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Pfizer, Inc. /ˈfaɪzər/ is an American multinational pharmaceutical corporation headquartered in New York City, and with its research headquarters in Groton, Connecticut, United States. It is one of the world's largest pharmaceutical companies by revenues.Pfizer develops and produces medicines and vaccines for a wide range of medical disciplines, including immunology, oncology, cardiology, diabetology/endocrinology, and neurology. Pfizer's products include the blockbuster drug Lipitor , used to lower LDL blood cholesterol; Lyrica ; Diflucan , an oral antifungal medication; Zithromax , an antibiotic; Viagra ; and Celebrex/Celebra , an anti-inflammatory drug.Pfizer was founded by cousins Charles Pfizer and Charles F. Erhart in New York City in 1849 as a manufacturer of fine chemicals. Pfizer's discovery of Terramycin in 1950 put it on a path towards becoming a research-based pharmaceutical company. Pfizer has made numerous acquisitions, including Warner–Lambert in 2000, Pharmacia in 2003 and Wyeth in 2009. The Wyeth acquisition was the largest of the three at US$68 billion. Pfizer is listed on the New York Stock Exchange, and its shares have been a component of the Dow Jones Industrial Average since April 2004.In September 2009, Pfizer pleaded guilty to the illegal marketing of the arthritis drug Bextra for uses unapproved by the U.S. Food and Drug Administration , and agreed to a $2.3 billion settlement, the largest health care fraud settlement at that time. Pfizer also paid the U.S. government $1.3 billion in criminal fines related to the "off-label" marketing of Bextra, the largest monetary penalty ever rendered for any crime. Called a repeat offender by prosecutors, this was Pfizer's fourth such settlement with the U.S. Department of Justice in the previous ten years. Wikipedia.

Schindler R.J.,Pfizer
Journal of Nutrition, Health and Aging | Year: 2010

An increasing number of Alzheimer's disease (AD) clinical trials are being conducted in countries in which such trials have infrequently, if ever, been conducted. The infrastructure for conducting trials in many of these regions is not well developed, leading to particular challenges in collection of biomarkers, which are becoming increasingly important in trials in early AD. Linguistic and cultural differences make scale translation, adaptation, validation and implementation across countries and regions difficult. In addition, multiple translations and versions of scales and differences in their administration increase variability and thus decrease the chance of detecting a signal. These issues are magnified in trials in early AD, where detecting subtle neuropsychological deficits is even more challenging. Two additional significant factors for global AD research include: 1) Differing regulatory authority requirements resulting in the need for repeat studies to satisfy diverse regulatory requirements in different parts of the world; and 2) reimbursement and access may be limited due to different data requirements for country specific economic evaluations. While standardization of biochemical assays and neuroimaging protocols have recently been undertaken, there remains a pressing need for standardization of clinical measures (including translation, linguistic and cultural validation and administration). In addition, a global consensus on regulatory requirements for approval of drugs for the treatment of early AD and identification of universally accepted variables from a cost-effectiveness or value perspective would have significant impact on advancing drug development in early AD.

Gajiwala K.S.,Pfizer
Protein Science | Year: 2013

The carboxy terminal tail of epidermal growth factor receptor (EGFR) plays a critical role in the regulation of the enzyme activity of the kinase. There is a good structural model for the mechanism by which the C-terminal tail proximal to the kinase domain contributes to the negative regulation of the activity. Its conformation in the active state, conversely, has remained elusive due to its dynamic nature. A recently published structure of EGFR kinase domain shows the conformation of the proximal C-terminal tail in the active kinase. Analysis of this conformational state of the C-terminal tail is presented, and some of the mutagenesis data is revisited. © 2013 The Protein Society.

Tran D.N.,University of Cambridge | Battilocchio C.,University of Cambridge | Lou S.-B.,University of Cambridge | Hawkins J.M.,Pfizer | Ley S.V.,University of Cambridge
Chemical Science | Year: 2015

The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp2-sp3 cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO2 as the oxidant. © The Royal Society of Chemistry 2015.

Cesar-Razquin A.,Austrian Academy of Sciences | Snijder B.,Austrian Academy of Sciences | Frappier-Brinton T.,University of Toronto | Isserlin R.,University of Toronto | And 8 more authors.
Cell | Year: 2015

Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space. © 2015 Elsevier Inc.

Masseria C.,Pfizer | Krishnarajah G.,Glaxosmithkline
BMC Infectious Diseases | Year: 2015

Background: Pertussis is believed to be widely underreported and under-recognized, particularly among adults. The aim of this study was to estimate the incidence of private practitioner-attended cough illness that could be attributed to Bordetella pertussis in adults aged ≥50 years in the US. Methods: Multiple linear regressions were employed to estimate the overall incidence of pertussis. Data were extracted from IMS' private practice database of longitudinal, patient-level claims and IMS' commercial laboratory database during 4/1/2006-12/31/2010. Patients were ≥50 years old and had ≥1 ICD-9-CM claim for cough illness relating to pertussis, cough, or acute bronchitis. Pertussis positive laboratory tests, seasonal and secular variables were used for estimating the B. pertussis attributable fraction of cough illness. Results: During the study period, there were 20.7 million cases of cough illness among people aged 50-64 and 27.5 million cases among those ≥65; of which the model attributed 2.5 and 1.7 %, respectively, to B. pertussis. The estimated incidences of cough illness attributed to B. pertussis during the study period were on average 202 and 257/100,000 among people aged 50-64 and ≥65 years, respectively, and increased over the years in both age groups. Depending on the year, estimated pertussis incidences were 42 to 105 times higher than medically attended ones in the same database. Conclusions: These findings indicate that the B. pertussis disease incidence in adults aged ≥50 years is significantly higher than generally estimated. Additional research regarding pertussis reporting and diagnosis in the adult populations is needed to validate these findings. © 2015 Masseria and Krishnarajah.

Cappon G.D.,Pfizer
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2011

The earlier inclusion of children into clinical trials has challenged toxicologists to develop nonclinical strategies to support these trials early in the drug development process, and the routine practise of global development strategies (i.e., concomitant development and filing in multiple geographical regions) adds another complication. Ideally, one would like to develop a stagey that would meet regulatory requirements from all regions. This presentation illustrated the challenges faced in developing a strategy regarding the need to perform a toxicity study in juvenile animals and the design of any necessary study that will receive global regulatory agreement. © 2011 Wiley-Liss, Inc.

Fujiwara Y.,Scripps Research Institute | Dixon J.A.,Scripps Research Institute | Rodriguez R.A.,Scripps Research Institute | Baxter R.D.,Scripps Research Institute | And 4 more authors.
Journal of the American Chemical Society | Year: 2012

Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO 2CF 2H) 2, DFMS) for the innate difluoromethylation of organic substrates via a radical process. This mild, operationally simple, chemoselective, and scalable difluoromethylation method is compatible with a range of nitrogen-containing heteroarene substrates of varying complexity as well as select classes of conjugated π-systems and thiols. Regiochemical comparisons suggest that the CF 2H radical generated from the new reagent possesses nucleophilic character. © 2012 American Chemical Society.

Catterall J.B.,Duke University | Stabler T.V.,Duke University | Flannery C.R.,Pfizer | Kraus V.B.,Duke University
Arthritis Research and Therapy | Year: 2010

Introduction: Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers.Methods: We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA.Results: We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for sfC-Reactive protein (CRP) (P = 0.039), sflubricin (P = 0.008) and the proteoglycan biomarkers: sfGlycosaminoglycan (GAG) (P = 0.019), and sfAlanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: sfC-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), sfC1,2C (P = 0.039), sfC-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and sfN-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038).Conclusions: These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis.Trial registration: The samples used in this study were derived from a clinical trial NCT00332254 registered with ClinicalTrial.gov. © 2010 Catterall et al.; licensee BioMed Central Ltd.

Ghosh S.,Mapi Values | Chandran A.,Pfizer | Jansen J.P.,Mapi Values
AIDS Research and Human Retroviruses | Year: 2012

We sought to identify and summarize the incidence and prevalence of neuropathy among HIV patients and subgroups. A systematic search of the literature was performed using MEDLINE and EMBASE. The relevant literature was identified based on predefined criteria. Prevalence data were collected from cross-sectional and cohort studies. Incidence data were collected from cohort and case-control studies. Thirty-seven studies were included of which there were 23 cohort studies, 13 cross-sectional studies, and one case-control study. The prevalence of neuropathy among HIV patients derived from 25 studies varied from 1.2% to 69.4%. Regarding the development of neuropathy among HIV-positive patients, standardized by study duration, the rates per 100 person-years ranged from 0.7 to 39.7. Among older patients there is a greater risk of neuropathy. The same seems to be the case for patients with more severe disease. Currently available studies providing information on the incidence and prevalence of neuropathy among HIV patients suggest a significant burden, but there is a great variation in results across studies. There is no definitive explanation for the variation. However, it underscores the fact that complexity of the disease, along with absence of standardized diagnostic criteria, has considerably influenced the methodologies and outcomes of the studies. © Copyright 2012, Mary Ann Liebert, Inc.

Woods D.,Pfizer
Advances in Experimental Medicine and Biology | Year: 2010

Drug discovery is an iterative process with high risks and low chance of success. New genomics technologies allow veterinary medicine and agrochemical companies to validate and functionally screen new receptor-based targets, including neuropeptide G-protein coupled receptors, which were previously not amenable to high throughput screening. However this is just the first step in a long process to translate a mechanistic assay hit into a drug on the market. In addition to effectively eradicating pests on crops and parasites on their host, the molecules must also be safe, cheap to synthesise, formulatable and patentable. This is a costly process in which early attrition of unsuitable molecules is key to any successful program. Although first principle discovery is risky the ultimate benefits are considerable and future genomics resources will help to generate higher quality hits to strengthen the discovery pipeline. © 2010 Landes Bioscience and Springer Science+Business Media.

Ralph M.J.,Pfizer
Current Organic Chemistry | Year: 2011

Photochemical transformations have long been known as methods of constructing organic molecules through electronic excitationswith examples spanning all areas of organic synthesis [1, 2]. However, its application to organic heterocyclic synthesis has yet to behighlighted as a powerful alternative to thermal reactions. Heterocyclic ring systems have been extensively investigated for their biologicalactivities and new ways of constructing more unusual and complex ring systems is fast becoming a significant challenge for contemporaryorganic chemists in order to explore novel molecular space. This review includes up-to-date highlights of where organic photochemistryhas been applied to the synthesis of heterocyclic compounds and what chemistry learnings have arisen from their discovery.Current techniques of photochemistry in flow are also explored as a scalable alternative to traditional batch-wise processes and other meritsof photo-flow chemistry described. © 2011 Bentham Science Publishers Ltd.

Flannery C.R.,Pfizer
Current Drug Targets | Year: 2010

Therapeutic alleviation of the pathophysiology of osteoarthritis (OA) is a great and unmet medical challenge. At the basic science level, significant progress has facilitated the identification of distinct pathways and targets which appear to be central to the OA-associated deterioration of articular cartilage. For example, the dysregulated activities of aggrecanases such as ADAMTS-4 and ADAMTS-5, and collagenases such as MMP-13, point to strategies for the development of selective protease inhibitors to curtail OA disease progression. Likewise, blockade of disease-associated "pro-catabolic" cytokines may offer promising opportunities in this regard. Other novel biotherapeutic approaches are also emerging, including the use of recombinant lubricin molecules for intraarticular supplementation. Expression profiling of cartilage (and other joint tissues) to identify OA-associated genes continues to yield new potential therapeutic options, including the 'upstream' targeting of key intracellular regulators. Moving forward into the clinic, the critical evaluation and optimization of modalities for therapeutic delivery, as well as the availability and utility of appropriate disease biomarkers and ability to determine relevant patient populations, will be other important considerations in directing the advancement of novel OA therapies. © 2010 Bentham Science Publishers Ltd.

Fernandez-Canigia L.,Laboratorio Of Microbiologia | Dowzicky M.J.,Pfizer
Annals of Clinical Microbiology and Antimicrobials | Year: 2012

Background: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance study of antimicrobial susceptibility. This study reports data from Gram-negative isolates collected from centers in Latin America between 2004 and 2010.Methods: Consecutive bacterial isolates were tested at each center using broth microdilution methodology as described by the Clinical Laboratory Standards Institute (CLSI). Susceptibility was determined using the CLSI interpretive criteria. For tigecycline the US Federal Drug Administration (FDA) criteria were used.Results: A total of 16 232 isolates were analyzed. Susceptibility to imipenem, meropenem, and tigecycline was >95% against both non-extended-spectrum β-lactamase (ESBL) and ESBL producing Escherichia coli. Susceptibility to amikacin was also >95% for non-ESBL E. coli. 24.3% of E. coli were ESBL producers, ranging from 11.2% (58/519) in Colombia to 40.3% (31/77) in Honduras. Greater than 90% of non-ESBL Klebsiella pneumoniae were susceptible to tigecycline, carbapenems and amikacin. 35.3% of K. pneumoniae were ESBL producers, ranging from 17.2% (36/209) in Venezuela to 73.3% (55/75) in Honduras, with only imipenem and tigecycline maintaining >90% susceptibility. Greater than 90% of Klebsiella oxytoca, Enterobacter spp., and Serratia marcescens were susceptible to amikacin, carbapenems and tigecycline. The highest rates of susceptibility against Acinetobacter baumannii were seen for minocycline (89.4%) and imipenem (62.5%), while 95.8% of the A. baumannii isolates displayed an MIC ≤2 μg/mL for tigecycline.Conclusions: In this study carbapenems and tigecycline remain active against Enterobacteriaceae and A. baumannii; however, there is cause for concern with carbapenem non-susceptible isolates reported in all countries included in this study. © 2012 Fernández-Canigia and Dowzicky; licensee BioMed Central Ltd.

There is compelling clinical literature implicating a role for cytokines in the pathophysiology of major depressive disorder (MDD). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) are pleiotropic inflammatory cytokines that have been reported to be elevated in patients with MDD. The present studies were undertaken to investigate the relationship between IL-6 and IL-1β in animal models of depressive-like behavior. Analysis of brain tissue homogenates in the cortex of rats subjected to chronic stress paradigms revealed elevated levels of IL-6 protein in the absence of elevations in IL-1β. Central administration of recombinant mouse IL-6 produced depressive-like phenotypes in mice, which were not accompanied by IL-1β-induced increases in the brain tissue or IL-1β-related sickness behavior typical of a general central nervous system inflammatory response. Systemic administration of fluoxetine in the presence of centrally administered IL-6 failed to produce the expected antidepressant-like response in mice relative to sham-infused controls. Further, administration of fluoxetine to mice with endogenous overexpression of brain IL-6 (MRL/MpJ-Fas(LPR/LPR) (LPR mice)) failed to produce the expected antidepressant-like effect relative to fluoxetine-treated control mice (MRL/MpJ(+/+)). Interestingly, blockade of IL-6 trans-signaling by coadministration of a gp130/Fc monomer or an anti-mouse IL-6 antibody with IL-6 prevented the IL-6-induced increases in immobility time as well as attenuated IL-6-induced increases of protein in the cortex. Taken together, these data indicate that elevations in IL-6 may have a pathophysiological role underlying depression and more specifically resistance to current classes of antidepressant medications and suggest that modulation of the IL-6 signaling pathway may have therapeutic potential for treatment-resistant depression.

Danesi R.,University of Pisa | Boni J.P.,Pfizer | Ravaud A.,Bordeaux University Hospital Center
Cancer Treatment Reviews | Year: 2013

Identification of the role of biological pathways in metastatic renal cell carcinoma (mRCC) has led to the development of targeted agents for its treatment, in particular those that inhibit the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin (mTOR). mTOR is central to signalling pathways that regulate cellular growth, proliferation and survival, and this paper focuses on the two currently licensed mTOR inhibitors, temsirolimus and everolimus. These agents are administered via different routes (intravenously and orally, respectively), and this has an impact on their pharmacokinetics; intravenous temsirolimus is not affected by variable absorption in the gastrointestinal tract or by food intake, unlike the orally administered mTOR inhibitor everolimus. Temsirolimus is administered weekly, whereas everolimus is currently approved for daily dosing. In general, intravenous administration is likely to ensure better control of plasma drug concentrations, greater treatment adherence, and more regular monitoring of toxicity and therapeutic response, although it can be uncomfortable and inconvenient for patients. Oral administration is preferred by patients for its convenience, but can be associated with suboptimal adherence to treatment, and poor and variable bioavailability. Temsirolimus and everolimus have both been associated with improved outcomes in patients with mRCC but, as reviewed in this paper, the pharmacokinetic characteristics of these agents differ in many respects. © 2013 Elsevier Ltd.

Sonnenberg G.F.,University of Pennsylvania | Monticelli L.A.,University of Pennsylvania | Elloso M.M.,Centocor Research and Development Inc. | Fouser L.A.,Pfizer | Artis D.,University of Pennsylvania
Immunity | Year: 2011

Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that after infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4+ LTi cell responses were IL-23 dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4+ LTi cells abrogated infection-induced expression of IL-22 and antimicrobial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4+ LTi cells are a critical source of IL-22 and identify a previously unrecognized function for CD4+ LTi cells in promoting innate immunity in the intestine. © 2011 Elsevier Inc.

Chapin R.E.,Pfizer | Creasy D.M.,Huntingdon Life science
Toxicologic Pathology | Year: 2012

When test article-related testicular toxicity or Leydig cell tumors are identified in nonclinical studies, the measurement of circulating hormones such as luteinizing hormone, follicle-stimulating hormone, inhibin, testosterone, or prolactin is often considered in order to aid mechanistic investigations or to identify potential biomarkers in man. Although some hormone levels are relatively constant, others are subject to wide variability owing to pulsatility of secretion, diurnal rhythms, and stress. To avoid being misled, it is important that this variation is factored into any study design that includes hormone measurements. Since all these possibilities start from the pathologist's reading of the tissue sections, we begin with a review of the morphologic changes that are tied to underlying alterations in hormones. We then provide the reader with basic information and representative hormone data, including coefficients of variation, for the major male reproductive hormones in the three main nonclinical species (rats, dogs, and cynomolgus monkeys). Power and probability tables for rats and dogs allow estimates of the number of animals or samples needed to provide a given likelihood of detecting a hormonal change of a given size. More importantly, we highlight the variability of this process and the real value in readers developing this information at their own site. © 2012 by The Author(s).

Koehn F.E.,Pfizer
MedChemComm | Year: 2012

Natural products are an unsurpassed source of lead structures for drug discovery. However, these molecules, many of which fall into the beyond-rule-of-5 chemical space, are often difficult to optimize by chemical means because of their complex structures. Biosynthetic engineering of the producing host organism offers an important tool for the modification of complex natural products, leading to analogues which are unattainable by chemical semisynthesis. This review describes the current role of natural products in lead generation and the principles behind biosynthetic medicinal chemistry. It then goes on to describe five distinct drugs - salinosporamide, geldanamycin, FK506, rapamycin and epothilone - to exemplify how biosynthetic engineering approaches have contributed to the advancement of natural product clinical candidates. © 2012 The Royal Society of Chemistry.

Kleiman R.J.,Harvard University | Ehlers M.D.,Pfizer
Science Translational Medicine | Year: 2016

The absence of mouse pharmacokinetic reference data hinders translation. An analysis of recent literature highlights a systematic lack of discussion regarding rationalefor the selection of dosing paradigms in preclinical studies, and in particular for neuroscience studies in which the lack of brain penetration can limit target-organ exposure. We propose solutions to improve study design.

Andrews N.,Pfizer
European journal of pain (London, England) | Year: 2012

Pain influences many aspects of daily living and effective analgesics should reinstate normal spontaneous daily behaviours. Experiments are described herein which show that the innate, spontaneous behaviour of burrowing by rats, which can be simply and objectively assessed by measuring the amount of gravel left in a hollow tube 1 h after presentation to the rat, is reduced by peripheral nerve injury (tibial nerve transection (TNT), L5 spinal nerve transection (SNT) and partial sciatic nerve ligation (PSNL)) and also following inflammation induced by intra-plantar injection of Complete Freund's Adjuvant (CFA). Gabapentin (100 mg/kg sc) but not at 30 mg/kg sc significantly reduced burrowing activity in naive rats. All peripheral nerve injuries and CFA reduced burrowing compared with shams and rats naive to surgery. The level of mechanical hypersensitivity in rats with peripheral nerve injury did not correlate with the deficit in burrowing indicating that different parameters of the holistic pain experience are measured in these paradigms. Gabapentin at 30 mg/kg sc, but not 100 mg/kg sc, reversed the deficit in burrowing induced by TNT and ibuprofen (30 mg/kg sc) reversed the effect of CFA on burrowing. These experiments show that measurement of burrowing is a simple, objective assay of innate rodent behaviour affected by pain that is ethologically relevant to the rat, does not rely wholly on evoking a reflex and can dissociate a selective analgesic dose of gabapentin from one inducing motor impairment in the same animal. © 2011 European Federation of International Association for the Study of Pain Chapters.

