Eli Lilly (United Kingdom)

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

OBJECTIVE: To determine the prevalence, type and treatment behaviour of women with urinary incontinence in four European countries. SUBJECTS AND METHODS: Data were collected using a postal survey which was sent to 29,500 community-dwelling women aged > or = 18 years in France, Germany, Spain and the UK. Subjects were asked about the type of urinary incontinence they had experienced and their treatment behaviour. RESULTS: Of the women who responded, 35% reported involuntary loss of urine in the preceding 30 days; stress urinary incontinence was the most prevalent type. The lowest prevalence was in Spain (23%), while the prevalence was 44%, 41% and 42% for France, Germany and the UK, respectively. About a quarter of women with urinary incontinence in Spain (24%) and the UK (25%) had consulted a doctor about it; in France (33%) and Germany (40%) the percentages were higher. Overall, <5% of the women had ever undergone surgery for their condition. While pads were used by half of the women, there were some differences among the countries. CONCLUSIONS: Millions of women in Europe have urinary incontinence; the consultation and treatment rates were low in the European countries included in this study.

Abstract At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). MONARCH 3 is a randomized, phase III, double-blind study of abemaciclib/placebo (150 mg twice daily, continuous) plus nonsteroidal AI (1 mg anastrozole or 2.5 mg letrozole, daily). A total of 493 postmenopausal women with HR+, HER2− ABC with no prior systemic therapy in this setting were enrolled. The primary endpoint was investigator-assessed PFS (final analysis after 240 events); other endpoints included response and safety evaluations. Here we analyze the final PFS data and update secondary endpoints. The abemaciclib arm had a significantly longer median PFS than the placebo arm (28.18 versus 14.76 months; hazard ratio [95% confidence interval], 0.540 [0.418–0.698]; p = .000002). The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm (measurable disease, p = .003). The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The safety profile was consistent with previous reports. The most frequent grade ≥ 3 adverse events in the abemaciclib versus placebo arms were neutropenia (23.9% versus 1.2%), diarrhea (9.5% versus 1.2%), and leukopenia (8.6% versus 0.6%). Abemaciclib plus a nonsteroidal AI was an effective initial treatment with an acceptable safety profile for HR+, HER2− ABC.

OBJECTIVE: To describe the development and validation of the Clinical Global Impression-Schizophrenia (CGI-SCH) scale, designed to assess positive, negative, depressive and cognitive symptoms in schizophrenia. METHOD: The CGI-SCH scale was adapted from the CGI scale. Concurrent validity and sensitivity to change were assessed by comparison with the Positive and Negative Symptom Severity (PANSS) and Global Assessment of Functioning (GAF) scales. To evaluate inter-rater reliability, all patients were assessed by two clinicians. RESULTS: Symptoms were assessed in 114 patients. Correlation coefficients between the CGI-SCH and the GAF and PANSS scores were high (most above 0.75), and were highest for positive and negative symptoms. Reliability was substantial (intraclass correlation coefficient, ICC > 0.70) in all but one dimension (depressive dimension, ICC = 0.64). CONCLUSION: The CGI-SCH scale is a valid, reliable instrument to evaluate severity and treatment response in schizophrenia. Given its simplicity, brevity and clinical face validity, the scale is appropriate for use in observational studies and routine clinical practice.

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.

The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

Dual and triple intracellular recordings with biocytin labelling in slices of adult neocortex explored small circuits of synaptically connected neurons. 679 paired recordings in rat and 319 in cat yielded 135 and 42 excitatory postsynaptic potentials (EPSPs) and 37 and 26 inhibitory postsynaptic potentials (IPSPs), respectively. Patterns of connectivity and synaptic properties were similar in the two species, although differences of scale and in the range of morphologies were observed. Excitatory 'forward' projections from layer 4 to 3, like those from layer 3 to 5, targeted pyramidal cells and a small proportion of interneurons, while excitatory 'back' projections from layer 3 to 4 selected interneurons, including parvalbumin immuno-positive basket cells. Layer 4 interneurons that inhibited layer 3 pyramidal cells included both basket cells and dendrite-targeting cells. Large interneurons, resembling cells previously described as large basket cells, in layers 4 and 3 (cat), with long myelinated horizontal axon collaterals received frequent excitatory inputs from both layers. A very high rate of connectivity was observed between pairs of interneurons, often with quite different morphologies, and the resultant IPSPs, like the EPSPs recorded in interneurons, were brief compared with those recorded in pyramidal and spiny stellate cells.

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. METHODS: Existing health state descriptions of metastatic breast cancer were revised to make them suitable as descriptions of metastatic NSCLC patients on second-line treatment. The existing health states were used in cognitive debrief interviews with oncologists (n = 5) and oncology specialist nurses (n = 5). Changes were made as suggested by the clinical experts. The resulting health states (n = 17) were piloted and used in a societal based valuation study (n = 100). Participants rated half of the total health states in a standard gamble interview to derive health state utility scores. Data were analysed using a mixed model analysis. RESULTS: Each health state described the symptom burden of disease and impact on different levels of functioning (physical, emotional, sexual, and social). The disutility related to each disease state and toxicity was estimated and were combined to give health state values. All disease states and toxicities were independent significant predictors of utility (p < 0.001). Stable disease with no toxicity (our base state) had a utility value of 0.653. Utility scores ranged from 0.673 (responding disease with no toxicity) to 0.473 for progressive disease. CONCLUSION: This study reflects the value that society place on the avoidance of disease progression and severe toxicities in NSCLC.

