analyte Ionization 410 Ion-Interaction Chromatography 411 Concluding Remarks 5 Normal-Phase HPLC (Yong Liu and Anant Vailaya) 51 Introduction 52 Theory of Retention in Normal-Phase Chromatography 53 Effect of Mobile Phase on Retention 54 Selectivity 55 Applications 56 Conclusions 6 Size-Exclusion Chromatography (Yuri Kazakevich and Rosario LoBrutto) 61 Separation of the Analyte Molecules by Their Size 62 Molecular Size and Molecular Weight 63 Separation Mechanism 64 Calibration 65 Columns 66 Molecular Weight Distribution 67 Effect of Eluent 68 Effect of Temperature 69 Detectors 610 Solving Mass Balance Issues 611 Aqueous SEC Applications 7 LC/MS: Theory, Instrumentation, and Applications to Small Molecules (Guodong Chen, Li-Kang Zhang, and Birendra N Pramanik) 71 Introduction 72 Ionization Methods and LC/MS Interfaces 73 Mass Analyzers 74 Role of Instrumental Parameters on Ionization Efficiency in LC/MS 75 Effect of Mobile-Phase Composition on Ionization Efficiency in LC/MS 76 MS Interpretation 77 Practical Applications 78 Conclusions 8 Method Development (Rosario LoBrutto) 81 Introduction 82 Types of Methods 83 Defining the Method 84 Method Development Considerations 85 Method Development Approaches 86 Effect of pH on UV Absorbance 87 Analyte pKa-From an Analytical Chemist's Perspective 88 Reversed-Phase Versus Normal-Phase Separations 89 Instrument/System Considerations 810 Column Testing (Stability and Selectivity) 811 Concluding Remarks 9 Method Validation (Rosario LoBrutto and Tarun Patel) 91 Introduction 92 Validation Report 93 Revalidation 94 Assignment of Validation Parameters 95 Distinguishing Drug-Related and Non-Drug-Related Degradation Products 96 Concluding Remarks 10 Computer-Assisted HPLC and Knowledge Management (Yuri Kazakevich, Michael McBrien, and Rosario LoBrutto) 101 Introduction 102 Prediction of Retention and Simulation of Profiles 103 Optimization of HPLC Methods 104 Structure-Based Tools 105 Conclusion PART II HPLC IN THE PHARMACEUTICAL INDUSTRY 11 The Expanding Role of HPLC in Drug Discovery (Daniel B Kassel) 111 Introduction 112 Applications of HPLC/MS for Protein Identification and Characterization 113 Applications of HPLC/MS/MS in Support of Protein Chemistry 114 Applications of HPLC/MS/MS in Support of Assay Development and Screening 115 Sources of Compounds for Biological Screening 116 HPLC/MS Analysis to Support Compound Characterization 118 Higher-Throughput Purification Strategies 119 ADME Applications 1110 Fast Serial ADME Analyses Incorporating LC-MS and LC-MS/MS 1111 Parallel Approaches to Speeding ADME Analyses 1112 Automated "Intelligent" Metabolic Stability and Metabolite ID 1113 Conclusions 12 Role of HPLC in Preformulation (Irina Kazakevich) 121 Introduction 122 Initial Physicochemical Characterization (Discovery Support) 123 Chemical Stability 124 Salt Selection 125 Polymorphism 126 Preformulation Late Stage (Development Support) 127 Conclusions 13 The Role of Liquid Chromatography-Mass Spectrometry in Pharmacokinetics and Drug Metabolism (Ray Bakhtiar, Tapan K Majumdar, and Francis L S Tse) 131 Introduction 133 Tandem-Mass Spectrometry (MS/MS) 134 Sample Preparation Using an Off-Line Approach 135 Automated Sample Transfer 136 Sample Processing Using an On-Line Approach 137 Matrix Effect and Ion Suppression 138 Regulatory Requirements for LC/MS Method Validation 139 Ritalin(r): An Application of Enantioselective LC-MS/MS 1310 GleevecTM (STI571) 1311 Biomarkers 1312 Conclusions 14 Role of HPLC in Process Development (Richard Thompson and Rosario LoBrutto) 