Abraham R.T.,Pfizer
Cell Metabolism | Year: 2016

The mechanistic target of rapamycin complex 1 (mTORC1) coordinates nutrient availability with cell growth. Recent reports by Sabatini and coworkers (Saxton et al., 2016; Wolfson et al., 2016) characterize a cytoplasmic amino acid receptor that couples the binding of leucine to the activation of mTORC1. © 2016 Elsevier Inc.

To manufacture a glycoprotein, mammalian cells expressing the desired protein are often grown in fed-batch mode. Feeding an undefined, nonanimal hydrolysate helps the cells receive sufficient nutrition, but makes systems difficult to optimize. Even different lots of the same hydrolysate may have significant variability; furthermore, individual components may actually be detrimental to the cells. Switching to fully defined feeds could eliminate these issues. For monoclonal antibody (mAb) production by fed-batch NS0 cells, this article describes the replacement of a hydrolysate-based feed with a fully defined, animal-component-free feed system. The defined feed initially had 67 components, but additional experiments allowed a reduction to 25 components. The mAb titer is approximately 20% higher than in the undefined system, and the feed volume is circa 20% lower. The two systems generated antibodies with similar glycosylation profiles. Other benefits of the defined feed system include lower raw material costs, the ability to optimize key nutrient concentrations, greater confidence in raw material quality, and the elimination of potential, hydrolysate-associated endotoxin issues. © 2010 American Institute of Chemical Engineers

Clayton A.H.,University of Virginia | Ninan P.T.,Pfizer
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2010

Objective: The purpose of this review was to examine the risk of depression onset in perimenopausal and postmenopausal women, discuss the importance and rationale for screening for major depressive disorder (MDD) in women in the menopausal transition, and review therapeutic options for management of MDD in perimenopausal and postmenopausal women. Data Sources: PubMed was searched (1970 to 2008) using combinations of the following terms: major depressive disorder, perimenopause, postmenopause,mood disorder, risk factors, reproductive period, family practice, differential diagnosis, hormone, estrogen replacement therapy, reuptake inhibitors, andneurotransmitter. Study Selection: All relevant articles identified via the search terms reporting original data and published in English were considered for inclusion. Twenty-two cross-sectional and longitudinal studies were utilized to evaluate the relationship between the menopausal transition and risk of mood disorders and to formulate recommendations for screening and management of MDD in perimenopausal and postmenopausal women. Data Extraction: Research studies utilized the following measures: postal questionnaires, Women's Health Questionnaire, Beck Depression Inventory, Center for Epidemiologic Studies-Depression scale, Modified Menopause Symptom Inventory, 12-item symptom questionnaire, or Structured Clinical Interview for DSM-IV. Data Synthesis: Menopause is a normal, and for most women largely uneventful, part of life. For some women, however, the menopausal transition is a period of biologic vulnerability with noticeable physiologic, psychological, and somatic symptoms. The perimenopausal period is associated with a higher vulnerability for depression, with risk rising from early to late perimenopause and decreasing during postmenopause. Women with a history of depression are up to 5 times more likely to have a MDD diagnosis during this time period. Conclusions: Routine screening of this at-risk population followed by careful assessment for depressive symptoms can help identify the presence of MDD in the menopausal transition. Recognition of menopausal symptoms, with or without depression, is important given their potential impact on quality of life. © 2010 Physicians Postgraduate Press, Inc.

Gupta-Ostermann D.,University of Bonn | Shanmugasundaram V.,Pfizer | Bajorath J.,University of Bonn
Journal of Chemical Information and Modeling | Year: 2014

The SAR matrix data structure organizes compound data sets according to structurally analogous matching molecular series in a format reminiscent of conventional R-group tables. An intrinsic feature of SAR matrices is that they contain many virtual compounds that represent unexplored combinations of core structures and substituents extracted from compound data sets on the basis of the matched molecular pair formalism. These virtual compounds are candidates for further exploration but are difficult, if not impossible to prioritize on the basis of visual inspection of multiple SAR matrices. Therefore, we introduce herein a compound neighborhood concept as an extension of the SAR matrix data structure that makes it possible to identify preferred virtual compounds for further analysis. On the basis of well-defined compound neighborhoods, the potency of virtual compounds can be predicted by considering individual contributions of core structures and substituents from neighbors. In extensive benchmark studies, virtual compounds have been prioritized in different data sets on the basis of multiple neighborhoods yielding accurate potency predictions. © 2014 American Chemical Society.

Sakr S.,Yale University | Sakr S.,Alexandria University | Naqvi H.,Yale University | Komm B.,Pfizer | Taylor H.S.,Yale University
Endocrinology | Year: 2014

Endometriosis is a disease defined by the ectopic growth of uterine endometrium. Stem cells contribute to the generation of endometriosis as well as to repair and regeneration of normal endometrium. Here we demonstrate that the selective estrogen receptor modulator bazedoxifene (BZA), administered with conjugated estrogens (CEs), leads to regression of endometriosis lesions as well as reduction in stem cell recruitment to the lesions. Female mice underwent transplantation of male bone marrow. Endometrium was transplanted in the peritoneal cavity of half to create experimental endometriosis. Mice with or without experimental endometriosis were randomized to BZA/CE or vehicle treatment. Endometriosis lesions, bone marrow-derived mesenchymal stem cell engraftment of the lesions, and eutopic endometrium as well as ovarian stimulation were assessed. BZA treatment significantly reduced lesion size, gland number, and expression of proliferation marker proliferating cell nuclear antigen. Ovarian weight was not affected. Stem cells were recruited to the endometriosis lesions, and this recruitment was dramatically reduced by BZA/CE treatment. Stem cell engraftment was reduced in the uterus of animals with endometriosis; however the number of stem cells engrafting the uterus was completely restored by treatment with BZA/CE. Competition between endometriosis and the eutopic endometrium for a limited supply of stem cells and depletion of normal stem cells flux to the uterus is a novel mechanism by which endometriosis interferes with endometrial function and fertility. BZA/CE not only treats lesions of endometriosis, it also dramatically reduces stem cell recruitment to the lesions and restores stem cell engraftment of the uterine endometrium. Copyright © 2014 by the Endocrine Society.

PGVL Hub is an integrated molecular design desktop tool that has been developed and globally deployed throughout Pfizer discovery research units to streamline the design and synthesis of combinatorial libraries and singleton compounds. This tool supports various workflows for design of singletons, combinatorial libraries, and Markush exemplification. It also leverages the proprietary PGVL virtual space (which contains 10(14) molecules spanned by experimentally derived synthesis protocols and suitable reactants) for lead idea generation, lead hopping, and library design. There had been an intense focus on ease of use, good performance and robustness, and synergy with existing desktop tools such as ISIS/Draw and SpotFire. In this chapter we describe the three-tier enterprise software architecture, key data structures that enable a wide variety of design scenarios and workflows, major technical challenges encountered and solved, and lessons learned during its development and deployment throughout its production cycles. In addition, PGVL Hub represents an extendable and enabling platform to support future innovations in library and singleton compound design while being a proven channel to deliver those innovations to medicinal chemists on a global scale.

Guico-Pabia C.J.,Pfizer
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2010

Objective: To quantify the negative impact that major depressive disorder (MDD) has on quality of life, disability, and work, family, and overall psychosocial functioning. Available scales that assess these areas of impairment as they relate to patients with MDD are described. Data Sources: PubMed searches were conducted using the following terms: (MDD OR major depressive disorder) AND (absenteeism OR absente*); AND (quality of life OR QOL); AND (psychosocial function*); AND (presente* OR presenteeism); AND (health care cost* OR [health care] cost*); AND (health outcome*); AND (functional outcome*); AND (family life); AND (disabil* OR disability); AND (work function*); AND (unemployment OR unemploy*). The literature search was conducted in July 2008 and was restricted to English language articles. There were no limits set on the dates of the search. Study Selection: Two hundred twenty potential articles were identified. Among these studies, 48 presented primary data directly demonstrating the effect of MDD on quality of life, disability, and work, family, and overall psychosocial functioning. Data Extraction: Primary data were compiled from these studies and are summarily described. Available scales that assess quality of life, disability, and work, family, and overall psychosocial functioning are also described. Data Synthesis: MDD was found to be associated with significant disability and declines in functioning and quality of life. The Sheehan Disability Scale, the 36-item Short-Form Health Survey, and the Work Limitations Questionnaire were the most commonly used scales according to this review of the literature, but the majority of studies used direct and indirect disability measures, such as health care and other disability-related costs. Conclusions: In addition to assessing symptomatic outcomes, physicians should routinely assess their depressed patients on "real-world" outcomes. The development of a concise functional outcome measure specific to MDD is necessary for busy clinical practices. © 2010 Physicians Postgraduate Press, Inc.

Van Der Linden M.,RWTH Aachen | Reinert R.R.,Pfizer
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2010

This retrospective analysis examined the pneumococcal serotype distribution of acute otitis media in Germany from 1995 to 2007. Data from the German National Reference Centre for Streptococci included 512 cases of pneumococcal otitis media in children and adults. Infections were mainly seen in children aged <5 years, who represented 67.0% of all reported cases. Most isolates (86.7%) were from spontaneous ruptures of the tympanum; 11.1% of the isolates were from otogenic sepsis or meningitis. Serotype 19F was the leading serotype (21.5%); serotype 3 (13.9%) was also often encountered. In children aged <5 years, the 7-valent, 10-valent, and 13-valent pneumococcal conjugate vaccines covered 54.3%, 60.2%, and 84.6% of the serotypes, respectively. Reduced penicillin susceptibility (minimum inhibitory concentration ≥0.1 mg/l) was seen in 11.0% of strains; 22.4% of strains were resistant to macrolides. Although based on a very limited selection of acute otitis media isolates, this analysis provides an estimate of the pneumococcal serotypes responsible for otitis media in Germany and underscores the need for future prospective studies. © 2010 Springer-Verlag.

There is an increased emphasis on hyphenated techniques such as immunoaffinity LC/MS/MS (IA-LC/MS/MS) or IA-LC/MRM. These techniques offer competitive advantages with respect to sensitivity and selectivity over traditional LC/MS and are complementary to ligand binding assays (LBA) or ELISA's. However, these techniques are not entirely straightforward and there are several tips and tricks to routine sample analysis. We describe here our methods and procedures for how to perform online IA-LC/MS/MS including a detailed protocol for the preparation of antibody (Ab) enrichment columns. We have included sample trapping and Ab methods. Furthermore, we highlight tips, tricks, minimal and optimal approaches. This technology has been shown to be viable for several applications, species and fluids from small molecules to proteins and biomarkers to PK assays. © 2011 Elsevier Inc.

Mukherjee H.,California Institute of Technology | Martinez C.A.,Pfizer
ACS Catalysis | Year: 2011

In this work, we utilized commercial lipases (from Thermomyces lanuginosa, Rhizopus delemar, and Mucor miehei) as biocatalysts for the efficient synthesis of precursors of Β-substituted-γ-amino acids. This biocatalytic route provides a practical and efficient synthesis of a wide range of optically active compounds by accepting a number of aliphatic and aromatic 3-substituted-3-cyano-2-(ethoxycarbonyl)propanoic acid ethyl esters (2) without compromising enantioselectivity or yields. The resolution step allows for the nearly quantitative recovery of the unreacted enantiomer of R-(2) as well as the newly formed 3-substituted-3-cyano-2-(ethoxycarbonyl)propanoic acid (3) in high enantio and diastereoselectivity. The use of a facile thermal decarboxylation of (3) in aqueous solution to produce 3-substituted-3-cyanopropanoic acid ethyl esters (4) enable us to prepare a wide range of optically active precursors of Β-Substituted-γ-Amino Acids. © 2011 American Chemical Society.

Rodgers G.L.,Pfizer | Klugman K.P.,Emory University | Klugman K.P.,University of Witwatersrand
Vaccine | Year: 2011

Pneumococcal disease (PD) is the leading cause of vaccine preventable deaths in children <5 years of age worldwide, with most of the deaths occurring in the developing world. Prevention of PD in children has been achieved by vaccination with pneumococcal conjugate vaccine (PCV), the basis for which is induction of a protective antibody response against the bacterial polysaccharide capsule. Conjugation of the polysaccharide capsule to a protein carrier enables the generation of an immunologic response to the vaccine in young children, leading to protection against infection. The heptavalent PCV, which contains 7 of the 93 known pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) was the first PCV available, licensed in the US in 2000 and subsequently in many countries worldwide, including Latin American and Caribbean countries. Since its introduction, PCV7 has been documented effective for reducing invasive PD mortality and burden, as well as that of pneumonia and otitis media. Additionally, PD caused by the vaccine serotypes has decreased in the unimmunized population due to herd immunity induced by PCV7. Despite this success, significant disease burden still exists globally due to serotypes not included in PCV7. Currently there are 2 new PCVs that have been approved for use in children, a 10-valent vaccine (includes PCV7 serotypes plus serotypes 1, 5 and 7F) and a 13-valent vaccine (includes PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F and 19A). The selection of new serotypes to be included was based on importance of these serotypes as causes of PD. An additional 15-valent vaccine (includes PCV 7 serotypes plus serotypes 1, 3, 5, 6A, 7F, 19A, 22F and 33F) is undergoing clinical trial testing. In view of the 93 serotypes that are currently known, it seems clear that vaccines with greater coverage, likely based on proteins common to all serotypes, will be needed in the future. Technical and regulatory challenges to the development and approval of newer PCVs include a need for licensing criteria of common protein vaccines, establishment of correlates of protection for disease manifestations other than invasive disease, comparative efficacy data, and clinical trial testing of concomitant immunization of higher valency PCVs with other vaccines. © 2011 Elsevier Ltd.

Mayne D.,Sacred Heart Hospital | Dowzicky M.J.,Pfizer
Diagnostic Microbiology and Infectious Disease | Year: 2012

As part of the Tigecycline Evaluation and Surveillance Trial (TEST), bacterial isolates were collected consecutively from centers globally between 2004 and 2009. MICs were determined locally using Clinical and Laboratory Standards Institute broth microdilution methodology. A total of 3114 anaerobic and 99,256 aerobic isolates were included in this study. The most active agents against Gram-negative anaerobes were metronidazole and meropenem (resistance ranges 0.0-0.5% and 0.0-0.9%, respectively); piperacillin-tazobactam was also active (resistance range 0.5-9.4%). Among Gram-positive anaerobes, resistance rates were lowest for meropenem, piperacillin-tazobactam, and metronidazole (ranges 0.0-0.5%, 0.0-1.8%, and 0.0-3.2% respectively). Tigecycline MIC90 values for anaerobes ranged from 0.12 to 2 μg/mL. The most active antimicrobial agent against Gram-negative aerobes (excluding Pseudomonas aeruginosa) was tigecycline, with resistance ranging from <0.01% to 1.4%. Resistance was also low for imipenem (0.3-9.4%) and meropenem (0.7-15.1%). Extended-spectrum beta-lactamases were produced by 12.2% and 19.7% of E. coli and K. pneumoniae isolates, respectively. © 2012 Elsevier Inc.

Liska D.,Sloan Kettering Cancer Center | Chen C.-T.,Sloan Kettering Cancer Center | Bachleitner-Hofmann T.,Sloan Kettering Cancer Center | Christensen J.G.,Pfizer | Weiser M.R.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2011

Purpose: Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), is active in colorectal cancer (CRC). However, response rates range from only 10% to 20%. Here, we investigate hepatocyte growth factor (HGF)-dependent mesenchymal-epithelial transition factor (MET) activation as a mediator of cetuximab resistance through signal diversification in CRC cell lines. Experimental Design: DiFi, GEO, and LIM1215 cells were treated with varying concentrations and combinations of EGF, HGF, cetuximab, and PHA-665752 (a highly specific MET kinase inhibitor). Biological end points included proliferation, cell cycle arrest, and apoptosis. Proliferation was measured using WST-1 assays and synergy investigated via isobolograms. Expression and signaling were examined using immunoblotting. Results: EGFR and MET are coexpressed in these CRC cell lines, and dual receptor activation synergistically increased proliferation. Cetuximab inhibited cell growth by 60%-80% with an associated dephosphorylation of EGFR, MAPK, and/or AKT. Addition of HGF to cetuximab-treated cells phosphorylated MET, but not EGFR or ErbB3, restimulated the MAPK and AKT pathways, restored cell proliferation, and rescued cells from G1 arrest and apoptosis. Importantly, this effect could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating MET expression with RNAi. Conclusions: HGF-induced MET activation is a novel mechanism of cetuximab resistance in CRC. Inhibition of the HGF-MET pathway may improve response to EGFR inhibitors in CRC, and combination therapy should be further investigated. ©2010 AACR.

Missing variances, on the basis of the summary-level data, can be a problem when an inverse variance weighted meta-analysis is undertaken. A wide range of approaches in dealing with this issue exist, such as excluding data without a variance measure, using a function of sample size as a weight and imputing the missing standard errors/deviations. A non-linear mixed effects modelling approach was taken to describe the time-course of standard deviations across 14 studies. The model was then used to make predictions of the missing standard deviations, thus, enabling a precision weighted model-based meta-analysis of a mean pain endpoint over time. Maximum likelihood and Bayesian approaches were implemented with example code to illustrate how this imputation can be carried out and to compare the output from each method. The resultant imputations were nearly identical for the two approaches. This modelling approach acknowledges the fact that standard deviations are not necessarily constant over time and can differ between treatments and across studies in a predictable way. Copyright © 2012 John Wiley & Sons, Ltd.

Di L.,Pfizer
Expert Opinion on Drug Metabolism and Toxicology | Year: 2014

Introduction: Metabolism is one of the most important clearance pathways representing the major clearance route of 75% drugs. The four most common drug metabolizing enzymes (DME) that contribute significantly to elimination pathways of new chemical entities are cytochrome P450s, UDP-glucuronosyltransferases, aldehyde oxidase and sulfotransferases. Accurate prediction of human in vivo clearance by these enzymes, using both in vitro and in vivo tools, is critical for the success of drug candidates in human translation. Areas covered: Important recent advances of key DME are reviewed and highlighted in the following areas: major isoforms, tissue distribution, generic polymorphism, substrate specificity, species differences, mechanism of catalysis, in vitro-in vivo extrapolation and the importance of using optimal assay conditions and relevant animal models. Expert opinion: Understanding the clearance mechanism of a compound is the first step toward successful prediction of human clearance. It is critical to apply appropriate in vitro and in vivo methodologies and physiologically based models in human translation. While high-confidence prediction for P450-mediated clearance has been achieved, the accuracy of human clearance prediction is significantly lower for other enzyme classes. More accurate predictive methods and models are being developed to address these challenges. © Informa UK, Ltd.

Ito K.,Pfizer | Murphy D.,ADI NV INC
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

Visualization is a powerful mechanism for extracting information from data. ggplot2 is a contributed visualization package in the R programming language, which creates publication-quality statistical graphics in an efficient, elegant, and systematic manner. This article summarizes key features of the package with examples from pharmacometrics and pointers to available resources for learning ggplot2. © 2013 ASCPT.

Chronic kidney disease has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by metabolism or nonrenal transport. Guidance documents from regulatory agencies on the pharmacokinetics of drugs in patients with impaired kidney function provide a framework for facilitating study design, conduct, data analysis, and the generation of dosing recommendations. Design considerations include establishment of appropriate enrollment criteria, selection of appropriate matched control group(s), and staging of impaired kidney function by estimated glomerular filtration rate or creatinine clearance. When studies in hemodialysis patients are conducted, optimizing the timing of characterization of the pharmacokinetics profile based on the schedule of hemodialysis sessions will allow for a robust assessment in these patients. In addition to traditional noncompartmental approaches, the use of pharmacometric approaches can integrate data from multiple clinical studies and provide a quantitative rationale for dose selection in patients with impaired kidney function. This article addresses the challenges and opportunities associated with the design, conduct, analysis, and interpretation of clinical studies to allow for their future facilitation and for the establishment of safe and efficacious dosing in patients with impaired kidney function.

Cant A.A.,University of Edinburgh | Roberts L.,Pfizer | Greaney M.F.,University of Edinburgh
Chemical Communications | Year: 2010

ortho C-H activation of benzoic acids with Pd(ii) generates an oxapalladacycle that can decarboxylate to produce a palladium-associated aryne. The arynes then undergo [2+2+2] trimerisation to afford triphenylenes. © 2010 The Royal Society of Chemistry.

