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Showing papers by "Eli Lilly and Company published in 2008"


Journal ArticleDOI
TL;DR: Exen atide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight.

968 citations


Journal ArticleDOI
TL;DR: The identification and characterization of human GOAT is reported, the ghrelin O-acyl transferase, the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue, and it is demonstrated the relevance of GOAT in the acylation of Ghrelin and further implicates acylated gh Relin in pancreatic function.
Abstract: The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.

778 citations


Journal ArticleDOI
TL;DR: Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
Abstract: Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of ≥ 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 µg exenatide, or 10 µg exenatide for 30 weeks, followed by 5 µg exenatide BID for 4 weeks, then 10 µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.Results: 217 patients (64% male, age 58 ± 10 years, weight 99 ± 18 kg, BMI 34 ± 5 kg/m2, A1C 8.2 ± 1.0% [mean ± SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (−1.1 ± 0.1% [mean ± SEM]) were sustained to 3 years (−1.0 ± 0.1%; p < 0.0001), with 46% ac...

738 citations


Journal ArticleDOI
TL;DR: Neither facilitation of PCI with reteplase plus abcximab nor facilitation with abciximab alone significantly improved the clinical outcomes, as compared with ab ciximabs given at the time of PCI, in patients with ST-segment elevation myocardial infarction.
Abstract: In this international, double-blind, placebo-controlled study, we randomly assigned patients with ST-segment elevation myocardial infarction who presented 6 hours or less after the onset of symptoms to receive combination-facilitated PCI, abciximabfacilitated PCI, or primary PCI. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary end point was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. Results A total of 2452 patients were randomly assigned to a treatment group. Significantly more patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; P = 0.01 and P = 0.003, respectively). The primary end point occurred in 9.8%, 10.5%, and 10.7% of the patients in the combination-facilitated PCI group, abciximab-facilitated PCI group, and primary-PCI group, respectively (P = 0.55); 90-day mortality rates were 5.2%, 5.5%, and 4.5%, respectively (P = 0.49). Conclusions Neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab alone significantly improved the clinical outcomes, as compared with abciximab given at the time of PCI, in patients with ST-segment elevation myocardial infarction. (ClinicalTrials.gov number, NCT00046228.)

616 citations


Journal ArticleDOI
TL;DR: The authors recommend experimental and statistical approaches for the validation of immunoassay performance characteristics, intended to foster a more unified approach to antibody testing across the biopharmaceutical industry.

493 citations


Journal ArticleDOI
TL;DR: Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose, and the wide interindividual variation and the induction of ketogenesis independent of F GF21 levels indicate that the physiological role of FGF 21 in humans may differ from that in mice.

472 citations


Journal ArticleDOI
TL;DR: It is demonstrated here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts and were restrained by CD200 expressed on airway epithelium, which limits inflammatory amplitude and duration during pulmonary influenza infection.
Abstract: The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts Lung macrophages were restrained by CD200 expressed on airway epithelium Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death The administration of agonists that bind CD200R, however, prevented inflammatory lung disease Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection

417 citations


Journal ArticleDOI
TL;DR: The data indicate that skeletal muscle is a source of FGF21 and that its expression is regulated by a phosphatidylinosistol 3‐kinase (PI3‐kinases)/Akt1 signaling pathway‐dependent mechanism.

375 citations


Journal ArticleDOI
TL;DR: These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size, however, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.
Abstract: Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492 900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