BACKGROUND: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. RESULTS: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. CONCLUSIONS: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. METHODS: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. RESULTS: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). CONCLUSIONS: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

An increasing number of failures in clinical stages of drug development have been related to the effects of candidate drugs in a sub-group of patients rather than the 'average' person. Expectation of extreme effects or lack of therapeutic effects in some subgroups following administration of similar doses requires a full understanding of the issue of variability and the importance of identifying covariates that determine the exposure to the drug candidates in each individual. In any drug development program the earlier these covariates are known the better. An important component of the drive to decrease this failure rate in drug development involves attempts to use physiologically-based pharmacokinetics 'bottom-up' modeling and simulation to optimize molecular features with respect to the absorption, distribution, metabolism and elimination (ADME) processes. The key element of this approach is the separation of information on the system (i.e. human body) from that of the drug (e.g. physicochemical characteristics determining permeability through membranes, partitioning to tissues, binding to plasma proteins or affinities toward certain enzymes and transporter proteins) and the study design (e.g. dose, route and frequency of administration, concomitant drugs and food). In this review, the classical 'top-down' approach in covariate recognition is compared with the 'bottom-up' paradigm. The determinants and sources of inter-individual variability in different stages of drug absorption, distribution, metabolism and excretion are discussed in detail. Further, the commonly known tools for simulating ADME properties are introduced.

The aim of the study was to obtain United Kingdom-based societal preferences for distinct stages of metastatic breast cancer (MBC) and six common toxicities. Health states were developed based on literature review, iterative cycles of interviews and a focus group with clinical experts. They described the burden of progressive, responding and stable disease on treatment; and also febrile neutropenia, stomatitis; diarrhoea/vomiting; fatigue; hand-foot syndrome (grade 3/4 toxicities) and hair loss. One hundred members of the general public rated them using standard gamble to determine health state utility. Data were analysed with a mixed model analysis. The study sample was a good match to the general public of England and Wales by demographics and current quality of life. Stable disease on treatment had a utility value of 0.72, with a corresponding gain of +0.07 following a treatment response and a decline by 0.27 for disease progression. Toxicities lead to declines in utility between 0.10 (diarrhoea/vomiting) and 0.15 (febrile neutropenia). This study underlines the value that society place on the avoidance of disease progression and severe side effects in MBC. This may be the largest preference study in breast cancer designed to survey a representative general public sample.

Acetylcholine (ACh) is an important neurotransmitter in the mammalian brain; it is implicated in arousal, learning, and other cognitive functions. Recent studies indicate that nicotinic receptors contribute to these cholinergic effects, in addition to the established role of muscarinic receptors. In the hippocampus, where cholinergic involvement in learning and memory is particularly well documented, alpha7 nicotinic acetylcholine receptor subunits (alpha7 nAChRs) are highly expressed, but their precise ultrastructural localization has not been determined. Here, we describe the results of immunogold labeling of serial ultrathin sections through stratum radiatum of area CA1 in the rat. Using both anti-alpha7 nAChR immunolabeling and alpha-bungarotoxin binding, we find that alpha7 nAChRs are present at nearly all synapses in CA1 stratum radiatum, with immunolabeling present at both presynaptic and postsynaptic elements. Morphological considerations and double immunolabeling indicate that GABAergic as well as glutamatergic synapses bear alpha7 nAChRs, at densities approaching those observed for glutamate receptors in CA1 stratum radiatum. Postsynaptically, alpha7 nAChRs often are distributed at dendritic spines in a perisynaptic annulus. In the postsynaptic cytoplasm, immunolabeling is associated with spine apparatus and other membranous structures, suggesting that alpha7 nAChRs may undergo dynamic regulation, with insertion into the synapse and subsequent internalization. The widespread and substantial expression of alpha7 nAChRs at synapses in the hippocampus is consistent with an important role in mediating and/or modulating synaptic transmission, plasticity, and neurodegeneration.

The microtubule-associated protein Tau plays a critical role in the pathogenesis of Alzheimer disease and several related disorders (tauopathies). In the disease Tau aggregates and becomes hyperphosphorylated forming paired helical and straight filaments, which can further condense into higher order neurofibrillary tangles in neurons. The development of this pathology is consistently associated with progressive neuronal loss and cognitive decline. The identification of tractable therapeutic targets in this pathway has been challenging, and consequently very few clinical studies addressing Tau pathology are underway. Recent active immunization studies have raised the possibility of modulating Tau pathology by activating the immune system. Here we report for the first time on passive immunotherapy for Tau in two well established transgenic models of Tau pathogenesis. We show that peripheral administration of two antibodies against pathological Tau forms significantly reduces biochemical Tau pathology in the JNPL3 mouse model. We further demonstrate that peripheral administration of the same antibodies in the more rapidly progressive P301S tauopathy model not only reduces Tau pathology quantitated by biochemical assays and immunohistochemistry, but also significantly delays the onset of motor function decline and weight loss. This is accompanied by a reduction in neurospheroids, providing direct evidence of reduced neurodegeneration. Thus, passive immunotherapy is effective at preventing the buildup of intracellular Tau pathology, neurospheroids, and associated symptoms, although the exact mechanism remains uncertain. Tau immunotherapy should therefore be considered as a therapeutic approach for the treatment of Alzheimer disease and other tauopathies.

ABSTRACT Meta-analyses conducted &amp;gt;15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.

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.