Bolleddula D.A.,University of Washington | Berchielli A.,Pfizer | Aliseda A.,University of Washington
Advances in Colloid and Interface Science | Year: 2010

Droplet impact has been studied for over a hundred years dating back to the pioneering work of Worthington [1]. In fact, much of his ingenuity contributed to modern day high speed photography. Over the past 40 years significant contributions in theoretical, numerical, and experimental work have been made. Droplet impact is a problem of fundamental importance due to the wealth of applications involved, namely, spray coating, spray painting, delivery of agricultural chemicals, spray cooling, inkjet printing, soil erosion due to rain drop impact, and turbine wear. Here we highlight one specific application, spray coating. Although most studies have focused their efforts on low viscosity Newtonian fluids, many industrial applications such as spray coating utilize more viscous and complex rheology liquids. Determining dominant effects and quantifying their behavior for colloidal suspensions and polymer solutions remains a challenge and thus has eluded much effort. In the last decade, it has been shown that introducing polymers to Newtonian solutions inhibits the rebounding of a drop upon impact, Bergeron et al. [2]. Furthermore Bartolo et al. [3] concluded that the normal stress component of the elongational viscosity was responsible for the rebounding inhibition of polymer based non-Newtonian solutions. We aim to uncover the drop impact dynamics of highly viscous Newtonian and complex rheology liquids used in pharmaceutical coating processes. The generation and impact of drops of mm and μm size drops of coating liquids and glycerol/water mixtures on tablet surfaces are systematically studied over a range of We ∼ O(1-300), Oh ∼ O(10- 2-1), and Re ∼ O(1-700). We extend the range of Oh to values above 1, which are not available to previous studies of droplet impacts. Outcomes reveal that splashing and rebounding are completely inhibited and the role of wettability is negligible in the early stages of impact. The maximum spreading diameter of the drop is compared with three models demonstrating reasonable agreement. © 2010 Elsevier B.V. All rights reserved.

Sapra P.,Pfizer
Expert review of clinical pharmacology | Year: 2013

Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. Here we discuss the clinical pharmacology and safety of ADCs that are either approved or in late stages of clinical development. We have taken examples of ADCs employing either DNA damaging payloads (such as calicheamicin) or tubulin depolymerizing agents (such as auristatins and maytansinoids) to discuss the impact of dose and dosage intervals on pharmacokinetics/pharmacodynamics (PK/PD) and safety of ADCs. We also discuss the development of PK/PD models that were validated using preclinical and clinical data from two approved ADCs (ado-trastuzumab emtansine (T-DM1, Kadcyla™) and brentuximab vedotin (SGN-35, Adcetris™). These models could be used to predict clinical efficacious doses of ADCs.

Wang C.,University of Liverpool | Pettman A.,Pfizer | Basca J.,University of Liverpool | Xiao J.,University of Liverpool
Angewandte Chemie - International Edition | Year: 2010

An iridium catalyst enables the reductive amination of carbonyl groups with unprecedented substrate scope, selectivity, and activity using formic acid as the hydrogen source (see scheme) The catalyst system provides significant improvement over commonly used boron hydrides. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Zhou Y.,Pfizer
Frontiers of medicine | Year: 2013

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.

Wallis R.S.,Pfizer | Wallis R.S.,Case Western Reserve University | Wallis R.S.,Rutgers University | Kim P.,National Institute of Allergy and Infectious Diseases | And 7 more authors.
The Lancet Infectious Diseases | Year: 2013

Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges. © 2013 Elsevier Ltd.

Background: The Tigecycline Evaluation and Surveillance Trial (TEST) was initiated in 2004 to chart the activity of tigecycline and comparator antimicrobial agents against gram-positive and gram-negative organisms globally. Objectives: This study aimed to provide an analysis of the antimicrobial susceptibility of gram-positive organisms collected from the 9 census regions of the United States between 2004 and 2009. Methods: The MICs and antimicrobial susceptibility were determined using Clinical and Laboratory Standards Institute methodology. For tigecycline, US Food and Drug Administration susceptibility criteria were used. Results: A total of 8782 Staphylococcus aureus isolates (54.5% methicillin-resistant S aureus) were collected, with the highest percentage of MRSA isolates collected from the South Central region (67.9%). All S aureus isolates were susceptible to tigecycline, linezolid, and vancomycin. Overall, 4.6% of Enterococcus faecalis (n = 3753) and 69.1% of Enterococcus faecium (n = 1417) isolates were vancomycin resistant, with the highest rates in the East North Central region for E faecalis (7.1%) and the South Atlantic region for E faecium (79.5%). Small numbers of linezolid nonsusceptible E faecalis (n = 13) were identified. MIC 90 values for tigecycline were ≤0.25 mg/L against E faecalis and 0.12 mg/L against E faecium. Of the Streptococcus pneumoniae isolates collected (n = 4541), 1.1% were penicillin resistant. All S pneumoniae isolates were susceptible to linezolid and vancomycin; susceptibility to tigecycline varied between 80.9% (Pacific region) and 95.2% (West North Central region). Conclusions: The rates of MRSA and vancomycin-resistant Enterococcus spp varied among the 9 census regions; however, susceptibility to linezolid, vancomycin, and tigecycline remained consistent, with low MIC 90 values and high rates of antimicrobial susceptibility. © 2011 Elsevier HS Journals, Inc.

Cucurull-Sanchez L.,Pfizer
Journal of Computer-Aided Molecular Design | Year: 2010

The results of a new method developed to identify well defined structural transformations that are key to improve a certain ADME profile are presented in this work. In particular Naïve Bayesian statistics and SciTegic FCFP-6 molecular fingerprints have been used to extract, from a dataset of 1,169 compounds with known in vitro UGT glucuronidation clearance, those changes in chemical structure that lead to a significant increase in this property. The effectiveness in achieving that goal of the thus found 55,987 transformations has been quantified and compared to classical medicinal chemistry transformations. The conclusion is that on average the new transformations found via in silico methods induce increases of UGT clearance by twofold, whilst the classical transformations are on average unable to alter that endpoint significantly in any direction. When both types of transformations are combined via substructural searches (SSS) the average twofold increase in glucuronidation is maintained. The implications of these findings for the drug design process are also discussed, in particular when compared to other methods previously described in the literature to address the question 'Which compound do I make next?' © 2010 Springer Science+Business Media B.V.

Dichter G.S.,University of North Carolina at Chapel Hill | Damiano C.A.,University of North Carolina at Chapel Hill | Allen J.A.,Pfizer
Journal of Neurodevelopmental Disorders | Year: 2012

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider pre-clinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe rewardcircuitry dysfunction, with the ultimate goal of improved intervention strategies. © 2012 Dichter et al.

Liu P.,Pfizer | Mould D.R.,Projections Research Inc.
Antimicrobial Agents and Chemotherapy | Year: 2014

To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n=176]) and safety (hepatic [n=238], visual [n=199], and psychiatric [n=183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [Cmin]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and Cmin) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479). Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Morfin-Otero R.,Hospital Civil de Guadalajara | Dowzicky M.J.,Pfizer
Clinical Therapeutics | Year: 2012

Background: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) began in 2004 to monitor global antimicrobial susceptibility to tigecycline and a range of comparator antimicrobials among gram-positive and gram-negative organisms. Objective: The aim of this study was to report changes in MIC for tigecycline and other antimicrobial agents among 10,149 . Acinetobacter baumannii isolates collected globally between 2004 and 2009. Methods: MICs of 10,149 isolates were determined locally using Clinical Laboratory and Standards Institute (CLSI) methodologies. Antimicrobial susceptibility was ascertained according to CLSI interpretive criteria (no interpretive criteria have been approved for tigecycline against . Acinetobacter spp). Results: Increases in resistance were noted for most antimicrobial agents in all regions. Significant (P < 0.05) increases in percentage resistance were reported for all antimicrobial agents globally. The smallest changes in cumulative geometric mean MICs were reported for tigecycline (0.2 mg/L) and cefepime (3.5 mg/L). MIC 90s were at the top of their testing ranges for most agents against both multidrug-resistant (MDR) and non-MDR isolates; only tigecycline showed little change in MIC 90 between MDR (2 mg/L) and non-MDR (1 mg/L) isolates. Resistance was higher among isolates from the intensive care unit (ICU) compared with non-ICU isolates. Conclusion: These findings suggest that resistance is increasing among clinical isolates of . A baumannii globally. Although resistance to tigecycline has been reported in the treatment of infections caused by . A baumannii, it retains in vitro activity against this pathogen. © 2012 Elsevier HS Journals, Inc.

Nguyen D.P.,U.S. National Institute on Aging | Nguyen D.P.,Pfizer | Lin S.-C.,U.S. National Institute on Aging
eLife | Year: 2014

Event-related potentials (ERPs) are widely used in both healthy and neuropsychiatric conditions as physiological indices of cognitive functions. Contrary to the common belief that cognitive ERPs are generated by local activity within the cerebral cortex, here we show that an attention-related ERP in the frontal cortex is correlated with, and likely generated by, subcortical inputs from the basal forebrain (BF). In rats performing an auditory oddball task, both the amplitude and timing of the frontal ERP were coupled with BF neuronal activity in single trials. The local field potentials (LFPs) associated with the frontal ERP, concentrated in deep cortical layers corresponding to the zone of BF input, were similarly coupled with BF activity and consistently triggered by BF electrical stimulation within 5-10 msec. These results highlight the important and previously unrecognized role of long-range subcortical inputs from the BF in the generation of cognitive ERPs.

Zhang X.,Pfizer | Long Q.,Emory University
Statistics in Medicine | Year: 2010

Patient accrual in clinical trials is a topic of interest for important practical reasons. It has implications in both the initial planning and ongoing monitoring of trials. Slow accrual is of particular concern when it leads to reduced sample size. Although accrual in clinical trials has been studied and its estimation has been proposed and implemented, the existing methods are usually over-simplified by assuming a constant or piecewise constant accrual rate, and more flexible and realistic methods are needed. In this paper, we discuss a principled framework to monitor and predict trial accrual. We model trial accrual using a non-homogeneous Poisson process and model the underlying time-dependent accrual rate using cubic B-splines. The statistical inference and prediction procedure for the model are studied in a Bayesian paradigm. We conduct simulation studies to investigate the performance of the proposed approach and compare with a constant accrual rate model discussed by Gajewski et al. (Statist. Med. 2008; 27: 2328-2340). With satisfactory results, we illustrate the proposed method using accrual data from a real oncology trial. Our results show that the proposed model is more robust and achieves substantially better performance compared with the existing methods. Copyright © 2010 John Wiley & Sons, Ltd.

Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected pre-clinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional set-shifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise. © 2014 Bentham Science Publishers.

Padwa A.,Emory University | Flick A.C.,Pfizer
Advances in Heterocyclic Chemistry | Year: 2013

Certain aromatic heterocycles are known to undergo Diels-Alder cycloaddition reactions despite their aromaticity and hence expected decreased reactivity. In particular, the furanyl ring system undergoes ready [4 + 2]-cycloadditions with a variety of dienophiles, such as activated alkenes, alkynes, or allenes. As highlighted in this mini-review, a growing area of interest in organic synthesis involves the use of tethered alkenyl substituted furans for the preparation of many natural products. Cascade reactions proceeding by an intramolecular Diels-Alder cycloaddition are of substantial interest to the synthetic organic community because of the increase in molecular complexity. involved and the higher isolated yields when compared to their stepwise counterparts. Central to these syntheses is the use of 2-heterosubstituted furans such as oxy- and aminofurans. The preparation of the robust 2-amido furanyl system makes use of a number of different procedures depending upon the scale and the specific furan desired. Elegant routes to a variety of alkaloid and polyoxygenated natural products have resulted from the basic methodology research on these amido-substituted furans. © 2013 Elsevier Inc.

Zhou W.,Pfizer | Christiani D.C.,Harvard University
Chinese Journal of Cancer | Year: 2011

Lung cancer is the leading cause of cancer death worldwide, with large variation of the incidence and mortality across regions. Although the mortality of lung cancer has been decreasing, or steady in the US, it has been increasing in Asia for the past two decades. Smoking is the leading cause of lung cancer, and other risk factors such as indoor coal burning, cooking fumes, and infections may play important roles in the development of lung cancer among Asian never smoking women. The median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients, particularly among never-smokers. Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced from candidate polymorphisms and genome-wide association studies. Recent epidemiologic studies and clinical trials have shown consistently that Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC), independent of smoking status. Compared with Caucasian patients with NSCLC, East Asian patients have a much higher prevalence of epidermal growth factor receptor (EGFR) mutation (approximately 30% vs. 7%, predominantly among patients with adenocarcinoma and never-smokers), a lower prevalence of K-Ras mutation (less than 10% vs. 18%, predominantly among patients with adenocarcinoma and smokers), and higher proportion of patients who are responsive to EGFR tyrosine kinase inhibitors. The ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations.

Zientek M.A.,Pfizer | Youdim K.,Hoffmann-La Roche
Drug Metabolism and Disposition | Year: 2014

During the process of drug discovery, the pharmaceutical industry is faced with numerous challenges. One challenge is the successful prediction of the major routes of human clearance of new medications. For compounds cleared by metabolism, accurate predictions help provide an early risk assessment of their potential to exhibit significant interpatient differences in pharmacokinetics via routes of metabolism catalyzed by functionally polymorphic enzymes and/or clinically significant metabolic drug-drug interactions. This review details the most recent and emerging in vitro strategies used by drug metabolism and pharmacokinetic scientists to better determine rates and routes of metabolic clearance and how to translate these parameters to estimate the amount these routes contribute to overall clearance, commonly referred to as fraction metabolized. The enzymes covered in this review include cytochrome P450s together with other enzymatic pathways whose involvement in metabolic clearance has become increasingly important as efforts to mitigate cytochrome P450 clearance are successful. Advances in the prediction of the fraction metabolized include newly developed methods to differentiate CYP3A4 from the polymorphic enzyme CYP3A5, scaling tools for UDP-glucuronosyltranferase, and estimation of fraction metabolized for substrates of aldehyde oxidase. © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Li J.D.,Pfizer
Biometrical Journal | Year: 2011

Major objectives of a clinical trial are commonly stated in a hierarchical order as primary and secondary. The parallel gatekeeping testing strategy provides an opportunity to assess secondary objectives when all or partial primary objectives are achieved. The current available gatekeeping procedures have different pros and cons so users either need to justify the assumption associated with some procedures or tolerate suboptimal power performance of other procedures. By applying the Holm test with a flexible alpha splitting technique, we propose a procedure which (1) is powerful for assessing the primary objectives, (2) can be used when no assumption can be made on the dependency structure of test statistics, and (3) has the full flexibility to allocate user-preferred alpha to assess the secondary objectives based on the number of primary objectives achieved. A real clinical trial example is used for illustration of the proposed procedure. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Frederick C.B.,Merck And Co. | Obach R.S.,Pfizer
Clinical Pharmacology and Therapeutics | Year: 2010

To address questions relating to the safety assessment of circulating drug metabolites in humans, the US Food and Drug Administration (FDA) and the International Conference on Harmonisation (ICH) have recently issued regulatory guidances1,2 that effectively require metabolite profiling in humans during early clinical development of a candidate drug. The clinical metabolite profiling results may require separate safety assessment studies in humans of stable circulating metabolites if such metabolites are not formed in sufficient concentrations in the plasma during nonclinical safety assessment of the parent drug. © 2009 American Society for clinical Pharmacology and Therapeutics.

Sonnenberg G.F.,University of Pennsylvania | Fouser L.A.,Pfizer | Artis D.,University of Pennsylvania
Advances in Immunology | Year: 2010

Expression of interleukin (IL)-22, a member of the IL-10 cytokine family, has recently been reported in a number of human diseases, including mucosal-associated infections and inflammatory disorders of the intestine, skin, and joints. Both T cells and an emerging category of innate lymphoid cells are sources of IL-22, while the IL-22 receptor complex is reported to be restricted to cells of nonhematopoietic origin. The ligand-receptor distribution of IL-22-IL-22R permits immune cells to regulate responses of epithelial cells, endothelial cells, fibroblasts, and other tissue-resident stromal cells. This pathway appears to be critically important at barrier surfaces where epithelial cells play an active role in the initiation, regulation, and resolution of immune responses. Functional studies in murine model systems indicate that IL-22 has immunoregulatory properties in infection, inflammation, autoimmunity, and cancer. In these models, the functional consequences of IL-22 expression can be either pathologic or protective, depending on the context in which it is expressed. Therefore, advancing our understanding of the biology of IL-22-IL-22R may yield novel therapeutic targets in multiple human diseases. In this review, we discuss recent findings on the expression, regulation, and function of IL-22 at barrier surfaces, and offer insights into the next frontiers to be studied in this complex cytokine pathway. © 2010 Elsevier Inc.

The use of phase appropriate technologies is critical for efficiently moving drug candidates forward in the early stages of drug discovery and development. Phase appropriate purification technology develops the analytical method and subsequently scales up the method and turns the sample around quickly (Kennedy et al., J Chromatogr A 2004; 1046:55). In this article, separation results and conditions from supercritical fluid chromatography (SFC), high-performance liquid chromatography (HPLC), and steady-state recycling (SSR) for the resolutions of three pharmaceutical intermediates in the early stage of the drug development are discussed. The first study used SFC and SSR to separate an impurity for a Good Manufacturing Practice (GMP) campaign. The analytical method development and scale-up conditions are discussed. Productivity, solvent usage, and sample solubility under SFC and SSR conditions are also compared. The second study compared SFC to batch HPLC in separating a diastereomer. Due to higher separation efficiency, SFC was able to resolute multiple peaks. The third study involved the addition of dichloromethane as a co-solvent in SFC purification--improving sample selectivity and solubility. From the separation results of these purifications, SFC and SSR are clearly phase appropriate technologies in the early drug development stage. © 2010 Wiley-Liss, Inc.

Rankin E.B.,Stanford University | Wu C.,Stanford University | Khatri R.,Harvard University | Wilson T.L.S.,Harvard University | And 9 more authors.
Cell | Year: 2012

Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment. PaperClip: © 2012 Elsevier Inc.

Ericson J.F.,Pfizer
Integrated environmental assessment and management | Year: 2014

The Organisation for Economic Co-operation and Development (OECD) 308 water-sediment transformation test has been routinely conducted in Phase II Tier A testing of the environmental risk assessment (ERA) for all human pharmaceutical marketing authorization applications in Europe, since finalization of Environmental Medicines Agency (EMA) ERA guidance in June 2006. In addition to the "Ready Biodegradation" test, it is the only transformation test for the aquatic/sediment compartment that supports the classification of the drug substance for its potential persistence in the environment and characterizes the fate of the test material in a water-sediment environment. Presented is an overview of 31 OECD 308 studies conducted by 4 companies with a focus on how pharmaceuticals behave in these water-sediment systems. The geometric mean (gm) parent total system half-life for the 31 pharmaceuticals was 30 days with 10th/90th percentile (10/90%ile) of 14.0/121.6 d respectively, with cationic substances having a half-life approximately 2 times that of neutral and anionic substances. The formation of nonextractable residues (NER) was considerable, with gm (10/90%ile) of 38% (20.5/81.4) of the applied radioactivity: cationic substances 50.8% (27.7/87.6), neutral substances 31.9% (15.3/52.3), and anionic substances 16.7% (9.5/30.6). In general, cationic substances had fewer transformation products and more unchanged parent remaining at day 100 of the study. A review of whether a simplified 1-point analysis could reasonably estimate the parent total system half-life showed that the total amount of parent remaining in the water and sediment extracts at day 100 followed first-order kinetics and that the theoretical half-life and the measured total system half-life values agreed to within a factor of 1.68. Recommendations from this 4-company collaboration addressed: 1) the need to develop a more relevant water-sediment transformation test reflecting the conditions of the discharge scenario more representative of human pharmaceuticals, 2) potential use of a 1-point estimate of parent total system half-life in the EMA ERA screening phase of testing, 3) the need for a more consistent and transparent interpretation of the results from the transformation study; consistent use of terminology such as dissipation, transformation, depletion, and degradation in describing their respective processes in the ERA, 4) use of the parent total system dissipation half-life in hazard classification schemes and in revising predicted environmental concentration in ERA, and 5) further research into cationic pharmaceuticals to assess whether their classification as such serves as a structural alert to high levels of NER; and whether this results in reduced bioavailability of those residues. © 2013 SETAC.