363 citations


Journal ArticleDOI
15 Jun 2008-Pain
TL;DR: It is demonstrated that duloxetine at doses of 60 mg/day and 120 mg/ day appears to be safe and efficacious in patients with fibromyalgia.
Abstract: The primary objectives of this study were to assess the efficacy and safety of duloxetine for reducing pain severity in fibromyalgia patients with or without current major depressive disorder. This was a 6-month, multicenter, randomized, double-blind, placebo-controlled study. In total, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20-mg/day group titrated to 60 mg/day). The co-primary outcome measures were the Brief Pain Inventory (BPI) average pain severity score and Patient Global Impressions of Improvement (PGI-I) score. Safety was assessed via treatment-emergent adverse events, and changes in vital sign, laboratory, and ECG measures. Compared with placebo-treated patients, those patients treated with duloxetine 120 mg/day improved significantly more on the co-primary outcome measures at 3 months (change in BPI score [-2.31 vs -1.39, P<0.001] and PGI-I [2.89 vs 3.39, P=0.004]) and at 6 months (change in BPI [-2.26 vs -1.43, P=0.003] and PGI-I [2.93 vs 3.37, P=0.012]). Compared with placebo, treatment with duloxetine 60 mg/day also significantly improved the co-primary measures at 3 months and BPI at 6 months. Duloxetine was efficacious in patients both with and without major depressive disorder. There were no clinically significant differences between treatment groups in changes in vital signs, laboratory measures, or ECG measures. Study results demonstrated that duloxetine at doses of 60 mg/day and 120 mg/day appears to be safe and efficacious in patients with fibromyalgia.

362 citations


Journal ArticleDOI
TL;DR: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone.

Journal ArticleDOI
TL;DR: It is envisaged that further development of silica nanoparticles will provide a variety of advanced tools for molecular biology, genomics, proteomics and medicine.
Abstract: Advanced bioanalysis, including accurate quantitation, has driven the need to understand biology and medicine at the molecular level. Bioconjugated silica nanoparticles have the potential to address this emerging challenge. Particularly intriguing diagnostic and therapeutic applications in cancer and infectious disease as well as uses in gene and drug delivery, have also been found for silica nanoparticles. In this review, we describe the synthesis, bioconjugation, and applications of silica nanoparticles in different bioanalysis formats, such as selective tagging, barcoding, and separation of a wide range of biomedically important targets. Overall, we envisage that further development of these nanoparticles will provide a variety of advanced tools for molecular biology, genomics, proteomics and medicine.

Journal ArticleDOI
TL;DR: These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD and their continued use in their original and translated forms are described.
Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD) The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD An approach to evaluating neuroimages did not meet the standards desired Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver The information that was developed in the US and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning CERAD materials and data remain available for those wishing to use them

Journal ArticleDOI
TL;DR: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies.
Abstract: Objective To evaluate the safety, tolerability, and amyloid β (Aβ) response to the γ-secretase inhibitor LY450139 in Alzheimer disease. Design Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. Setting Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. Main Outcome Measures Primary outcome measures were adverse events, plasma and cerebrospinal fluid Aβ levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. Results Group differences were seen in skin and subcutaneous tissue concerns ( P =.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event‐related discontinuations, including 1 transient bowel obstruction. The plasma Aβ 40 concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group ( P Conclusions LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Aβ concentrations were consistent with inhibition of γ-secretase. Trial Registration clinicaltrials.gov Identifier:NCT00244322

Journal ArticleDOI
TL;DR: Although this study was limited by a 2-week duration of exposure, data demonstrate that, exenatide had a greater effect than sitagliptin to lower postprandial glucose and a more potent effect to increase insulin secretion and reduce insulin secretion in T2D patients.
Abstract: Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric e...

Journal ArticleDOI
TL;DR: The conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasingABCA1 function may have a therapeutic effect on AD are supported.
Abstract: APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1–/– mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe–/– mice: there was significantly less amyloid β-peptide (Aβ) deposition, a redistribution of Aβ to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S–positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.

Journal ArticleDOI
TL;DR: Results indicate that βKlotho and FGFRs form the cognate FGF‐21 receptor complex, mediating F GF‐21 cellular specificity and physiological effects.
Abstract: Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that βKlotho is an integral part of an activated FGF-21-βKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking βKlotho did not respond to FGF-21; the introduction of βKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that βKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, βKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that βKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects. J. Cell. Physiol. 215: 1–7, 2008. © 2007 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking pr asugrel with a proton pump inhibitor such as lansoprazole.
Abstract: Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y(12) ADP receptor. In this open-label, 4-period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. C(max) and AUC(0-tlast) of prasugrel's active metabolite, R-138727, and clopidogrel's inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R-138727 AUC(0-tlast) and C(max) by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.