141 Responsibilities of the Analytical Chemist During Process Development 142 HPLC Separation Modes 143 Sample Preparation 144 HPLC Detectors 145 Method Development 146 In-Process Monitoring 147 Impurity Identification 148 Establishment of HPLC Selectivity by Stress Studies 149 HPLC Method Validation 1410 Technology Transfer 1411 Concluding Remarks 15 Role of HPLC During Formulation Development (Tarun S Patel and Rosario LoBrutto) 151 Introduction 152 Prerequisite for Analytical Chemists During Formulation Development 153 Properties of Drug Substance 154 Properties of Excipients 155 Impact of Excipients on Degradation of API(s) 156 Test Methods for Most Common Dosage Forms in which HPLC Is the Primary Technique 157 Forced Decomposition 158 Compatibility of Excipients with API(s) (Type and Ratio) 159 Mass Balance 1510 Summary of Assay and Related Substances 1511 Uniformity of Dosage Units 1512 Blend Uniformity (BU) 1513 Cleaning Verification 1514 Extractables/Leachables 1515 Dissolution 1516 Method Development 1517 Method Validation 1518 Testing of Samples 1519 Automation Opportunities 1520 Implementation of Alternative Technologies 1521 Challenges and Future Trends A151 Addendum (Common Functional Groups) A1511 Carbonyls A1512 Nitrogen Functional Groups A1513 Ethers, Thioethers A1514 Alkyl/Aryl Halides A1515 Hydroxyls A1516 Thiols A1517 Phenols A1518 Olefins A1519 Dimerization A15110 Ring Transformations 16 The Role of HPLC in Technical Transfer and Manufacturing (Joseph Etse) 161 Introduction 162 Prerequisites for Transfer of HPLC Methods 163 Types of Technical Transfer 164 Different Approaches for Technical Transfer and Manufacturing 165 Potential Pitfalls During Technical Transfer and Manufacturing 166 Conclusion PART III HYPHENATED TECHNIQUES AND SPECIALIZED HPLC SEPARATIONS 17 Development of Fast HPLC Methods (Anton D Jerkovich and Richard V Vivilecchia) 171 Introduction 172 Basic Theory 173 Monolithic Columns 174 Ultra-High-Pressure Liquid Chromatography 175 Separations on Chips 176 Optimizing Gradient Separations for Speed 177 Instrumental Requirements for Operating High-Efficiency Columns 178 Conclusions 18 Temperature as a Variable in Pharmaceutical Applications (Roger M Smith) 181 The Influence of Temperature on Chromatography 182 Effects on Method Transferability and Reproducibility 183 Elevated Temperature and Pharmaceutical Separations 184 Superheated Water Chromatography 186 Subambient Separations 187 Conclusion 19 LC/MS Analysis of Proteins and Peptides in Drug Discovery (Guodong Chen, Yan-Hui Liu, and Birendra N Pramanik) 191 Introduction 192 General Strategies for Analysis of Proteins/Peptides 193 Applications for Biotechnology Products and Drug Targets 194 Conclusions 20 LC-NMR Overview and Pharmaceutical Applications (Maria Victoria Silva Elipe) 201 Introduction 202 Historical Background of NMR 203 LC-NMR 204 LC-MS-NMR (or LC-NMR-MS or LC-NMR/MS) 205 Conclusions 21 Trends in Preparative HPLC (Ernst Kuesters) 211 Introduction 212 Method Development in Preparative HPLC 213 Columns and Stationary Phases 214 Choice of Preparative LC Technology 215 Detection Tools 216 Conclusion 22 Chiral Separations (Nelu Grinberg, Thomas Burakowski, and Apryll M Stalcup) 221 Introduction 222 Separation of Enantiomers Through the Formation of Diastereomers 223 Molecular Interactions 2235 Charge Transfer 224 Mixed Types of Interaction 225 Ligand Exchange 226 Chiral Mobile Phases 227 Method Development for Chiral Separation 228 Concluding Remarks CHEMICAL AND DRUG COMPOUND INDEX SUBJECT INDEX