Background: The Tigecycline Evaluation and Surveillance Trial is an antimicrobial susceptibility surveillance program that collects gram-positive and gram-negative organisms globally. Objective: This analysis reports on antimicrobial susceptibility among 23,918 gram-negative isolates collected from intensive care units globally between 2004 and 2009. Methods: MICs and susceptibility were determined according to the guidelines of the Clinical and Laboratory Standards Institute (US Food and Drug Administration breakpoints were applied against tigecycline). Results: Gram-negative isolates were collected from 6 geographical regions: North America, 8099 isolates; Europe, 9244; Asia-Pacific Rim, 1573; Latin America, 3996; the Middle East, 635; and Africa, 371. North America reported the lowest rates of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and Escherichia coli both overall (12.8% and 4.7%, respectively) and in each year of collection. High rates of ESBL production were reported among K pneumoniae from Latin America (45.5%) and Africa (54.9%) and for E coli from the Middle East (32.4%). Imipenem and tigecycline maintained >90% susceptibility against K pneumoniae, E coli, Klebsiella oxytoca, Enterobacter cloacae, and Serratia marcescens for all regions. Susceptibility to meropenem was >90% against all K oxytoca and S marcescens. Large regional variations in susceptibility among Acinetobacter baumannii were reported, with the largest variations reported for amikacin (75.2% in North America, 21.8% in the Middle East) and meropenem (60.4% in North America, 15.9% in Africa). MIC 90 values for tigecycline against A baumannii were low (1-2 mg/L) for all regions. Against P aeruginosa, susceptibility to amikacin (97.5% in North America, 67.5% in Latin America) and meropenem (79.1% in North America, 51.4% in Africa) had the largest variations. Conclusions: Antimicrobial resistance among gram-negative intensive care unit isolates was highly variable between geographic regions. The carbapenems were active in vitro against Enterobacteriaceae, . A baumannii and . P aeruginosa, and tigecycline continued to be active in vitro against members of the Enterobacteriaceae and . A baumannii collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa. © 2012 Elsevier HS Journals, Inc.

Kitchin N.R.E.,Pfizer
Expert Review of Vaccines | Year: 2011

Diphtheria, tetanus and pertussis vaccines have formed the cornerstone of childhood immunization programs for decades. Historically, these have comprised diphtheria and tetanus toxoids combined with inactivated whole-cell pertussis. More recently, advances have been made with the development of purified acellular pertussis vaccines, with improved reactogenicity profiles, and formulation with additional vaccines such as Haemophilus influenzae type b, hepatitis B virus and inactivated poliovirus. Development is currently focused on maximizing the number of vaccines that can be combined in a single formulation and strategies to provide protection against pertussis before the commencement of routine infant immunization. © 2011 Expert Reviews Ltd.

Henderson S.,University College London | Chakravarthy A.,University College London | Su X.,University of Houston | Boshoff C.,University College London | And 2 more authors.
Cell Reports | Year: 2014

APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV- HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for thegeneration of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Ourfindings implicate APOBEC activity as a key driverof PIK3CA mutagenesis and HPV-induced transformation. © 2014 The Authors.

Jay G.W.,Pfizer
Toxicologic pathology | Year: 2011

"Animal Models of Neural Disease" was the focus of General Session 5 at a 2010 scientific symposium that was sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The objective was to consider issues that dictate the choice of animal models for neuropathology-based studies used to investigate neurological diseases and novel therapeutic agents to treat them. In some cases, no animal model exists that recapitulates the attributes of the human disease (e.g., fibromyalgia syndrome). Alternatively, numerous animal models are available for other conditions, so an essential consideration is selecting the most appropriate experimental system (e.g., Alzheimer's disease). New technologies (e.g., genetically engineered rodent models) promise the opportunity to generate suitable animal models for syndromes that currently lack any in vivo animal model, while in vitro models offer the opportunity to evaluate xenobiotic effects in specific neural cell populations. The complex nature of neurological disease requires regular reassessment of available and potential options to ensure that animal-derived data sets support translational medicine efforts to improve public health.

The identification of neurotoxicity is a critical issue in drug development, and toxicologic pathologists play an important role in this effort. Neuropathology is a specialized area of toxicologic pathology in which a substantial number of nonroutine techniques and methods have been developed, and there are undoubtedly many instances in which these specialized procedures have helped characterize a neuropathologic lesion. Routine histopathologic methods employed in general toxicologic pathology studies are needed to identify the complete range of possible neuropathologic changes; once identified, many of these changes can be better defined by specialized techniques, such as immunohistochemistry, to confirm cell types involved. Sometimes, when neurotoxicity is expected, dedicated studies can be designed a priori and optimized for detection of the anticipated effects. However, when neurotoxicity arises unexpectedly or there is uncertainty around the potential for neurotoxicity, the decision of what to do can become more difficult. Recommendations to go ahead and perform the "optimal" study design that would accommodate all the potentially useful specialized techniques for characterizing a neuropathologic change are sometimes not practical and can be unnecessary and potentially detrimental to other end points in the study. In addition, there is not always agreement on when specialized techniques would be required and which ones should be used when necessary. Two techniques in particular that are commonly recommended to help facilitate the detection of neuropathologic lesions are perfusion fixation and the Fluoro-Jade stain. © Society of Toxicologic Pathology 2011.

Jones E.P.,Imperial College London | Jones P.,Pfizer | Barrett A.G.M.,Imperial College London
Organic Letters | Year: 2011

An aryne-mediated α-arylation reaction of Schöllkopf's bis-lactim ether is described. Arynes were generated via an ortho-lithiation approach, affording syn-arylated products in up to 94:6 dr with moderate to good yields and excellent regioselectivities. Hydrolysis provided a variety of substituted arylglycines containing a range of functional groups without racemization.(Figure Presented) © 2011 American Chemical Society.

Magee T.V.,Pfizer
Bioorganic and Medicinal Chemistry Letters | Year: 2015

Abstract Protein-protein interactions (PPIs) present a formidable challenge to medicinal chemistry. The extended and open nature of many binding sites at protein interfaces has made it difficult to find useful chemical matter by traditional screening methods using standard screening libraries. This Digest focuses on the progress that has been made in discovering small-molecule modulators for a diverse selection of PPI targets using fragment screening and highlights the utility of this strategy in this context. © 2015 Elsevier Ltd.

Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ∼2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets. ©2011 AACR.

Hughes A.D.,Theravance | Jones L.H.,Pfizer
Future Medicinal Chemistry | Year: 2011

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world today. Bronchodilators, particularly muscarinic antagonists and β 2 agonists, are recommended for patients with moderate to severe COPD. Dual-pharmacology muscarinic antagonist- β 2 agonist (MABA) molecules present an exciting new approach to the treatment of COPD by combining muscarinic antagonism and β 2 agonism in a single entity. They have the potential to demonstrate additive or synergistic bronchodilation over either pharmacology alone. Due to this enticing prospect, several companies have now reported MABA discovery efforts through a conjugated/linked strategy with one candidate (GSK-961081) demonstrating clinical proof of concept. Several MABA crystal forms have been identified, satisfying the requirements for inhaled dosing devices. There are significant challenges in designing MABAs, but the potential to achieve enhanced bronchoprotection in patients and facilitate 'triple therapy' makes this an extremely important and exciting area of pharmaceutical research. © 2011 Future Science Ltd.

Zillhardt M.,University of Chicago | Christensen J.G.,Pfizer | Lengyel E.,University of Chicago
Neoplasia | Year: 2010

Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer. Copyright © 2010 Neoplasia Press, Inc. All rights reserved.

The Immunogenicity: Prediction, Detection and Effective Assay Development conference, organized by the Pharma iQ, a division of IQPC, was held in Munich, Germany, 21-â€"23 June of 2010. The meeting covered a broad range of topics related to the unwanted immunogenicity of biotherapeutics. Perspectives from the US FDA and EMA were presented along with discussions focusing on analytical method development and validation, methodologies allowing for prediction of potential immunogenicity, risk-based assessment and mitigation of immunogenic potential of biologics, and other topics. The conference consisted of a preconference workshop and 2 days of plenary sessions, which included presentations as well as group discussions. Particular attention was drawn to the review of the FDA guidance and Committee for Medicinal Products for Human Use guidelines on immunogenicity evaluation. Presenters and meeting participants engaged in an active and productive discussion around scientific aspects involved in immunogenicity evaluation and methodologies involved during routine sample testing. Discussions also centered around challenges and opportunities related to detection and characterization of immunogenicity, as well as analysis of the latest technologies to enable accurate and meaningful interpretation of the results. The meeting attracted a broad range of participants from various sized companies, backgrounds and interests. © 2010 Future Science Ltd.

Xie Z.,Pfizer
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2010

We present a new approach for quantifying the degradation of knee cartilage in the medial meniscal tear (MMT) model of osteoarthritis in the rat. A statistical strategy was used to guide the selection of a region of interest (ROI) from the images obtained from a pilot study. We hypothesize that this strategy can be used to localize a region of cartilage most vulnerable to MMT-induced damage. In order to test this hypothesis, a longitudinal study was conducted in which knee cartilage thickness in a pre-selected ROI was monitored for three weeks and comparisons were made between MMT and control rats. We observed a significant decrease in cartilage thickness in MMT rats and a significant increase in cartilage thickness in sham-operated rats as early as one week post surgery when compared to pre-surgery measurements.

Grimm C.,Pfizer
Channels (Austin, Tex.) | Year: 2011

The transient receptor potential channel TRPV1 is a polymodal nociceptor. It is primarily expressed in dorsal root ganglia and peripheral sensory nerve endings, and to a much lesser extent, in the central nervous system. It has also been implicated in the functional properties of e.g. urinary and bronchial epithelia. TRPV1 has long been under intensive investigation by the pharmaceutical industry as a candidate drug target especially for pain conditions. This review summarizes the current knowledge of the molecular determinants of TRPV1 channel activation by heat, protons and capsaicin. Newly discovered heat and proton activation sites within the pore domain are discussed as well as potential consequences for drug discovery. Polymodal TRPV1 antagonists were found to cause hyperthermia in a species-dependent manner in-vivo, hence the discovery of euthermic compounds with an appropriate modality selectivity profile will be crucial for TRPV1's future as a drug target.

Peterson M.C.,Pfizer | Riggs M.M.,Metrum Research Group LLC
CPT: Pharmacometrics and Systems Pharmacology | Year: 2012

A mathematical model component that extends an existing physiologically based multiscale systems pharmacology model (MSPM) of calcium and bone homeostasis was developed, enabling prediction of nonlinear changes in lumbar spine bone mineral density (LSBMD). Data for denosumab, a monoclonal antibody osteoporosis treatment, dosed at several levels and regimens, was used for fitting the BMD component. Bone marker and LSBMD data extracted from the literature described on/off-treatment effects of denosumab over 48 months [Miller, P.D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222?229 (2008)]. An indirect model linking bone markers to LSBMD was embedded in the existing MSPM, reasonably predicting nonlinear increases in LSBMD during treatment (24 months); LSBMD declines following discontinuation and increases upon treatment reinstitution. This study demonstrates the utility of MSPM extension to describe a phenomena of interest not originally in a model, and the ability of this updated MSPM to predict nonlinear longitudinal changes in the clinically relevant endpoint, LSBMD, with denosumab treatment. © 2012 AScpt All rights reserved.

Ogawa S.,International University of Health and Welfare | Shinohara Y.,The Mutual | Kanmuri K.,Pfizer
Circulation Journal | Year: 2011

Background: Guidelines recommend warfarin as the standard of care for patients with atrial fibrillation (AF) at moderate or high risk for stroke. This phase II study assessed the effects of 2 doses of the factor Xa inhibitor apixaban vs. warfarin in Japanese patients with non-valvular AF. The composite primary endpoint was major and clinically relevant non-major (CRNM) bleeding. Methods and Results: Two hundred and twenty-two patients with AF and 1 or more additional risk factors for stroke were randomized (1:1:1) to double-blind apixaban 2.5 or 5 mg b.i.d. or open-label warfarin (target international normalized ratio 2.0-3.0; 2.0-2.6 if age ≥70 years) for 12 weeks. The primary endpoint occurred in 1 patient (1.4%) in each apixaban group and 4 (5.3%) warfarin patients. There were no strokes, systemic emboli, myocardial infarctions, or deaths in either apixaban group. The warfarin group had 2 ischemic strokes and 1 subarachnoid hemorrhage, but there were no deaths. Major and CRNM bleeds each occurred with higher frequency in the warfarin group vs. either apixaban group. Most adverse events were mild or moderate. No patients had hepatic aminotransferase elevations greater than 3 times the upper limit of normal. Conclusions: In Japanese patients with AF, apixaban 2.5 and 5 mg b.i.d. were well tolerated over 12 weeks. A global phase III trial, which includes Japanese patients, is ongoing (ClinicalTrials.gov Identifier NCT00787150).

Sellers R.S.,Yeshiva University | Morton D.,Pfizer
Toxicologic Pathology | Year: 2014

The colon serves as the habitat for trillions of microbes, which it must maintain, regulate, and sequester. This is managed by what is termed the mucosal barrier. The mucosal barrier separates the gut flora from the host tissues; regulates the absorption of water, electrolytes, minerals, and vitamins; and facilitates host-flora interactions. Colonic homeostasis depends on a complex interaction between the microflora and the mucosal epithelium, immune system, vasculature, stroma, and nervous system. Disruptions in the colonic microenvironment such as changes in microbial composition, epithelial cell function/proliferation/differentiation, mucus production/makeup, immune function, diet, motility, or blood flow may have substantial local and systemic consequences. Understanding the complex activities of the colon in health and disease is important in drug development, as xenobiotics can impact all segments of the colon. Direct and indirect effects of pharmaceuticals on intestinal function can produce adverse findings in laboratory animals and humans and can negatively impact drug development. This review will discuss normal colon homeostasis with examples, where applicable, of xenobiotics that disrupt normal function. © 2013 by The Author(s).

Ma H.,NYU Langone Medical Center | Groth R.D.,Pfizer | Cohen S.M.,NYU Langone Medical Center | Emery J.F.,NYU Langone Medical Center | And 5 more authors.
Cell | Year: 2014

Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca2+/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, its phosphorylation at Thr287 by βCaMKII protects the Ca2+/CaM signal, and CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca2+/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders. © 2014 Elsevier Inc.

Patwa T.,Pfizer | Li C.,University of Michigan | Simeone D.M.,University of Michigan | Lubman D.M.,University of Michigan
Mass Spectrometry Reviews | Year: 2010

Protein glycosylation plays an important role in a multitude of biological processes such as cell-cell recognition, growth, differentiation, and cell death. It has been shown that specific glycosylation changes are key in disease progression and can have diagnostic value for a variety of disease types such as cancer and inflammation. The complexity of carbohydrate structures and their derivatives makes their study a real challenge. Improving the isolation, separation, and characterization of carbohydrates and their glycoproteins is a subject of increasing scientific interest. With the development of new stationary phases and molecules that have affinity properties for glycoproteins, the isolation and separation of these compounds have advanced significantly. In addition to detection with mass spectrometry, the microarray platform has become an essential tool to characterize glycan structure and to study glycosylation-related biological interactions, by using probes as a means to interrogate the spotted or captured glycosylated molecules on the arrays. Furthermore, the highthroughput and reproducible nature of microarray platforms have been highlighted by its extensive applications in the field of biomarker validation, where a large number of samples must be analyzed multiple times. This review covers a brief survey of the other experimental methodologies that are currently being developed and used to study glycosylation and emphasizes methodologies that involve the use of microarray platforms. This review describes recent advances in several options of microarray platforms used in glycoprotein analysis, including glycoprotein arrays, glycan arrays, lectin arrays, and antibody/lectin arrays. The translational use of these arrays in applications related to characterization of cells and biomarker discovery is also included. © 2010 Wiley Periodicals, Inc.

Nolan R.P.,Pfizer | Nolan R.P.,Tufts University | Lee K.,Tufts University
Metabolic Engineering | Year: 2011

Fed-batch cultures are extensively used for the production of therapeutic proteins. However, process optimization is hampered by lack of quantitative models of mammalian cellular metabolism in these cultures. This paper presents a new kinetic model of CHO cell metabolism and a novel framework for simulating the dynamics of metabolic and biosynthetic pathways of these cells grown in fed-batch culture. The model defines a subset of the intracellular reactions with kinetic rate expressions based on extracellular metabolite concentrations and temperature- and redox-dependent regulatory variables. The simulation uses the rate expressions to calculate pseudo-steady state flux distributions and extracellular metabolite concentrations at discrete time points. Experimental data collected in this study for several different CHO cell fed-batch cultures are used to derive the rate expressions, fit the parameters, and validate the model. The simulations accurately predicted the effects of process variables, including temperature shift, seed density, specific productivity, and nutrient concentrations. © 2010 Elsevier Inc.

Martinez-Finley E.J.,Vanderbilt University | Gavin C.E.,Pfizer | Aschner M.,Vanderbilt University | Gunter T.E.,University of Rochester
Free Radical Biology and Medicine | Year: 2013

Manganese (Mn) is an essential dietary nutrient, but an excess or accumulation can be toxic. Disease states, such as manganism, are associated with overexposure or accumulation of Mn and are due to the production of reactive oxygen species, free radicals, and toxic metabolites; alteration of mitochondrial function and ATP production; and depletion of cellular antioxidant defense mechanisms. This review focuses on all of the preceding mechanisms and the scientific studies that support them as well as providing an overview of the absorption, distribution, and excretion of Mn and the stability and transport of Mn compounds in the body. © 2013 Elsevier Inc. All rights reserved.

Xi H.,Pfizer
Methods in molecular biology (Clifton, N.J.) | Year: 2011

We present here a workflow for designing a kinase-targeted library (KTL) with the goal of capturing known kinase inhibitor chemical space. We validated our design retrospectively using recent, high-throughput screening data and found significant enrichment of kinase inhibitor hits while retaining majority of the active kinase inhibitor series. To further assist kinase projects in triaging KTL screen hits, we also developed a methodology to systematically annotate known kinase inhibitors in the KTL with regard to their binding modes.

Parmar D.,University of Manchester | Price K.,University of Manchester | Spain M.,University of Manchester | Matsubara H.,Osaka Prefecture University | And 2 more authors.
Journal of the American Chemical Society | Year: 2011

Lactones bearing two alkenes or an alkene and an alkyne undergo reductive cyclization cascades upon treatment with SmI2-H2O, giving decorated azulene motifs in excellent yields with good diastereocontrol. © 2011 American Chemical Society.

Glasson S.S.,Pfizer | Chambers M.G.,Eli Lilly and Company | Van Den Berg W.B.,Nijmegen Center for Molecular Life science | Little C.B.,University of Sydney
Osteoarthritis and Cartilage | Year: 2010

Aim: To describe a histologic scoring system for murine osteoarthritis (OA) that can be applied universally to instability, enzymatic, transgenic and spontaneous OA models. Methods: Scientists with expertise in assessing murine OA histopathology reviewed the merits and drawbacks of methods described in the literature. A semi-quantitative scoring system that could reasonably be employed in any basic cartilage histology laboratory was proposed. This scoring system was applied to a set of 10 images of the medial tibial plateau and femoral condyle to yield 20 scores. These images were scored twice by four experienced scorers (CL, SG, MC, TA), with a minimum time interval of 1 week between scores to obtain intra-observer variability. An additional three novice scorers (CR, CL and MM) with no previous experience evaluated the images to determine the ease of use and reproducibility across laboratories. Results: The semi-quantitative scoring system was relatively easy to apply for both experienced and novice scorers and the results had low inter- and intra-scorer variability. The variation in scores across both the experienced and novice scorers was low for both tibia and femur, with the tibia always having greater consistency. Conclusions: The semi-quantitative scoring system recommended here is simple to apply and required no specialized equipment. Scoring of the tibial plateaus was highly reproducible and more consistent than that of the femur due to the much thinner femoral cartilage. This scoring system may be a useful tool for both new and experienced scorers to sensitively evaluate models and OA mechanisms, and also provide a common paradigm for comparative evaluation across the many groups performing these analyses. © 2010 Osteoarthritis Research Society International.

Ricart A.D.,Pfizer
Clinical Pharmacology and Therapeutics | Year: 2011

The objective of immunoconjugate development is to combine the specificity of immunoglobulins with the efficacy of cytotoxic molecules. This therapeutic approach has been validated in hematologic malignancies; however, several obstacles to achieving efficacy in treating solid tumors have been identified. These include insufficient specificity of targets and poor antibody delivery, most specifically to the tumor core. Heterogeneous antigen expression, imperfect vascular supply, and elevated interstitial fluid pressure have been suggested as the factors responsible for the poor delivery of antibodies. Promising immunoconjugates are in development: immunoconjugates targeting the prostate-specific membrane antigen, trastuzumab-DM1, lorvotuzumab mertansine, and SS1P. Advances in cancer biology and antibody engineering may overcome some of the challenges. New small antibody formats, such as single-chain Fv, Fab, and diabodies, may improve penetration within tumor masses. Nevertheless, the cost of treatment might require justification in terms of demonstrable improvement in quality of life in addition to efficacy; further economic evaluation might be necessary before this approach can replace the current standards of care in clinical practice. © 2011 ASCPT.