Journal ArticleDOI
TL;DR: IL-11 was identified as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1 and reducing STAT3 activity in gp130F/Y757F mice, normalized gastric IL-11 expression and alleviated gastric tumor burden.
Abstract: Deregulated activation of STAT3 is frequently associated with many human hematological and epithelial malignancies, including gastric cancer. While exaggerated STAT3 signaling facilitates an antiapoptotic, proangiogenic, and proproliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 hyperactivation remain poorly understood. Using the gp130(Y757F/Y757F) mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130(Y757F/Y757F) mice, when compared with unaffected gastric tissue in wild-type mice, while gp130(Y757F/Y757F) mice lacking the IL-11 ligand-binding receptor subunit (IL-11Ralpha) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130(Y757F/Y757F) mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130(Y757F/Y757F) mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1.

Journal ArticleDOI
TL;DR: The results suggest that the addition of a PCSK9 inhibitor to statin therapy may result in even further LDL-C decreases, which are currently seen in patients treated with atorvastatin.

Journal ArticleDOI
TL;DR: Both the loading dose and maintenance dose of prasugrel were superior to clopidogrel for the reduction of ischemic events in a TRITON-TIMI 38 analysis, emphasizing the importance of maintaining high levels of inhibition of platelet aggregation via P2Y(12) receptor inhibition during long-term follow-up.

Journal ArticleDOI
TL;DR: The increased susceptibility of tumor tissues to eIF4E inhibition is illustrated and support the notion that the enhanced eif4E function common to many tumor types may represent an Achilles' heel for cancer.
Abstract: The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers in relation to disease progression and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Enhanced eIF4E function results from eIF4E overexpression and/or activation of the ras and phosphatidylinositol 3-kinase/AKT pathways and selectively increases the translation of key mRNAs involved in tumor growth, angiogenesis, and cell survival. Consequently, by simultaneously and selectively reducing the expression of numerous potent growth and survival factors critical for malignancy, targeting eIF4E for inhibition may provide an attractive therapy for many different tumor types. Recent work has now shown the plausibility of therapeutically targeting eIF4E and has resulted in the advance of the first eIF4E-specific therapy to clinical trials. These studies illustrate the increased susceptibility of tumor tissues to eIF4E inhibition and support the notion that the enhanced eIF4E function common to many tumor types may represent an Achilles' heel for cancer.

Journal ArticleDOI
TL;DR: This document provides recommendations for antibody testing strategies stemming from the experience of contributing authors to foster a more unified approach to antibody testing across the biopharmaceutical industry.

Journal ArticleDOI
TL;DR: UK societal based utility values for different stages of NSCLC and different grade III-IV toxicities commonly associated with chemotherapy treatments reflects the value that society place on the avoidance of disease progression and severe toxicities in NSCLCs.
Abstract: Background Existing reports of utility values for metastatic non-small cell lung cancer (NSCLC) vary quite widely and are not all suitable for use in submissions in the UK. The aim of this study was to elicit UK societal based utility values for different stages of NSCLC and different grade III-IV toxicities commonly associated with chemotherapy treatments. Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhoea, nausea and vomiting, rash and hair loss.

Journal ArticleDOI
TL;DR: Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms.

Journal ArticleDOI
TL;DR: Direct in vitro and in vivo information is added on the capacity of the transporter protein Pgp to efflux doxorubicin and on the reversal of MDR by Pgp inhibitors in resistant cancer cells.
Abstract: P-glycoprotein (Pgp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells, and it plays a major role in causing multidrug resistance (MDR). Confocal microscopy was used to study in vitro and in vivo drug accumulation, net uptake and efflux, and MDR modulation by P-glycoprotein inhibitors in MDR1-transduced human MDA-MB-435mdr (MDR) cancer cells. The MDR cells were approximately 9-fold more resistant to the anticancer drug doxorubicin than their parental wild-type MDA-MB-435wt (WT) cells. Doxorubicin accumulation in the MDR cells was only 19% of that in the WT cells. The net uptake of doxorubicin in the nuclei of the MDR cells was 2-fold lower than that in the nuclei of the WT cells. Pgp inhibitors verapamil, cyclosporine A, or PSC833 increased doxorubicin accumulation in the MDR cells up to 79%, and it reversed drug resistance in these cells. In living animals, doxorubicin accumulation in MDA-MB-435mdr xenograft tumors was 68% of that in the wild-type tumors. Administration of verapamil, cyclosporine A, or PSC833 before doxorubicin treatment of the animals increased doxorubicin accumulation in the MDR tumors up to 94%. These studies have added direct in vitro and in vivo information on the capacity of the transporter protein Pgp to efflux doxorubicin and on the reversal of MDR by Pgp inhibitors in resistant cancer cells.