Berry M.D.,University College London | Berry P.D.,Pfizer
Journal of Sexual Medicine | Year: 2013

Introduction: The introduction of phosphodiesterase type 5 inhibitors has revolutionized the armamentarium of clinicians in the field of sexual medicine. However, pharmacotherapy as a stand-alone treatment option has been criticized, particularly by psychosocial therapists, as incomplete. Specifically, it is widely argued that drug treatment alone often does not meet the standards of biopsychosocial (BPS) therapy. Aim: A literature review was performed to explore the role of the biopsychosocial paradigm in the treatment of sexual dysfunction and outline some of the key challenges and possible shortcomings in the current application of biopsychosocial treatment. Main Outcome Measure: Published treatment outcomes of integrative biopsychosocial clinical practice, including medical outcomes, psychological and relational factors, treatment of comorbid conditions, cost of treatment, and treatment efficacy, were investigated. Methods: Using Medline, PubMed, and EMBASE databases, a literature search for articles published from January 1, 1980, to March 1, 2013, was performed, examining current approaches to the biopsychosocial model of sexual dysfunction and sexual medicine. Data were reviewed and combined, allowing characterization of current treatment approaches and recommendations for clinical practice and future research. Results: The biopsychosocial model of treatment appears to have an intuitively obvious meaning (i.e., treatment of all three facets of the patient's biological-psychological-social condition). However, research suggests that clear treatment algorithms are still in development. By virtue of the ongoing development of biopsychosocial methods in sexual medicine, new models and research initiatives may be warranted. The evidence identified allows for characterization of some of the current clinical, professional, financial, and systemic challenges to biopsychosocial treatment, with the aim of helping identify possible directions for future research. Conclusion: Implementation of biopsychosocial treatment, though mandated by process-of-care guidelines, may be limited in the field of sexual health owing to resource limitations, limitations in physician training curricula, and structural obstacles preventing interdisciplinary collaboration. Nonetheless, a number of current treatment developments are biopsychosocially integrative, and a number of established models are biopsychosocially informed. These models and concrete strategies may provide a way forward for developing further initiatives to advance BPS treatment. © 2013 International Society for Sexual Medicine.

Dunn P.J.,Pfizer
Chemical Society Reviews | Year: 2012

Green Chemistry or Sustainable Chemistry is defined by the Environmental Protection Agency as "the design of chemical products that reduce or eliminate the use of hazardous substances" In recent years there is a greater societal expectation that chemists and chemical engineers should produce greener and more sustainable chemical processes and it is likely that this trend will continue to grow over the next few decades. This tutorial review gives information on solvents and solvent selection, basic environmental metrics collection and three industrial case histories. All three case histories involve enzymatic chemistry. Pregabalin (Lyrica®) is produced using a lipase based resolution and is extremely unusual in that all four manufacturing steps to make pregabalin are performed in water. Sitagliptin (Januvia®) uses a transaminase in the final chemical step. Finally a rosuvastatin (Crestor®) intermediate is produced using a deoxy ribose aldolase (DERA) enzyme in which two carbon-carbon bonds and two chiral centres are formed in the same process step. © 2012 The Royal Society of Chemistry.

Lenden P.,University of Oxford | Entwistle D.A.,Pfizer | Willis M.C.,University of Oxford
Angewandte Chemie - International Edition | Year: 2011

More rings for your rhodium: Rhodium-catalyzed intermolecular alkyne hydroacylations deliver γ-hydroxy-α,β-enones, which can be cyclized in situ to deliver di-and trisubstituted furans. Functionalization of the intermediates using Heck chemistry allows the formation of regioisomeric furans. The use of an alternative Rh I catalyst delivers 1,4-dicarbonyl compounds and hence pyrroles, thiophenes, and pyridazines, all from the same two starting materials. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Many children with idiopathic short stature (ISS) remain short as adults. Height can be improved permanently by growth hormone (GH) treatment, as in children with Turner syndrome or born small for gestational age. Although GH treatment for ISS is an approved indication in the United States, there is ongoing controversy in Europe about approving GH treatment for this indication as well as determining the optimal mode of treatment. In addition to data from randomized controlled trials, data from pharmacoepidemiological surveys such as the Pfizer International Growth Study Database (KIGS) have provided substantial information about the short-term and long-term effects of GH on growth and adult height in children with ISS. Based on published articles and a recent survey from KIGS on 454 patients who have reached adult height, we attempted to categorize those children with ISS who have the greatest chances of achieving a normal adult height, or at least gain the most height following GH treatment. This analysis provides a rational basis for discussion about the most efficacious and cost-effective uses of GH treatment in children with ISS. Copyright © 2011 S. Karger AG, Basel.

Pirie-Shepherd S.,Pfizer
Current Angiogenesis | Year: 2012

A new era of precision medicine is mandating that drug discovery and development in the field of oncology proceed in parallel with biomarker discovery that will allow patient populations to be stratified for response. This is of particular importance in the field of anti-angiogenic drug development. New therapeutic targets are being explored, and each new target will require a more complete understanding of the biology in order for predictive biomarkers to be identified, and validated, leading to more efficient clinical trials. This article reviews the current state of the art regarding potential biomarkers for anti-angiogenic therapy, including such biomarkers as hypertension, imaging parameters that measure blood flow in a tumor, as well as circulating growth factors and circulating endothelial cells. The limitations of these current biomarkers within the larger context of tumor vasculature heterogeneity are discussed. © 2012 Bentham Science Publishers.

Allais C.,Aix - Marseille University | Allais C.,Pfizer | Grassot J.-M.,Aix - Marseille University | Rodriguez J.,Aix - Marseille University | Constantieux T.,Aix - Marseille University
Chemical Reviews | Year: 2014

Multicomponent reactions (MCR) are very attractive because of their efficiency and simplicity, appealing for pharmaceutical companies interested in rapidly accessing new medicines. The compilation of the existent literature focuses on the pyridine ring construction and has been organized according to the main reaction involved in each process. It is interesting to note that although they have known significant developments in the past decade, most of them are based on old but well-known reactions. As early as 1980, Kambe and Saito were interested in a synthetic approach to 2-aminopyridines and thought about using malononitrile in the modified Chichibabin synthesis. A single example demonstrated that the reaction could be performed with 2- naphthol derivatives as well.

MM-GB/SA scoring and free energy perturbation (FEP) calculations have emerged as reliable methodologies to understand structural and energetic relationships to binding. In spite of successful applications to elucidate the structure-activity relationships for few pairs of ligands, the reality is that the performance of FEP calculations has rarely been tested for more than a handful of compounds. In this work, a series of 13 benzene sulfonamide inhibitors of carbonic anhydrase with binding free energies determined by isothermal titration calorimetry was selected as a test case. R2 values of 0.70, 0.71, and 0.49 with the experiment were obtained with MM-GB/SA and FEP simulations run with MCPRO+ and Desmond, respectively. All methods work well, but the results obtained with Desmond are inferior to MM-GB/SA and MCPRO+. The main contrast between the methods is the level of sampling, ranging from full to restricted flexibility to single conformation for the complexes in Desmond, MCPRO+, and MM-GB/SA, respectively. The current and historical results obtained with MM-GB/SA qualify this approach as a more attractive alternative for rank-ordering; it can achieve equivalent or superior predictive accuracy and handle more structurally dissimilar ligands at a fraction of the computational cost of the rigorous free-energy methods. As for the large theoretical dynamic range for the binding energies, that seems to be a direct result of the degree of sampling in the simulations since MCPRO+ as well as MM-GB/SA are plagued by this. Vant Hoff analysis for selected pairs of ligands suggests that the wider scoring spread is not only affected by missing entropic contributions due to restricted sampling but also exaggerated enthalpic separation between the weak and potent compounds caused by diminished shielding of electrostatic interactions, thermal effects, and protein relaxation/strain. © 2011 American Chemical Society.

Xie Z.,Pfizer
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2010

rTg4510 transgenic mouse model demonstrates features resembling Alzheimer's disease including neurofibrillary degeneration and progressive neuronal loss. We investigated the volumetric differences of brain structures between transgenic and wild-type mice using MR images of fourteen 5.5 month old female mice. Tensor-based morphometry and atlas-based segmentation were applied to MRI images. Severe atrophy of hippocampus and neocortex as well as ventricular dilatation were observed in the transgenic mice. These findings were confirmed by histopathologic evaluation of the same mice. The results suggest that MRI should be useful for evaluating disease-modifying therapies for Alzheimer's disease in the rTg4510 model and comparing treatment responses in mice and humans.

Katon W.,University of Washington | Guico-Pabia C.J.,Pfizer
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2011

Objective: To establish the need for a chronic disease management strategy for major depressive disorder (MDD), discuss the challenges involved in implementing guideline-level treatment for MDD, and provide examples of successful implementation of collaborative care programs. Data Sources: A systematic literature search of MEDLINE and the US National Library of Medicine was performed. Study Selection: We reviewed clinical studies evaluating the effectiveness of collaborative care interventions for the treatment of depression in the primary care setting using the keywords collaborative care, depression, and MDD. This review includes 45 articles relevant to MDD and collaborative care published through May 2010 and excludes all non-English-language articles. Results: Collaborative care interventions include a greater role for nonmedical specialists and a supervising psychiatrist with the major goal of improving quality of depression care in primary care systems. Collaborative care programs restructure clinical practice to include a patient care strategy with specific goals and an implementation plan, support for self-management training, sustained patient follow-up, and decision support for medication changes. Key components associated with the most effective collaborative care programs were improvement in antidepressant adherence, use of depression case managers, and regular case load supervision by a psychiatrist. Across studies, primary care patients randomized to collaborative care interventions experienced enhanced treatment outcomes compared with those randomized to usual care, with overall outcome differences approaching 30%. Conclusions: Collaborative care interventions may help to achieve successful, guideline-level treatment outcomes for primary care patients with MDD. Potential benefits of collaborative care strategies include reduced financial burden of illness, increased treatment adherence, and long-term improvement in depression symptoms and functional outcomes. © 2011 Physicians Postgraduate Press, Inc.

Epigenetic modifications to DNA and its associated histone proteins are major influences on gene expression. This regulatory process is disrupted in cancer and a range of chronic human diseases, and provides attractive new intervention points and targets for drug discovery. © 2012 The Royal Society of Chemistry.

Biomarkers play an increasingly important role for drug efficacy and safety evaluation in all stages of drug development. It is especially important to develop and validate sensitive and selective biomarkers for diseases where the onset of the disease is very slow and/or the disease progression is hard to follow, i.e., osteoarthritis (OA). The degradation of Type II collagen has been associated with the disease state of OA. Matrix metalloproteinases (MMPs) are enzymes that catalyze the degradation of collagen and therefore pursued as potential targets for the treatment of OA. Peptide biomarkers of MMP activity related to type II collagen degradation were identified and the presence of these peptides in MMP digests of human articular cartilage (HAC) explants and human urine were confirmed. An immunoaffinity LC/MS/MS assay for the quantification of the most abundant urinary type II collagen neoepitope (uTIINE) peptide, a 45-mer with 5 HO-proline residues was developed and clinically validated. The assay has subsequently been applied to analyze human urine samples from clinical studies. We have shown that the assay is able to differentiate between symptomatic OA and normal subjects, indicating that uTIINE can be used as potential biomarker for OA. This chapter discusses the assay procedure and provides information on the validation experiments used to evaluate the accuracy, precision, and selectivity data with attention to the specific challenges related to the quantification of endogenous protein/peptide biomarker analytes. The generalized approach can be used as a follow-up to studies whereby proteomics-based urinary biomarkers are identified and an assay needs to be developed. Considerations for the validation of such an assay are described.

Schwartz S.,Charite - Medical University of Berlin | Reisman A.,Pfizer | Troke P.F.,Old Court
Infection | Year: 2011

Purpose: The efficacy of voriconazole against fungal central nervous system (CNS) infections was examined retrospectively. Methods: Voriconazole-treated patients with proven (137) or probable (55) CNS infections were identified in the voriconazole database (114) and the literature (78). Investigator-determined success was a complete or partial response. Survival was calculated from the start of voriconazole therapy. Results: The patients' age range was <1-81 years (median 43) and 127 (66%) were male. Aspergillus spp. (63%) and Scedosporium spp. (18%) predominated, but 12 other genera were recorded. Underlying conditions were haematopoietic stem cell transplantation (HSCT, 35), haematologic malignancy (HM, 35), solid-organ transplantation (SOT, 25), chronic immunosuppression (CI, 40) and other conditions (OC, 57). The median voriconazole therapy duration was 93 days (range 1-1,128), with success in 93 patients (48%). Only 35 patients received primary therapy, with success in 63% versus 45% for salvage (p = 0.06 NS). Underlying conditions influenced success; HSCT 14%, HM 54%, SOT 40%, CI 45% and OC 72% (p < 0.001). Additional antifungal combination therapy (37 patients) gave a trend towards an improved response rate (p = 0.09) and superior survival (p = 0.0149), while patients receiving neurosurgical interventions (72) showed superior responses (p = 0.0174) and survival (p = 0.0399). In all, 49% of patients died, 71% (67/94) due to fungal infection. The overall median survival was 297 days (range 3 to >2,000). Paediatric (p = 0.014) and literature patients (p < 0.001) exhibited superior survival compared with adults and voriconazole database patients, respectively. Conclusions: Voriconazole shows encouraging efficacy against various CNS fungal infections. Combination therapy and/or CNS surgery may improve outcomes. © 2011 Springer-Verlag.

Benz J.P.,University of California at Berkeley | Chau B.H.,University of California at Berkeley | Chau B.H.,Pfizer | Zheng D.,University of California at Berkeley | And 3 more authors.
Molecular Microbiology | Year: 2014

Filamentous fungi are powerful producers of hydrolytic enzymes for the deconstruction of plant cell wall polysaccharides. However, the central question of how these sugars are perceived in the context of the complex cell wall matrix remains largely elusive. To address this question in a systematic fashion we performed an extensive comparative systems analysis of how the model filamentous fungus Neurospora crassa responds to the three main cell wall polysaccharides: pectin, hemicellulose and cellulose. We found the pectic response to be largely independent of the cellulolytic one with some overlap to hemicellulose, and in its extent surprisingly high, suggesting advantages for the fungus beyond being a mere carbon source. Our approach furthermore allowed us to identify carbon source-specific adaptations, such as the induction of the unfolded protein response on cellulose, and a commonly induced set of 29 genes likely involved in carbon scouting. Moreover, by hierarchical clustering we generated a coexpression matrix useful for the discovery of new components involved in polysaccharide utilization. This is exemplified by the identification of lat-1, which we demonstrate to encode for the physiologically relevant arabinose transporter in Neurospora. The analyses presented here are an important step towards understanding fungal degradation processes of complex biomass. © 2013 John Wiley & Sons Ltd.

Henry D.,Pennsylvania Hospital | Taylor C.,Pfizer
Seminars in Oncology | Year: 2014

Biologics are important treatments for a number of cancers, but they are also significant drivers of globally escalating healthcare costs. Biosimilars have the potential to offer cost-savings with comparable efficacy and safety to innovator products. They are being used in the European Union, Canada, Japan, and Australia and may help with improving health outcomes while minimizing costs to patients and global healthcare systems. The overall value of a biosimilar is not determined solely by its pricing. Efficacy and safety relative to the reference biologic drug and competitive agents as well as development and manufacturing costs, treatment administration costs, and results from long-term safety monitoring are considered. Optimizing economic efficiency is one part of an ongoing healthcare decision-making process with all therapeutics that aims to attain high levels of quality-of-care and safety given available resources. Some analytic tools stakeholders use to determine the pharmacoeconomic value of a therapy that are highlighted in this review article are opportunity cost, cost-effectiveness, and cost-minimization analyses. These methodologies can provide information to physicians, patients, and payers that may help reaffirm the value of a given biosimilar compared with its reference product throughout its life cycle. © 2014 Elsevier Inc. All rights reserved.

Owen K.,Pfizer | Owen K.,Imperial College London
Drug and Chemical Toxicology | Year: 2013

The preclinical safety studies required to support the development of inhaled drugs are generally the same as for other routes of administration. Repeat-dose toxicology studies should be conducted by inhalation to ensure the characterization of both the local (i.e., respiratory) and systemic toxicity, although some studies (e.g., reproductive) can be performed by utilizing alternative routes, when it is paramount to maximize systemic exposure. Respiratory tract changes in preclinical species can include irritancy of the larynx and nasal cavity, particularly in rodents. Such changes are not necessarily predictive of a risk to humans because of the exquisite sensitivity of the rodent larynx and the lack of exposure to the nasal cavity after oro-inhalation of drugs in the clinical setting. The design of poorly soluble molecules to limit systemic exposure places greater emphasis on the elimination of drugs from the lungs by macrophages. Consequently, an increase in macrophage numbers is often noted, and in the absence of any other changes, this is generally considered to be a nonadverse, physiological response to an inhaled particulate. Other changes in the lung, which can include an inflammatory response and/or epithelial hyperplasia, resulting from irritancy or particulate overload, are a safety concern and are not monitorable in humans. For such changes, safety margins can be calculated in terms of the drug deposited per unit weight of lung. These factors should be taken into account when designing preclinical studies or programs for inhaled drugs. © 2013 Informa Healthcare USA, Inc.

The European Medicines Agency guideline for the environmental risk assessment of medicinal products provides a step-bystep phased approach to evaluate the potential risks of new medicines to the environment. Phase I ("prescreen") estimates the initial exposure of the new medicine in the environment. Phase II A ("screen") estimates the fate and effects in the environment. The fate screen determines the inherent properties of the new medicinal active ingredient to sorb to sludge, soil, and sediment matrices and its potential to degrade in a sewage treatment plant and in the subsequent water-sediment compartment. Current ERA Guidance (2006) recommends the OECD 301B Ready Biodegradation Test for Phase II Tier A testing without a clear recommendation for Phase II Tier B testing when further refinement may be needed. With the recent approval of the OECD 314B method for activated sludge, there is now an alternative test method that may be better suited for Phase II Tier A testing and to the data needs of the ERA. As a batch test, it fits the needs of a Tier A screen. It is not designed to simulate the operational steps of a sewage treatment plant, such as the OECD 303 tests, and yet provides the following without considerable costs or resources of OECD 303: (1) useful kinetic information in a test that reflects the conditions of the sewage-treatment environment, i.e., realistic biomass solids concentrations and low level test material concentrations to simulate first-order (nongrowth) kinetics, (2) mass balance analysis for CO2 evolution and for residues found in mixed liquor, (3) use of an abiotic control to assess losses other than those attributed to biotic biodegradation,and(4) biotransformation profile of degradants. This paper presents the results of OECD 301B with that of OECD 314B for activated sludge biodegradation for five Pfizer drug substances. The use of this new method as an alternative to OECD 301B would strengthen the fate testing screen in Phase II Tier A of the EMEA ERA. It would provide a characterization of a substance's potential for biotransformation and mineralization duringsewagetreatment and provide a means for revising predicted environmental concentration of surface water for amount removed during sewage treatment. © 2010 American Chemical Society.

Mao Y.,Florida State University | Valeja S.G.,Florida State University | Rouse J.C.,Pfizer | Hendrickson C.L.,Florida State University | Marshall A.G.,Florida State University
Analytical Chemistry | Year: 2013

Top-down electron capture dissociation (ECD) Fourier transform ion cyclotron resonance (FTICR) mass spectrometry was performed for structural analysis of an intact monoclonal antibody (IgG1kappa (κ) isotype, ∼148 kDa). Simultaneous ECD for all charge states (42+ to 58+) generates more extensive cleavages than ECD for an isolated single charge state. The cleavages are mainly localized in the variable domains of both heavy and light chains, the respective regions between the variable and constant domains in both chains, the region between heavy-chain constant domains CH2 and C H3, and the disulfide bond (S-S)-linked heavy-chain constant domain CH3. The light chain yields mainly N-terminal fragment ions due to the protection of the interchain disulfide bond between light and heavy chain, and limited cleavage sites are observed in the variable domains for each chain, where the S-S spans the polypeptide backbone. Only a few cleavages in the S-S-linked light-chain constant domain, hinge region, and heavy-chain constant domains CH1 and CH2 are observed, leaving glycosylation uncharacterized. Top-down ECD with a custom-built 9.4 T FTICR mass spectrometer provides more extensive sequence coverage for structural characterization of IgG1κ than does top-down collision-induced dissociation (CID) and electron transfer dissociation (ETD) with hybrid quadrupole time-of-flight instruments and comparable sequence coverage for top-down ETD with orbitrap mass analyzers. © 2013 American Chemical Society.

Zhang X.,Pfizer | Long Q.,Emory University
Clinical Trials | Year: 2012

Background Modeling and prediction of subject accrual and event times in clinical trials has been a topic of considerable interest for important practical reasons. It has implications not only at the initial planning stage of a trial but also on its ongoing monitoring. Purpose To provide a systematic view of the recent research in the field of modeling and prediction of subject accrual and event times in clinical trials. Methods Two classes of methods for modeling and prediction of subject accrual are reviewed, namely, one that uses the Brownian motion and the other uses the Poisson process. Extensions of the accrual models in multicenter clinical trials are also discussed. Trials with survival endpoints require proper joint modeling of subject accrual and event/lost-to-follow-up (LTFU) times, the latter of which can be modeled either parametrically (e.g., exponential and Weibull) or nonparametrically. Results Flexible stochastic models are better suited when modeling real trials that does not follow constant underlying enrollment rate. The accrual model generally improves as center-specific information is accounted for in multicenter trials. The choice between parametric and nonparametric event models can depend on confidence on the underlying event rates. Limitations All methods reviewed in event modeling assume noninformative censoring, which cannot be tested. Conclusions We recommend using proper stochastic accrual models, in combination with flexible event time models when applicable, for modeling and prediction of subject enrollment and event times in clinical trials. © The Author(s), 2012.

O'Hara D.M.,Pfizer
Bioanalysis | Year: 2013

Bioanalytical laboratories develop and validate ligand-binding assays (LBA) used to quantify the concentration of analytes of interest in various buffers and relevant biological matrices. The building blocks of LBA are reagents that recognize molecular and structural motifs on ligands, which are combined in various LBA formats to minimize biological matrix interferences and specifically detect and quantify the analyte of interest. The use of these LBA-requiring critical reagents, can span decades as programs mature to commercialization. Since critical reagents are generated mostly from biological systems, attention to their life cycle management, quality, characterization and sustainability are vital to the success of bioanalytical laboratories. Integrating de novo reagent generation, reagent biophysical characterization, LBA development, validation, and use, with reagent resupply processes leverages interdisciplinary activities and ensures smooth operations of a bioanalytical laboratory.

Beal D.M.,University of Kent | Jones L.H.,Pfizer
Angewandte Chemie - International Edition | Year: 2012

Heteromultifunctional scaffolds that harness sequential "click" reactions will find significant utility in the areas of chemical biology and chemically enabled/enhanced biotherapeutics ("chemologics"). Here we review the existing synthetic technologies that illustrate the considerable potential of the field. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Most assays used to monitor enzymatic activities can be considered detection-coupled assays (i.e., indirect measurement of an analyte by using another chemical reaction for detection). The major reason for this is that the analyte that indicates the activity of the reaction cannot be directly measured or specifically directly measured by conventional means, such as optical density, fluorescence, and so on. By coupling another reaction to the enzymatic reaction of interest, the activity of the reaction can be monitored without modification to the analyte itself. However, due to the additional coupling reaction between the analyte and the detection reagents, the dynamic range of the assay could be greatly limited by the coupling reaction, and the apparent parameters of the enzymatic reaction could be much different from its uncoupled counterpart, causing significant deviations for IC50 measurement for an inhibition reaction of the enzyme. By using exact solutions for both the enzymatic and the coupling reactions, the effects of the coupling reaction on the dynamic range and accuracy of the IC50 measurement are reviewed and evaluated. In addition, real examples are provided to further illustrate the problem and validate the analysis. © 2010 Society for Biomolecular Sciences.

Battilocchio C.,University of Cambridge | Hawkins J.M.,Pfizer | Ley S.V.,University of Cambridge
Organic Letters | Year: 2013

A flow chemistry Meerwein-Ponndorf-Verley (MPV) reduction procedure using partially hydrated zirconium oxide via a machine-assisted approach is reported. The heterogeneous reductive system could be applied to a wide range of functionalized substrates, allowing clean and fast delivery of the alcohol products within a few minutes (6-75 min). In three examples the system was scaled to deliver 50 mmol of product. © 2013 American Chemical Society.

Bruder M.C.,Pfizer
Toxicologic pathology | Year: 2010

Anomalies of renal development comprise abnormalities in the amount of renal tissue (agenesis and hypoplasia); anomalies of renal position, form, and orientation; and renal dysplasia. There are previous reports of canine renal dysplasia in different breeds but none in the Beagle breed. This is the first report of renal dysplasia in this breed of dog. Morphologic descriptions of the range of microscopic features observed in four cases of renal dysplasia from preclinical studies in laboratory Beagle dogs are presented (including persistent primitive mesenchyme, persistence of metanephric ducts, asynchronous differentiation of nephrons, and atypical tubular epithelium), along with a basis for the classification of the lesion.

After the regulatory approval has been obtained, epidemiological studies are acknowledged scientific medical research methods for a new drug which provide additional knowledge about routine application of the drug in clinical daily routine. These studies are performed according to the recommendations of both international and national expert associations, the recommendations of the higher federal authorities in Germany and according to the recommendations of the associations of the pharmaceutical industry. Two surveys among the member companies of the Association of Research-based Pharmaceutical Companies investigated the status of the implementation of the recommendations in the years 2008 and 2010 and compared the results with each other. It could be shown that these recommendations were implemented successfully and were fully adhered to during the conduct of non-interventional studies in Germany. The recommendations define a quality standard which justifies a high level of confidence in the validity of the data collected and the results from these investigations.

Alebic-Kolbah T.,Pfizer | Modesitt M.S.,PPD Inc
Analytical and Bioanalytical Chemistry | Year: 2012

Anidulafungin is a semi-synthetic echinocandin with antifungal activity, usually administered as an intravenous infusion. In order to determine the pharmacokinetics (PK) of anidulafungin in pediatric patients, a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) bioanalytical method (M1) was developed and validated for quantification of anidulafungin in plasma. During analysis of incurred samples (samples collected from patients enrolled in a clinical study) an isobaric chromatographic interference was observed. The source of interferencewas identified as an anidulafungin open-ring form (D1) and its impact on the quantification of anidulafungin was investigated. It was found that accurately quantifying anidulafungin in incurred samples required chromatographic separation of the open-ring form from anidulafungin. The method was redeveloped to achieve the appropriate baseline separation and to avoid experimental conditions that favored opening the anidulafungin ring. The extraction of anidulafungin from plasma by protein precipitation remained unchanged, but the changes in chromatography warranted validation of a new method,M2, 2 years afterM1 was validated. Incurred samples from three studies that were previously analyzed by M1 and were within confirmed long-term frozen stability were then reanalyzed by M2. Although the incurred sample reproducibility tests on those samples passed for each of the two methods, comparison of concentrations from the same samples obtained by M1 and M2 revealed that an overestimation of anidulafungin following the M1 method exceeded acceptance criteria. The new HPLC-MS/MS method (M2) is applicable for quantification of anidulafungin within a nominal range 50-20,000 ng/mL and requires a 50 μL human plasma aliquot. A linear, 1/concentration squared weighted, leastsquares regression algorithm was used to generate the calibration curve and its parameters were used to quantitate the incurred samples. The inter-assay accuracy in heparin human plasma validation ranged from -4.33 to 0.0386 % and precision was ≤7.32 %. The method M2 was validated for use in regulated bioanalysis and is presently used to quantitate anidulafungin in plasma samples from clinical studies. © Springer-Verlag 2012.

Patti G.J.,University of Washington | Yanes O.,Scripps Research Institute | Yanes O.,Rovira i Virgili University | Shriver L.P.,University of California at San Diego | And 5 more authors.
Nature Chemical Biology | Year: 2012

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its chemical basis. We show by using untargeted metabolomics that sphingomyelin-ceramide metabolism is altered in the dorsal horn of rats with neuropathic pain and that the upregulated, endogenous metabolite N,N-dimethylsphingosine induces mechanical hypersensitivity in vivo. These results demonstrate the utility of metabolomics to implicate unexplored biochemical pathways in disease.

McDermott U.,Harvard University | Pusapati R.V.,Harvard University | Christensen J.G.,Pfizer | Gray N.S.,Dana-Farber Cancer Institute | Settleman J.,Harvard University
Cancer Research | Year: 2010

Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non-small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones. ©2010 AACR.

Smith D.A.,University of Liverpool | Dalvie D.,Pfizer
Xenobiotica | Year: 2012

The aim of most metabolism and excretion processes is to remove the drug and drug related material from the body; however, in most cases metabolites are present in abundance in circulation. To allow better in vitro/in vivo correlations a greater understanding of why metabolites formed in organs such as the liver are present in the circulation is necessary. Separating metabolites into highly lipid permeable and low lipid permeable allows the role of passive efflux from the liver and active transport to be dissected. Many drugs form glucuronide metabolites that circulate at high total concentrations and attention is drawn to low lipid permeability, efflux from the liver by MRP3, high plasma protein binding and restricted distribution as the explanation for this. The use of metabolite maps is suggested as a way of displaying complex processes in a simple form. © 2012 Informa UK, Ltd.

Richardson P.F.,Pfizer
Annual Reports in Medicinal Chemistry | Year: 2012

Narrow therapeutic index and side effects continue to be a hurdle for pharmacotherapy of cancer. Advances in our knowledge of molecular biology of cancer and pathways involved in malignant transformation of cells are revolutionizing the approach to cancer treatment in terms of the molecules employed. However, targeted drug delivery to tumor tissues remains an elusive challenge, and nanotechnology has been promoted as a promising solution to address this. Several nanoparticulate therapeutics are approved for use (e.g., Abraxane, Doxil), for cancer treatment, and have been on the market for some time. This chapter is intended to survey (i) the advantages that these therapeutics have over conventional therapeutics, (ii) the current development of new improved nanoparticulate therapeutics for cancer, and (iii) an overview of emerging technologies for the development of tumor-targeted nanomedicines. © 2012 Elsevier Inc.

Basu R.,University of Alabama at Birmingham | O'Quinn D.B.,University of Alabama at Birmingham | Silberger D.J.,University of Alabama at Birmingham | Schoeb T.R.,University of Alabama at Birmingham | And 4 more authors.
Immunity | Year: 2012

Interleukin-22 (IL-22) is central to host protection against bacterial infections at barrier sites. Both innate lymphoid cells (ILCs) and T cells produce IL-22. However, the specific contributions of CD4+ T cells and their developmental origins are unclear. We found that the enteric pathogen Citrobacter rodentium induced sequential waves of IL-22-producing ILCs and CD4+ T cells that were each critical to host defense during a primary infection. Whereas IL-22 production by ILCs was strictly IL-23 dependent, development of IL-22-producing CD4+ T cells occurred via an IL-6-dependent mechanism that was augmented by, but not dependent on, IL-23 and was dependent on both transcription factors T-bet and AhR. Transfer of CD4+ T cells differentiated with IL-6 in the absence of TGF-β (" Th22" cells) conferred complete protection of infected IL-22-deficient mice whereas transferred Th17 cells did not. These findings establish Th22 cells as an important component of mucosal antimicrobial host defense. © 2012 Elsevier Inc.

Selsby J.,Iowa State University | Morris C.,Pfizer
PLoS Currents | Year: 2012

Dystrophin deficiency leads to increased proteasome activity in skeletal muscle. Previous observations suggest short-term inhibition of the proteasome restores dystrophin expression. Contrary to our hypothesis, eight days of MG-132 administration to mdx mice increased susceptibility to contraction induced injury and Evan's blue dye penetration compared to controls. Following six weeks of MG-132 administration muscle function was similar to control animals. These data suggest that proteasome inhibition does not reduce the severity of muscle dysfunction caused by dystrophin-deficiency.

Villarino N.,University of Tennessee at Knoxville | Brown S.A.,Pfizer | Martin-Jimenez T.,University of Tennessee at Knoxville
Antimicrobial Agents and Chemotherapy | Year: 2012

Tulathromycin represents the first member of a novel subclass of macrolides, known as triamilides, approved to treat bovine and swine respiratory disease. The objectives of the present study were to assess the concentration-versus-time profile of tulathromycin in the plasma and lung tissue of healthy and neutropenic mice challenged intranasally with lipopolysaccharide (LPS) from Escherichia coli O111:B4. BALB/c mice were randomly allocated into four groups of 40 mice each: groups T-28 (tulathromycin at 28 mg/kg of body weight), T-7, T7-LPS, and T7-LPS-CP (cyclophosphamide). Mice in group T-28 were treated with tulathromycin at 28 mg/kg subcutaneously (s.c.) (time 0 h). The rest of the mice were treated with tulathromycin at 7 mg/kg s.c. (time 0 h). Animals in dose groups T-7-LPS and T7-LPS-CP received a single dose of E. coli LPS intranasally at -7 h. Mice in group T7-LPS-CP were also rendered neutropenic with cyclophosphamide (150 mg/kg intraperitoneally) prior to the administration of tulathromycin. Blood and lung tissue samples were obtained from 5 mice from each dose group at each sampling time over 144 h after the administration of tulathromycin. There were not statistical differences in lung tissue concentrations among groups T-7, T-7-LPS, and T7-LPS-CP. For all dose groups, the distribution of tulathromycin in the lungs was rapid and persisted at relatively high levels during 6 days postadministration. The concentration-versus-time profile of tulathromycin in lung tissue was not influenced by the intranasal administration of E. coli LPS. The results suggest that in mice, neutrophils may not have a positive influence on tulathromycin accumulation in lung tissue when the drug is administered during either a neutrophilic or a neutropenic state. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Mai C.-K.,University of Colorado at Boulder | Sommons M.F.,University of Colorado at Boulder | Sommons M.F.,Pfizer | Sammakia T.,University of Colorado at Boulder
Angewandte Chemie - International Edition | Year: 2010

(Figure Presented) Protecting groups are overrated! A formal total synthesis of diazonamide A is described. The key step in this synthesis is an intramolecular SNAr reaction between an oxindole and a bromooxazole. Interestingly, this reaction proceeds best using the mild base Na 2CO3, and with no protecting groups on the oxindole nitrogen atom or phenol groups of the cyclization precursor. © 2010 Wiley-VCH Verlag GmbH & Co. KCaA.

Early benefit assessment aims to prove a benefit of a new pharmaceutical over the appropriate comparator based on patient-relevant endpoints. In addition to mortality and morbidity, quality of life is a patient-relevant endpoint. Thus, phase III clinical trials are the basis of evidence. But HTA and health authorities attach different importance to quality of life. Using the example of oncology, the challenges with study design and analysis will be discussed. A particular challenge to the analysis of quality-of-life data is varying observation times in treatment arms with different effectiveness. Based on the example of Crizotinib possible solutions will be presented. (As supplied by publisher).

Qiu X.,Bristol Myers Squibb | Zhang H.,Pfizer | Lai Y.,Bristol Myers Squibb
AAPS Journal | Year: 2014

Although global proteomics has shown promise for discovery of many new proteins, biomarkers, protein modifications, and polymorphisms, targeted proteomics is emerging in the proteomics research field as a complement to untargeted shotgun proteomics, particularly when a determined set of low-abundance functional proteins need to be measured. The function and expression of proteins related to drug absorption, distribution, metabolism, and excretion (ADME) such as cytochrome P450 enzymes and membrane transporters are of great interest in biopharmaceutical research. Since the variation in ADME-related protein expression is known to be a major complicating factor encountered during in vitro-in vivo and in vivo-in vivo extrapolations (IVIVE), the accurate quantification of the ADME proteins in complex biological systems becomes a fundamental element in establishing IVIVE for pharmacokinetic predictions. In this review, we provide an overview of relevant methodologies followed by a summary of recent applications encompassing mass spectrometry-based targeted quantifications of membrane transporters. © 2014 American Association of Pharmaceutical Scientists.

Cronin J.G.,University of Swansea | Turner M.L.,University of Swansea | Goetze L.,Pfizer | Bryant C.E.,University of Cambridge | Sheldon I.M.,University of Swansea
Biology of Reproduction | Year: 2012

Infection of the bovine endometrium with Gram-negative bacteria commonly causes uterine disease. Toll-like receptor 4 (TLR4) on cells of the immune system bind Gram-negative bacterial lipopolysaccharide (LPS), stimulating the secretion of the proinflammatory cytokines interleukin 1B (IL1B) and IL6, and the chemokine IL8. Because the endometrium is the first barrier to infection of the uterus, the signaling cascade triggered by LPS and the subsequent expression of inflammatory mediators were investigated in endometrial epithelial and stromal cells, and the key pathways identified using short interfering RNA (siRNA) and biochemical inhibitors. Treatment of endometrial cells with ultrapure LPS stimulated an inflammatory response characterized by increased IL1B, IL6, and IL8 mRNA expression, and IL6 protein accumulation in epithelial cells, and by increased IL1B and IL8 mRNA expression, and IL6 and IL8 protein accumulation in stromal cells. Treatment of endometrial cells with LPS also induced the degradation of IKB and the nuclear translocation of NFKB, as well as rapid phosphorylation of mitogen-activated protein kinase 3/1 (MAPK3/1) and MAPK14. Knockdown of TLR4 or its signaling adaptor molecule, myeloid differentiation factor 88 (MYD88), using siRNA reduced the inflammatory response to LPS in epithelial and stromal cells. Biochemical inhibition of MAPK3/1, but not JNK or MAPK14, reduced LPS-induced IL1B, IL6, and IL8 expression in endometrial cells. In conclusion, epithelial and stromal cells have an intrinsic role in innate immune surveillance in the endometrium, and in the case of LPS this recognition occurs via TLR4- and MYD88-dependent cell signaling pathways. © 2012 by the Society for the Study of Reproduction, Inc.

Thuy-Boun P.S.,Scripps Research Institute | Villa G.,Scripps Research Institute | Dang D.,Scripps Research Institute | Richardson P.,Pfizer | And 2 more authors.
Journal of the American Chemical Society | Year: 2013

A protocol for the Pd(II)-catalyzed ortho-C-H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Monoprotected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated. © 2013 American Chemical Society.

Pelletier M.J.,Pfizer
Applied Spectroscopy | Year: 2013

Transmission Raman sensitivity for a representative commercial pharmaceutical tablet was increased by a factor of 40 using optics that returned lost laser and Raman photons to the tablet surface. A new achromatic one-way mirror is introduced that uses the spatial coherence of laser light to nondestructively force laser photons through the reflective tablet coating. Transmission Raman mapping and spatially offset Raman spectroscopy (SORS) mapping were developed and used to better understand the sensitivity-enhancement technology. Fundamental limitations of the sensitivity-enhancement approach are described and used to guide the design of the optics. The sensitivity- enhancement optics are compatible with commercial transmission Raman instruments. © 2013 Society for Applied Spectroscopy.

Wang X.,Scripps Research Institute | Truesdale L.,Pfizer | Yu J.-Q.,Scripps Research Institute
Journal of the American Chemical Society | Year: 2010

"Chemical equation presented" A Pd(II)-catalyzed C-H activation/trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent using diverse heterocycle directing groups is reported. The presence of trifluoroacetic acid is crucial for this catalytic reaction. © 2010 American Chemical Society.

Dai H.-X.,Scripps Research Institute | Li G.,Scripps Research Institute | Zhang X.-G.,Scripps Research Institute | Stepan A.F.,Pfizer | Yu J.-Q.,Scripps Research Institute
Journal of the American Chemical Society | Year: 2013

A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C-H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C-H functionalizations when functional groups are distal to target C-H bonds. The meta-C-H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds. © 2013 American Chemical Society.

Drug formulations of anhydrous solid forms are generally preferred over hydrated forms. This is due to the risks of low exposure and unacceptable physical and chemical stability in comparison with anhydrous formulations. The purpose of the current study was to determine which descriptors can be most efficiently applied to virtual screening in order to provide answers to the following questions: 1) what is the propensity to form a solid state hydrate of a pharmaceutical compound, and 2) in regards to cocrystalline formulation, which coformer would provide for the highest stability with respect to relative humidity (RH) conditions? A number of properties of different complexity were tested to provide answers to these questions, including COSMO-RS excess free energy Gex and enthalpy Hex of hydration of the compound in amorphous state; octanol-water partition coefficient clogP; polar surface area TPSA; different combinations of molecular H-bond donor and acceptor counts; an excess enthalpy of API (active pharmaceutical ingredient)-coformer mixing; and coformer solubilities. It was demonstrated that the Gex property provides the most efficient way of virtual screening of hydration propensity of solid pharmaceutical compounds. It was also demonstrated that a virtual coformer screening based on the API coformer miscibility, as measured by the COSMO-RS Hex property, may be efficiently used to guide the experimental selection of coformers which have an increased probability of cocrystallization and provide the highest RH stability. © The Royal Society of Chemistry 2015.

Seyhan A.A.,Pfizer
Human Genetics | Year: 2011

Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed. © 2011 Springer-Verlag.

Reinert R.,Pfizer | Jacobs M.R.,Case Western Reserve University | Kaplan S.L.,Baylor College of Medicine
Vaccine | Year: 2010

Streptococcus pneumoniae serotype 19A is associated with all forms of pneumococcal disease and was the first reported pneumococcal serotype with high-level penicillin and multidrug resistance. While the seven-valent pneumococcal conjugate vaccine (PCV7), which contains serotype 19F, has reduced rates of disease among children and adults, the incidence of disease due to nonvaccine and increasingly drug-resistant serotypes - predominantly serotype 19A - has increased. This review summarizes the published literature to analyze the factors contributing to the emergence of serotype 19A, the diseases associated with this serotype, and the importance of including this serotype in novel pneumococcal conjugate vaccines. A recently approved 13-valent vaccine includes this serotype, and is likely to significantly reduce the burden of disease due to serotype 19A. © 2010 Elsevier Ltd. All rights reserved.