Journal ArticleDOI
TL;DR: COXs, prost anoid synthases, and prostanoid receptors should provide fruitful targets for intervention in the pharmacological treatment of renal disease.
Abstract: Cyclooxygenase-derived prostanoids exert complex and diverse functions within the kidney. The biological effect of each prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and prostanoid synthase for the synthesis of bioactive prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived prostanoids act in an autocrine or a paracrine fashion and can serve as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. Through these actions, prostanoids play important roles in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly PGI2 and PGE2, play critical roles in maintaining blood pressure and renal function in volume-contracted states. Renal medullary COX2-derived prostanoids appear to have an antihypertensive effect in individuals challenged with a high-salt diet. Loss of EP2 or IP receptor is associated with salt-sensitive hypertension. COX2 also plays a role in maintaining renal medullary interstitial cell viability in the hypertonic environment of the medulla. Cyclooxygenase-derived prostanoids also are involved in certain pathological processes. The cortical COX2-derived PGI2 participates in the pathogenesis of renal vascular hypertension through stimulating renal renin synthesis and release. COX-derived prostanoids also appear to be involved in the pathogenesis of diabetic nephropathy. COXs, prostanoid synthases, and prostanoid receptors should provide fruitful targets for intervention in the pharmacological treatment of renal disease.

Journal ArticleDOI
TL;DR: The main conclusion is that the mixed model approach is more efficient and reliable as a method of primary analysis, and should be preferred to the inherently biased and statistically invalid simple imputation approaches.
Abstract: This position paper summarizes relevant theory and current practice regarding the analysis of longitudinal clinical trials intended to support regulatory approval of medicinal products, and it reviews published research regarding methods for handling missing data. It is one strand of the PhRMA initiative to improve efficiency of late-stage clinical research and gives recommendations from a cross-industry team. We concentrate specifically on continuous response measures analyzed using a linear model, when the goal is to estimate and test treatment differences at a given time point. Traditionally, the primary analysis of such trials handled missing data by simple imputation using the last, or baseline, observation carried forward method (LOCF, BOCF) followed by analysis of (co)variance at the chosen time point. However, the general statistical and scientific community has moved away from these simple methods in favor of joint analysis of data from all time points based on a multivariate model (eg, of a mixed-effects type). One such newer method, a likelihood-based mixed-effects model repeated measures (MMRM) approach, has received considerable attention in the clinical trials literature. We discuss specific concerns raised by regulatory agencies with regard to MMRM and review published evidence comparing LOCF and MMRM in terms of validity, bias, power, and type I error. Our main conclusion is that the mixed model approach is more efficient and reliable as a method of primary analysis, and should be preferred to the inherently biased and statistically invalid simple imputation approaches. We also summarize other methods of handling missing data that are useful as sensitivity analyses for assessing the potential effect of data missing not at random.

Journal ArticleDOI
TL;DR: Exenatide slows GE substantially in type 2 diabetes, which could be an important mechanism contributing to the beneficial effect of exen atide on postprandial glycemia.

Journal ArticleDOI
TL;DR: The discovery of a small molecule modulator, LY2033298, that is highly selective for human M4 receptors by virtue of targeting an allosteric site on this receptor is described, indicating its potential use as a first-in-class, selective,allosteric muscarinic antipsychotic agent.
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.