Cook J.A.,Pfizer | Davit B.M.,U.S. Food and Drug Administration | Polli J.E.,University of Maryland, Baltimore
Molecular Pharmaceutics | Year: 2010

The Biopharmaceutics Classification System (BCS) is employed to waive in vivo bioequivalence testing (i.e. provide "biowaivers") for new and generic drugs that are BCS class I. Granting biowaivers under systems such as the BCS eliminates unnecessary drug exposures to healthy subjects and provides economic relief, while maintaining the high public health standard for therapeutic equivalence. International scientific consensus suggests class III drugs are also eligible for biowaivers. The objective of this study was to estimate the economic impact of class I BCS-based biowaivers, along with the economic impact of a potential expansion to BCS class III. Methods consider the distribution of drugs across the four BCS classes, numbers of in vivo bioequivalence studies performed from a five year period, and effects of highly variable drugs (HVDs). Results indicate that 26% of all drugs are class I non-HVDs, 7% are class I HVDs, 27% are class III non-HVDs, and 3% are class III HVDs. An estimated 66 to 76 million dollars can be saved each year in clinical study costs if all class I compounds were granted biowaivers. Between 21 and 24 million dollars of this savings is from HVDs. If BCS class III compounds were also granted waivers, an additional direct savings of 62 to 71 million dollars would be realized, with 9 to 10 million dollars coming from HVDs. © 2010 American Chemical Society.

Woo C.M.,Yale University | Beizer N.E.,Yale University | Janso J.E.,Pfizer | Herzon S.B.,Yale University
Journal of the American Chemical Society | Year: 2012

We describe the isolation of (-)-lomaiviticins C-E (6-8), elucidation of the complete absolute and relative stereochemistry of (-)-lomaiviticin A (1), the synthetic conversion of (-)-lomaiviticin C (6) to (-)-lomaiviticin A (1), and the first evidence that the dimeric diazofluorene of (-)-lomaiviticin A (1) plays a defining and critical role in antiproliferative activity. © 2012 American Chemical Society.

Nilsson C.L.,Pfizer
Current Proteomics | Year: 2011

One of the greatest challenges of the post-genomic and post-proteomic era is to understand the role of post-translational modifications in global biological systems. Protein glycosylation is one of the most frequent post-translational modifications but has been poorly studied in global proteomes because of analytical challenges associated with glycan structural characterization. In recent years, technical advances in the study of protein glycosylation have been achieved by the use of lectins as an enrichment tool for subproteomes modified by specific types of glycan structures. Many clinical biomarkers are glycoproteins and glycoproteomic studies that use lectin affinity techniques have been shown to have a superior ability to determine structure-specific biomarkers of disease. This article reviews key techniques and workflows, including the use of single-and multiple lectin columns and glycan detection by lectins. © 2011 Bentham Science Publishers.

Strop P.,Pfizer
Bioconjugate Chemistry | Year: 2014

Although microbial transglutaminases (mTGs) were initially discovered to offset the cost of producing mammalian transglutaminases for food applications, they have quickly become important tools in research and biotechnology. Today, mTGs are utilized for a large number of applications to conjugate proteins and peptides to small molecules, polymers, surfaces, and DNA, as well as to other proteins. It is important to know how to maximize the advantages of the enzymatic approach and avoid undesired cross-linking. This review focuses on the versatility of transglutaminases in the field of bioconjugation and covers recent developments in utilizing mTG for generating antibody drug conjugates (ADCs) for therapeutic applications. © 2014 American Chemical Society.

The main purpose of this study is to define the major limiting factor in the accuracy of the quantitative structure-property relationship (QSPR) models of the thermodynamic intrinsic aqueous solubility of the drug-like compounds. For doing this, the thermodynamic intrinsic aqueous solubility property was suggested to be indirectly "measured" from the contributions of solid state, Gfus, and nonsolid state, Gmix, properties, which are estimated by the corresponding QSPR models. The QSPR models of Gfus and Gmix properties were built based on a set of drug-like compounds with available accurate measurements of fusion and thermodynamic solubility properties. For consistency Gfus and Gmix models were developed using similar algorithms and descriptor sets, and validated against the similar test compounds. Analysis of the relative performances of these two QSPR models clearly demonstrates that it is the solid state contribution which is the limiting factor in the accuracy and predictive power of the QSPR models of the thermodynamic intrinsic solubility. The performed analysis outlines a necessity of development of new descriptor sets for an accurate description of the long-range order (periodicity) phenomenon in the crystalline state. The proposed approach to the analysis of limitations and suggestions for improvement of QSPR-type models may be generalized to other applications in the pharmaceutical industry. © 2015 American Chemical Society.

Xing L.,Pfizer | Huang A.,Wellesley College
Future Medicinal Chemistry | Year: 2014

Bruton's TK (BTK) is a promising biological target for therapeutic intervention of several diseases including inflammatory diseases and cancer/B cell malignancies. Numerous research groups are actively engaged in investigating the functions of BTK, and discovering potent and selective BTK inhibitors as drug candidates. Revealed by X-ray crystal structures with ligands of diverse chemical structures, the ability of BTK kinase domain to adopt various inactive conformations offers unique opportunities to identify highly potent and exquisitely selective inhibitors. Both reversible and covalent inhibitor approaches have yielded candidates demonstrating safety profiles and efficacies in multiple preclinical models of autoimmunity and oncology. Two BTK inhibitors have entered human clinical trials for oncology indications. Ibrutinib won the US FDA approval in November 2013 to become the first-in-class BTK inhibitor for treating mantle cell lymphoma. This encouraging outcome and the other on-going human studies could ultimately expand the utility of BTK inhibitors to broader autoimmune disease areas. © 2014 Future Science Ltd.

One of the biggest challenges in drug development is interpretation of findings suggestive of immunostimulation, particularly when the findings are unexpected based on the known mechanism of action of the drug. Findings suggestive of immunostimulation do not necessarily preclude development of the drug. By understanding mechanism, the patient population, and species differences and by careful clinical monitoring, many of the drugs that produce immunostimulation can be successfully developed. This opinion piece describes various types of immunostimulation and a risk assessment strategy for management of unexpected immunostimulation in toxicity studies. © 2014 by The Author(s).

Srivastava D.P.,Northwestern University | Woolfrey K.M.,Northwestern University | Liu F.,Pfizer | Brandon N.J.,Northwestern University | Penzes P.,Northwestern University
Journal of Neuroscience | Year: 2010

Brain-synthesized estrogen has been shown to influence synaptic structure, function, and cognitive processes. However, the molecular mechanisms underlying the rapid effects of estrogen on the dendritic spines of cortical neurons are not clear. Estrogen receptor β (ERβ) is expressed in cortical neurons, and ERβ knock-out mice display impaired performance in cortically mediated processes, suggesting that signaling via this receptor has profound effects on cortical neuron function. However, the effect of rapid signaling via ERβ on dendritic spines and the signaling pathways initiated by this receptor in cortical neurons are unknown. Here, we show that activation of ERβ with the specific agonist WAY-200070 results in increased spine density and PSD-95 (postsynaptic density-95) accumulation in membrane regions. Activation of ERβ by WAY-200070 also resulted in the phosphorylation of p21-activated kinase (PAK) and extracellular signal-regulated kinase 1/2 (ERK1/2) in cultured cortical neurons, suggesting a mechanism for the regulation of the actin cytoskeleton. Moreover, we found that aromatase, an enzyme critical for estrogen production, is present at presynaptic termini, supporting a role for brain-synthesized estrogen as a neuromodulator in the cortex. These results implicate ERβ signaling in controlling dendritic spine morphology, in part via a PAK/ERK1/2-dependent pathway, and provide mechanistic insight into the rapid cellular effects of estrogen on brain function. Copyright © 2010 the authors.

Reynolds I.S.,Pew Charitable Trusts | Rising J.P.,Pew Charitable Trusts | Coukell A.J.,Pew Charitable Trusts | Paulson K.H.,Pew Charitable Trusts | And 2 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE: Postmarketing surveillance is critical to evaluating the safety and effectiveness of medical devices. The US Food and Drug Administration (FDA) may order the manufacturer of a high-risk device to conduct postmarketing surveillance studies, known as postapproval studies (PASs), at the time of approval. OBJECTIVES: To understand the characteristics of PASs ordered in recent years and inform discussions about the direction of the PASs program. DESIGN: Descriptive study of the PASs ordered for medical devices using the FDA's PASs website, the Premarket Approval database, and supplemental information provided by the FDA. MAIN OUTCOMES AND MEASURES: The proportion of medical devices that received a PAS order and study characteristics. RESULTS: Between January 1, 2005, and December 31, 2011, the FDA ordered 223 studies of 158 medical devices, including studies for 93 (48%) new high-risk devices approved during this period. The median required sample size for a study was 350 patients (interquartile range, 160-1500). If the protocol of a study was not in place at the time the device was approved, which occurred frequently, a median of 180 days elapsed until the protocol was agreed on. The FDA has never issued a warning letter or penalty owing to study delays, inadequate progress, or any other issue related to a PAS. Of the approved protocols, 41 (19%) were subsequently revised, including 29 (21%) protocols in place by application approval. Some studies generated significant clinical findings. The most common effect of a PAS finding after study completion was that the FDA requested a labeling change for 31 studies (53%). CONCLUSIONS AND RELEVANCE: Postapproval studies have the potential to provide additional information to better understand medical device performance. However, small sample sizes, delays in reaching protocol agreement, and lack of availability of findings may hinder their ability to be clinically useful. Owing to the lack of information on the effect of studies, it is unclear whether the program achieves its aims. Improved completion and accessibility of PASs could help answer important questions of safety and effectiveness about medical devices. To better understand the real-world performance of these products, they should be better integrated with other sources of information about device performance. Copyright 2014 American Medical Association. All rights reserved.

Rak Tkaczuk K.H.,University of Maryland, Baltimore | Jacobs I.A.,Pfizer
Seminars in Oncology | Year: 2014

Biologics play an integral role in the treatment of cancer not only for their therapeutic effects and ability to improve outcomes, but also as supportive care agents. Biologics are more complex to manufacture and take longer to bring to market. Because biologics are considerably more costly than small-molecule drugs, their use has placed an increasing economic demand on healthcare systems worldwide. Biosimilars are designed to be highly similar to existing branded biologics, but because biologics cannot be exactly copied, biosimilars should not be referred to as generic, exact versions of the innovator biologic. Biosimilars have the potential to increase access and provide lower cost options for cancer care as patent protection for some of the most widely used biologics begins to expire. Regulatory requirements for biosimilars are evolving, as are global harmonization and/or standardization strategies that can facilitate their robust clinical development. This review highlights critical factors involved with the integration of biosimilars into oncology treatment paradigms and practices. Clinicians will likely seek out practice guidelines and position statements from established scientific societies to help evaluate key information regarding biosimilars, such as efficacy, safety, comparability, and interchangeability with the reference biologic. Automatic substitution, nomenclature, extrapolation of clinical data from one indication to another, as well as parameters for ongoing pharmacovigilance are evolving considerations. Education of physicians and other healthcare providers, payers, and patients about biosimilars may facilitate informed decision making, promote acceptance of biosimilars into clinical practice, increase accessibility, and expedite associated health and economic benefits. © 2014 Elsevier Inc. All rights reserved.

Ugbode C.I.,University of Reading | Ugbode C.I.,University of Bradford | Hirst W.D.,Pfizer | Rattray M.,University of Bradford
Journal of Neurochemistry | Year: 2014

Recent evidence suggests that the predominant astrocyte glutamate transporter, GLT-1/ Excitatory Amino Acid Transporter 2 (EAAT2) is associated with mitochondria. We used primary cultures of mouse astrocytes to assess co-localization of GLT-1 with mitochondria, and tested whether the interaction was dependent on neurons, actin polymerization or the kinesin adaptor, TRAK2. Mouse primary astrocytes were transfected with constructs expressing V5-tagged GLT-1, pDsRed1-Mito with and without dominant negative TRAK2. Astrocytes were visualized using confocal microscopy and co-localization was quantified using Volocity software. Image analysis of confocal z-stacks revealed no co-localization between mitochondria and GLT-1 in pure astrocyte cultures. Co-culture of astrocytes with primary mouse cortical neurons revealed more mitochondria in processes and a positive correlation between mitochondria and GLT-1. This co-localization was not further enhanced after neuronal depolarization induced by 1 h treatment with 15 mM K+. In pure astrocytes, a rho kinase inhibitor, Y27632 caused the distribution of mitochondria to astrocyte processes without enhancing GLT-1/mitochondrial co-localization, however, in co-cultures, Y27632 abolished mitochondrial:GLT-1 co-localization. Disrupting potential mitochondrial: kinesin interactions using dominant negative TRAK2 did not alter GLT-1 distribution or GLT-1: mitochondrial co-localization. We conclude that the association between GLT-1 and mitochondria is modest, is driven by synaptic activity and dependent on polymerized actin filaments. Mitochondria have limited co-localization with the glutamate transporter GLT-1 in primary astrocytes in culture. Few mitochondria are in the fine processes where GLT-1 is abundant. It is necessary to culture astrocytes with neurones to drive a significant level of co-localization, but co-localization is not further altered by depolarization, manipulating sodium ion gradients or Na/K ATPase activity. Mitochondria have limited co-localization with the glutamate transporter GLT-1 in primary astrocytes in culture. Few mitochondria are in the fine processes where GLT-1 is abundant. It is necessary to culture astrocytes with neurones to drive a significant level of co-localization, but co-localization is not further altered by depolarization, manipulating sodium ion gradients or Na/K ATPase activity. © 2014 The Authors.

The hydrolysis of carboxylic acid esters is often catalyzed by carboxylesterases in human liver microsomes, which is also a common 'noise' in the microsomal stability assay, a widely used screening protocol in drug discovery to monitor the activity of cytochrome P450 enzymes. Herein, we captured this 'noise', the hydrolysis signal of small alkyl ester drugs and prodrugs with a unique pairwise analysis of Pfizer's microsomal clearance database. The hydrolysis mechanisms were further elucidated with density functional theory and molecular docking approaches. The results suggested that the electronic properties of ester moieties, tetrahedral intermediate formation energies, and specific drug-enzyme molecular interactions are key factors for the determination of the metabolic fate of the studied alkyl esters, but individually these factors failed to correlate with the observed rate of hydrolysis. © 2011 Elsevier Ltd. All rights reserved.

Gomez C.F.,University of North Texas | Constantine L.,Pfizer | Huggett D.B.,University of North Texas
Chemosphere | Year: 2010

The potential for xenobiotic compounds to bioconcentrate is typically expressed through the bioconcentration factor (BCF), which has gained increased regulatory significance over the past decade. Due to the expense of in vivo bioconcentration studies and the growing regulatory need to assess bioconcentration potential, BCF is often calculated via single-compartment models, using KOW as the primary input. Recent efforts to refine BCF models have focused on physiological factors, including the ability of the organism to eliminate the compound through metabolic transformation. This study looks at the ability of in vitro biotransformation assays using S9 fractions to provide an indication of metabolic potential. Given the importance of the fish gill and liver in metabolic transformation, the metabolic loss of ibuprofen, norethindrone and propranolol was measured using rainbow trout (Oncorhynchus mykiss) and channel catfish (Ictalurus punctatus) gill and liver S9 fractions. Metabolic transformation rates (kM) were calculated and integrated into a refined BCF model. A significant difference was noted between BCF solely based on KOW and BCF including kM. These studies indicate that the inclusion of kM in BCF models can bring predicted bioconcentration estimates closer to in vivo values. © 2010 Elsevier Ltd.

Constantine L.A.,Pfizer | Huggett D.B.,University of North Texas
Chemosphere | Year: 2010

Scientific researchers and regulators are focusing attention on trace quantities of pharmaceuticals in wastewater effluents and surface waters, resulting in an increased level of concern regarding the potential environmental impact of these compounds. The current European regulatory guideline requires evaluation of the chronic effects of active pharmaceutical ingredients on Daphnia magna. Based on the life cycle of D. magna, chronic studies to establish survival and reproductive endpoints require a 21. d exposure period. A similar organism, Ceriodaphnia dubia, has a shorter life cycle and therefore survival and reproductive endpoints may be established following 7. d of exposure. No observed effect concentrations and lowest observed effect concentrations for survival and reproduction were obtained for D. magna and C. dubia following exposure to six human pharmaceuticals and two metabolites (i.e. celecoxib, linezolid, varenicline, sunitinib, Compound A, ziprasidone and the M1 and M4 metabolites of torcetrapib). These data were evaluated to determine whether one organism may be considered more sensitive. Survival and reproduction data obtained from the C. dubia study provide similar outcomes to D. magna when determining the predicted environmental concentration/predicted no effect concentration (PEC/PNEC) ratios for surface water. Based on these data, C. dubia may be used as a cost-effective alternative and representative invertebrate species when assessing the potential risk of human pharmaceuticals. © 2010 Elsevier Ltd.

Sciabola S.,Pfizer
Methods in molecular biology (Clifton, N.J.) | Year: 2011

In this chapter we present an application of in silico quantitative structure-activity relationship (QSAR) models to establish a new ligand-based computational approach for generating virtual libraries. The Free-Wilson methodology was applied to extract rules from two data sets containing compounds which were screened against either kinase or PDE gene family panels. The rules were used to make predictions for all compounds enumerated from their respective virtual libraries. We also demonstrate the construction of R-group selectivity profiles by deriving activity contributions against each protein target using the QSAR models. Such selectivity profiles were used together with protein structural information from X-ray data to provide a better understanding of the subtle selectivity relationships between kinase and PDE family members.

Na J.,Pfizer
Methods in molecular biology (Clifton, N.J.) | Year: 2011

A successful fragment-based lead discovery (FBLD) campaign largely depends on the content of the fragment collection being screened. To design a successful fragment collection, several factors must be considered, including collection size, property filters, hit follow-up considerations, and screening methods. In this chapter, we will discuss each factor and how it was applied to the design and assembly of one or more fragment collections in a major pharmaceutical company setting. We will also present examples and statistics of screening results from such collections and how subsequent collections can be improved. Lastly, we will provide a summary comparison of selected fragment collections from literature.

Brown A.D.,Pfizer
ChemMedChem | Year: 2015

RSC, Cambridge 2014. 384pp., hardcover, £175.00.-ISBN978-1-84973-186-7 © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Didenko T.,Scripps Research Institute | Liu J.J.,Scripps Research Institute | Horst R.,Scripps Research Institute | Horst R.,Pfizer | And 2 more authors.
Current Opinion in Structural Biology | Year: 2013

Fluorine-19 is a spin-1/2 NMR isotope with high sensitivity and large chemical shift dispersion, which makes it attractive for high resolution NMR spectroscopy in solution. For studies of membrane proteins it is further of interest that 19F is rarely found in biological materials, which enables observation of extrinsic 19F labels with minimal interference from background signals. Today, after a period with rather limited use of 19F NMR in structural biology, we witness renewed interest in this technology for studies of complex supramolecular systems. Here we report on recent 19F NMR studies with the G protein-coupled receptor family of membrane proteins. © 2013 Elsevier Ltd.

Wu F.,University of Pittsburgh | Green M.E.,University of Pittsburgh | Green M.E.,Pfizer | Floreancig P.E.,University of Pittsburgh
Angewandte Chemie - International Edition | Year: 2011

A ten-step program: The potent cytotoxin pederin and several analogues have been prepared through an efficient route that proceeds in ten steps (longest linear sequence) from isobutyraldehyde. The key transformation is a multicomponent N-acylaminal construction (see scheme) that allows for late-stage fragment coupling and diversification. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

When the Drug Metabolism Discussion Group was instigated in 1971, metabolite identification by mass spectrometry was a slow and laborious process undertaken by mass spectrometrists who seemed to continually disappoint their colleagues by failing to obtain the metabolite spectra. This was usually because not enough material was supplied or the material was impure. Today, accurate metabolite information can be obtained rapidly with little material by utilizing a range of mass spectrometers with complementary properties. This review will discuss how both technology and strategy have evolved over the past forty years to meet the changing demands of metabolism studies within the pharmaceutical industry. © 2011 Informa UK, Ltd.

Kennedy M.J.,Duke University | Hughes R.M.,Duke University | Peteya L.A.,Duke University | Schwartz J.W.,Duke University | And 3 more authors.
Nature Methods | Year: 2010

Dimerizers allowing inducible control of protein-protein interactions are powerful tools for manipulating biological processes. Here we describe genetically encoded light-inducible protein-interaction modules based on Arabidopsis thaliana cryptochrome 2 and CIB1 that require no exogenous ligands and dimerize on blue-light exposure with subsecond time resolution and subcellular spatial resolution. We demonstrate the utility of this system by inducing protein translocation, transcription and Cre recombinase-mediated DNA recombination using light. © 2010 Nature America, Inc. All rights reserved.

Fabian L.,Pfizer | Brock C.P.,University of Kentucky
Acta Crystallographica Section B: Structural Science | Year: 2010

A list of 181 organic kryptoracemates has been compiled. This class of crystallographic oddities is made up of racemic compounds (i.e. pairs of resolvable enantiomers) that happen to crystallize in Sohnke space groups (i.e. groups that include only proper symmetry operations). Most (151) of the 181 structures could have crystallized as ordered structures in non-Sohnke groups. The remaining 30 structures do not fully meet this criterion but would have been classified as kryptoracemates by previous authors. Examples were found and checked with the aid of available software for searching the Cambridge Structural Database, for generating and comparing InChI strings, and for validating crystal structures. The pairs of enantiomers in the true kryptoracemates usually have very similar conformations; often the match is near-perfect. There is a pseudosymmetric relationship of the enantiomers in about 60% of the kryptoracemate structures, but the deviations from inversion or glide symmetry are usually quite easy to spot. Kryptoracemates were found to account for 0.1% of all organic structures containing either a racemic compound, a meso molecule, or some other achiral molecule. The centroid of a pair of enantiomers is more likely (99.9% versus 99% probability) to be located on an inversion center than is the centroid of a potentially centrosymmetric molecule. © 2010 International Union of Crystallography Printed in Singapore - all rights reserved.

Efforts to discover protein biomarkers in plasma are hampered by the high abundance of few proteins, which interfere with the detection of low-abundant proteins. Different commercially available protein-partitioning products were tested for their ability to lower the detection limit of proteins in 2-D gels. Immuno-depletion using polyclonal antibodies raised against the proteins of highest abundance (Seppro IgY14 System) was compared with a two-step immuno-depletion strategy, where depletion with the Seppro IgY14 column was followed by depletion with the Seppro IgY-SuperMix system. The third strategy tested was protein prefractionation using the ProteoMiner kit, where proteins compete for binding sites on beadbound peptide hexamers with different binding properties. The pre-fractionated protein samples were analyzed using 2-DE, which revealed stunning differences in protein patterns. However, detectable protein spots in the different plasma fractions contained exclusively high-abundant proteins normally present in plasma at concentrations between 1 ug and 40mg/mL. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA.

In Nicaragua, 30% of current morbidities are associated with tobacco smoking. Tobacco control policy measures have been initiated in this Central American country; however, the population does not have a complete understanding of the long-term consequences of tobacco use. The aim of this study was to compare the direct medical costs of smoking cessation therapies with varenicline, bupropion, nicotine replacement therapy, and unaided cessation in Nicaragua over 5 time horizons: 2, 5, 10, and 20 years, and lifetime. The current annual costs of chronic obstructive pulmonary disease, lung cancer, coronary heart disease, and stroke were estimated based on the current annual incidence for each disease using 1 public hospital database (Hospital Lenin Fonseca, 2010). The Benefits of Smoking Cessation on Outcomes simulation model was used to obtain the projected direct costs for each strategy. An adult cohort (N = 3 639 948) from Nicaragua was used and the assessment was conducted using the health care payer's perspective. Costs were discounted at 5% annually. Probabilistic sensitivity analyses were conducted using a Monte Carlo second-order approach. Varenicline is associated with the highest health care cost-savings compared with the other 3 alternatives at 5, 10, and 20 years, and lifetime. At lifetime, varenicline would result in savings of US$4 545 008, US$5 859 300, and US$11 033 221 when compared with bupropion, nicotine replacement therapy, and unaided cessation, respectively. Varenicline also avoided the highest number of smoking-related deaths in comparison with the alternatives. At year 10, varenicline avoided 96, 124, and 234 more deaths than bupropion, nicotine replacement therapy, and unaided cessation, respectively. The results of probabilistic sensitivity analyses support these findings. The use of a smoking cessation therapy with varenicline would generate long-term savings to Nicaragua's health care institutions of > US$11 million in the lifetime time horizon.

In Central American countries, the economic burden of tobacco has not been assessed. In Costa Rica, a study demonstrated that tobacco-related diseases represent high costs for the health care system. The aim of this study was to assess the cost-effectiveness of varenicline compared with other existing strategies for smoking cessation within a 10-year time horizon in an adult population cohort from Central American and Caribbean countries using the health care payer's perspective. The Benefits of Smoking Cessation on Outcomes simulation model was used for an adult cohort in Costa Rica (n = 2 474 029), Panama (n = 2 249 676), Nicaragua (n = 3 639 948), El Salvador (n = 4 537 803), and the Dominican Republic (n = 6 528 125) (N = 19 429 581). Smoking cessation therapies compared were varenicline (0.5-2 mg/day) versus bupropion (300 mg/day), nicotine replacement therapy (5-15 mg/day), and unaided cessation. Effectiveness measures were: life-years (LYs) gained and quality-adjusted life-years (QALYs) gained. Resource use and cost data were obtained from a country's Ministry of Health and/or Social Security Institutions (2008-2010). The model used a 5% discount rate for costs (expressed in 2010 US$) and health outcomes. Probabilistic sensitivity analyses were conducted and acceptability curves were constructed. Varenicline reduced smoking-related morbidity, mortality, and health care costs in each country included in the study. Accumulatively, mortality in the varenicline arm was reduced by 1190, 1538, and 2902 smoking-related deaths compared with bupropion, nicotine replacement therapy, and unaided cessation, respectively. The net average cost per additional quitter showed that varenicline was cost-saving when compared with competing alternatives. Regarding LYs and QALYs gained in 10 years, varenicline obtained the greatest number of QALYs and LYs in each country, while unaided cessation obtained the fewest. Cost-effectiveness analyses in all 5 countries showed that varenicline was the dominant strategy. Acceptability curves showed that, independent of the willingness to pay, the probability that varenicline is cost-effective was 99% for this region. The results of the probabilistic sensitivity analyses support the robustness of the findings. Smoking cessation therapy with varenicline is cost-saving for the Central American and Caribbean countries included. These results could help to reduce the tobacco-related disease burden and align cost-containment policies.

Horst R.,Scripps Research Institute | Horst R.,Pfizer | Liu J.J.,Scripps Research Institute | Stevens R.C.,Scripps Research Institute | Wuthrich K.,Scripps Research Institute
Angewandte Chemie - International Edition | Year: 2013

Proteins in slow motion: 19F NMR studies indicate that equilibria between active and inactive states of the human β2- adrenergic receptor require extensive structural rearrangements (arrows in picture). This was shown by an enthalpy difference of ΔHo≈40 kJ mol-1 and a slow exchange rate, with kex10 s -1. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mapel D.W.,Lovelace Clinic Foundation | Marton J.P.,Pfizer
International Journal of COPD | Year: 2013

Background: The purpose of this study was to describe the prevalence of renal and hepatic disease, related laboratory abnormalities, and potentially hepatotoxic and nephrotoxic medication use in a population-based cohort of persons with chronic obstructive pulmonary disease (COPD).Methods: This was a retrospective case-control cohort analysis of COPD patients enrolled in one regional health system for at least 12 months during a 36-month study period (n = 2284). Each COPD patient was matched by age and gender to up to three persons not diagnosed with COPD (n = 5959).Results: The mean age for cases and controls was 70.3 years, and 52.5% were women. The COPD cohort had signifcantly higher prevalences (cases/100) of acute, chronic, and unspecifed renal failure as compared with controls (1.40 versus 0.59, 2.89 versus 0.79, and 1.09 versus 0.44, respectively). Among the cases, 31.3% had at least one renal or urinary tract diagnosis during the study period, as compared with 21.1% of controls. COPD cases also had more gallbladder disease (2.76 versus 1.63) and pancreatic disease (1.40 versus 0.60), but not hepatic disease. COPD patients were more likely to have at least one serum creatinine level (5.1 versus 2.1) or liver aspartate aminotransferase level (4.5 versus 2.7) that was more than twice the upper limit of normal. COPD patients had prescription flls for an average of 17.6 potentially nephrotoxic and 27.4 hepatotoxic drugs during the study period, as compared with 13.6 and 19.9 for the controls (P value for all comparisons, 0.01).Conclusion: COPD patients have a substantially increased prevalence of renal, gallbladder, and pancreatic diseases, as well as abnormal renal and hepatic laboratory values, but not diagnosed liver disease. COPD patients are also more likely to be prescribed medications with potentially toxic renal or hepatic side effects. © 2013 Mapel and Marton, publisher and licensee Dove Medical Press Ltd.

The Tigecycline Evaluation and Surveillance Trial (TEST) was designed to monitor susceptibility to commonly used antimicrobial agents among important pathogens. We report here on susceptibility among Gram-negative pathogens collected globally from pediatric patients between 2004 and 2012. Antimicrobial susceptibility was determined using guidelines published by the Clinical and Laboratory Standards Institute (CLSI). Most Enterobacteriaceae showed high rates of susceptibility (>95%) to amikacin, tigecycline, and the carbapenems (imipenem and meropenem); 90.8% of Acinetobacter baumannii isolates were susceptible to minocycline, and susceptibility rates were highest in North America, Europe, and Asia/Pacific Rim. Amikacin was the most active agent against Pseudomonas aeruginosa (90.4% susceptibility), with susceptibility rates being highest in North America. Extended-spectrum β-lactamases (ESBLs) were reported for 11.0% of Escherichia coli isolates and 24.2% of Klebsiella pneumoniae isolates globally, with rates reaching as high as 25.7% in the Middle East and >43% in Africa and Latin America, respectively. Statistically significant (P < 0.01) differences in susceptibility rates were noted between pediatric age groups (1 to 5 years, 6 to 12 years, or 13 to 17 years of age), globally and in some regions, for all pathogens except Haemophilus influenzae. Significant (P < 0.01) differences were reported for all pathogens globally and in most regions, considerably more frequently, when pediatric and adult susceptibility results were compared. Amikacin, tigecycline, and the carbapenems were active in vitro against most Gram-negative pathogens collected from pediatric patients; A. baumannii and P. aeruginosa were susceptible to fewer antimicrobial agents. Susceptibility rates among isolates from pediatric patients were frequently different from those among isolates collected from adults. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Meekings K.N.,Thomson Reuters | Williams C.S.M.,Pfizer | Arrowsmith J.E.,Thomson Reuters
Drug Discovery Today | Year: 2012

Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Although the targeting of orphan diseases is seen by industry as an attractive strategy, there are limited economic data available to support its use. In this paper we show that the revenue-generating potential of orphan drugs is as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success. The data support the targeting of rare diseases as an important component of a successful biopharma R&D strategy. © 2012 Elsevier Ltd.

Rosentha A.,Alector Inc. | Lin J.C.,Pfizer
Handbook of Experimental Pharmacology | Year: 2014

The neurotrophin family is comprised of the structurally related secreted proteins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophine-4 (NT-4). They bind and activate the tyrosine kinase receptors Trk A, B, and C in a ligand-specific manner and additionally bind a shared p75NTR receptor. The neurotrophins were originally defined by their ability to support the survival and maturation of embryonic neurons. However, they also control important physiological functions of the adult nervous system including learning and memory, sensation, and energy homeostasis. For example, NGF/trkA signaling is critical for normal and pathological sensation of pain. Likewise, the BDNF/trkB pathway controls feeding and metabolism, and its dysfunction leads to severe obesity. Antibodies can modulate neurotrophin signaling. Thus, NGF blocking agents can attenuate pain in several animal models, and a recombinant humanized NGF blocking antibody (Tanezumab) has shown promising results in human clinical trials for osteoarthritic pain. On the other hand trkB agonist antibodies can modulate food intake and body weight in rodents and nonhuman primates. The power of monoclonal antibodies to modulate neurotrophin signaling promises to turn the rich biological insights into novel human medicines. © Springer-Verlag Berlin Heidelberg 2014.

Sawant A.D.,Pfizer
Xenobiotica; the fate of foreign compounds in biological systems | Year: 2010

1. 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide (1), developed for general anxiety disorder, was discontinued from clinical development due to unsuitable oral pharmacokinetics. 2. In humans, (1) demonstrated an unacceptable high apparent oral clearance (Cl(p)/F) that also demonstrated a supraproportional dose-exposure relationship. Secondary peaks in the plasma concentration-time profile suggested possible enterohepatic recirculation of (1). A combination of in vitro mechanistic tools was applied to better understand the processes underlying these complex clinical pharmacokinetic profiles of (1). 3. In metabolism experiments, (1) was shown to be a substrate of monoamine oxidase A (MAO-A) as well as being metabolized by cytochrome P450. The former appeared to be a high K(M) process with a high capacity, while the latter showed saturation between 1 and 10 microM, consistent with the supraproportional dose-exposure relationship. 4. In a sandwich-cultured hepatocyte model, (1) was shown to be a substrate for both uptake and efflux into the canicular space, which is consistent with the observation of pharmacokinetics suggestive of enterohepatic recirculation. Finally, in human epithelial colon adenocarcinoma cell line (Caco-2) and Madin-Darby canine kidney cells transwell flux experiments, (1) was shown to have relatively low permeability and a basolateral-to-apical flux ratio consistent with the activity of P-glycoprotein. 5. In combination, a compounding of the contributions of MAO-A, hepatic uptake and efflux transporters, and P-glycoprotein to the disposition of (1) may underlie the low oral exposure, saturable clearance, and aberrant concentration versus time profiles observed for this compound in humans.

Schmidt B.J.,University of California at San Diego | Papin J.A.,University of Virginia | Musante C.J.,Pfizer
Drug Discovery Today | Year: 2013

A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. © 2012 Elsevier Ltd.

With the advances in cell culture methodologies and molecular biology that have occurred over the past several decades, biologics have become as common as small molecules within the portfolios of the pharmaceutical industry. Toxicologic pathologists should be aware of some of the fundamental differences between small molecules and biologics. Effects are not always observed in studies following administration of biologics. When findings are observed, the toxicologic pathologist should initially determine whether the effect(s) are mediated (directly or indirectly) via the intended pharmacology, exaggerated pharmacology, an immune response, and/or off target effects. Following this determination, the toxicologic pathologist should provide an assessment regarding the relevance of the findings to the intended clinical population, usually humans. The toxicologic pathologist may also be asked to assess unusual species and models. Given their broad background in physiology and immunology, toxicologic pathologists are uniquely positioned to provide this input to drug development teams. © 2013 by The Author(s).

Zhao S.,Janssen Research and Development LLC | Zhao S.,Pfizer
PLoS ONE | Year: 2014

RNA-Seq has become increasingly popular in transcriptome profiling. The major challenge in RNA-Seq data analysis is the accurate mapping of junction reads to their genomic origins. To detect splicing sites in short reads, many RNA-Seq aligners use reference transcriptome to inform placement of junction reads. However, no systematic evaluation has been performed to assess or quantify the benefits of incorporating reference transcriptome in mapping RNA-Seq reads. In this paper, we have studied the impact of reference transcriptome on mapping RNA-Seq reads, especially on junction ones. The same dataset were analysed with and without RefGene transcriptome, respectively. Then a Perl script was developed to analyse and compare the mapping results. It was found that about 50-55% junction reads can be mapped to the same genomic regions regardless of the usage of RefGene model. More than one-third of reads fail to be mapped without the help of a reference transcriptome. For "Alternatively" mapped reads, i.e., those reads mapped differently with and without RefGene model, the mappings without RefGene model are usually worse than their corresponding alignments with RefGene model. For junction reads that span more than two exons, it is less likely to align them correctly without the assistance of reference transcriptome. As the sequencing technology evolves, the read length is becoming longer and longer. When reads become longer, they are more likely to span multiple exons, and thus the mapping of long junction reads is actually becoming more and more challenging without the assistance of reference transcriptome. Therefore, the advantages of using reference transcriptome in the mapping demonstrated in this study are becoming more evident for longer reads. In addition, the effect of the completeness of reference transcriptome on mapping of RNA-Seq reads is discussed. © 2014 Shanrong Zhao.

Currently, 13-valent pneumococcal conjugate vaccine (PCV); and ten-valent PCV vaccine are marketed. Neither vaccine obtained regulatory approval based on efficacy trials, but instead were approved based on a surrogate end point: immunogenicity data measuring effective antibody levels. Therefore, direct measures of efficacy were unavailable at the time economic analyses were conducted. The authors systematically reviewed cost-effectiveness studies of ten-valent PCV and 13-valent PCV from the literature to analyze the methodologies and compare the assumptions made about vaccine effectiveness. The following three inputs were found the most variant across analyses: efficacy against acute otitis media; inclusion of indirect effects; and cross protection. These assumptions are discussed with regard to the validity of supporting data and implications on decision-making.

Although gastrointestinal (GI) toxicity is a significant dose-limiting safety concern noted in multiple therapeutic areas, there are no GI biomarkers that can accurately track, precede, or reliably correlate with histologic evidence of injury. While significant efforts have been made within the pharmaceutical industry, academia, and consortia to address the biomarker gaps in other target organs such as liver, kidney, and muscle (cardiac and skeletal), there have been no concerted efforts in the area of GI biomarkers. Using PAK4 inhibitor as a preclinical rat model of gastric toxicity, selected candidate biomarkers from literature were evaluated to test their usefulness as gastric injury biomarkers in this study. Biomarkers selected in this study include plasma diamino oxidase and citrulline, fecal calprotectin, bile acids, and miRNA. Based on the results, L-citrulline and miR-194 results appear to correlate well with histopathology findings. Although these biomarkers will need additional assay validation and qualification to test if they truly predict the injury prior to histopathology, the results provide promise for further testing using additional GI toxicants. In addition, this article highlights important gaps in GI biomarkers and provides substrate and rationale for additional investments either for further testing of already available biomarkers or to pursue extensive biomarker discovery approaches.

Weak peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARα agonist CP-778875 on peroxisomal β-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARα agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARα receptor, leading to increased β-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000→1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle β-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart β-oxidation (3.4- to 5.1-fold control) and AOX mRNA (2.4- to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. β-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6- to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARα agonism and support the link between increased cardiac and skeletal muscle β-oxidation and resultant muscle injury in the rat.

Atkin T.A.,University College London | Brandon N.J.,Pfizer | Kittler J.T.,University College London
Human Molecular Genetics | Year: 2012

Disrupted in Schizophrenia 1 (DISC1) is a key susceptibility gene implicated in major mental illnesses, such as schizophrenia, depression, bipolar disorder and autism, but the link between this protein and the pathology of these diseases remains unclear. Recently, DISC1 has been demonstrated to form insoluble protein aggregates in vitro and in human post-mortem brain tissue but the cellular dynamics of these DISC1 aggregates and their effects on neuronal function are unknown. Using a combination of biochemistry and live cell confocal and video microscopy, we characterize the properties of DISC1 aggregates and their effects on cellular function. We demonstrate that DISC1 protein aggregates are recruited to the aggresome and degraded there by the autophagic pathway. We show that there is a compromised exchange between DISC1 in aggresomes and the cytosolic DISC1 pool, and that the large DISC1 aggregates, which can also co-recruit endogenous soluble DISC1, exhibit altered trafficking. Moreover, we demonstrate that large DISC1 aggregates have a pathological effect in neurons by causing the disruption of intracellular transport of key organellar cargo, such as mitochondria. These data, therefore, show that DISC1 is recruited to aggresomes with negative effects on neuronal function, and suggests a novel DISC1-based mechanism for neuronal pathology. © The Author 2012. Published by Oxford University Press. All rights reserved.

Nolting B.,Pfizer
Methods in Molecular Biology | Year: 2013

Antibody-drug conjugates (ADCs), which combine the specificity, favorable pharmacokinetics, and biodistribution of a monoclonal antibody (mAb) with the cytotoxic potency of a drug, are promising new therapies for cancer. Along with the development of monoclonal antibodies (mAbs) and cytotoxic drugs, the design of the linker is of essential importance, because it impacts the efficacy and tolerability of ADCs. The linker needs to provide sufficient stability during systemic circulation but allow for the rapid and efficient release of the cytotoxic drug in an active form inside the tumor cells. This review provides an overview of linker technologies currently used for ADCs and advances that have resulted in linkers with improved properties. Also provided is a brief summary of some considerations for the conjugation of antibody and drug linker such as drug-to-antibody ratio and site of conjugation. © Springer Science+Business Media, LLC 2013.

Stuart S.A.,University of Bristol | Butler P.,Pfizer | Munafo M.R.,University of Bristol | Nutt D.J.,Imperial College London | Robinson E.S.J.,University of Bristol
Neuropsychopharmacology | Year: 2013

The subjective measures used to study mood disorders in humans cannot be replicated in animals; however, the increasing application of objective neuropsychological methods provides opportunities to develop translational animal tasks. Here we describe a novel behavioral approach, which has enabled us to investigate similar affective biases in rodents. In our affective bias test (ABT), rats encounter two independent positive experiences-the association between food reward and specific digging substrate-during discrimination learning sessions. These are performed on separate days under either neutral conditions or during a pharmacological or affective state manipulation. Affective bias is then quantified using a preference test where both previously rewarded substrates are presented together and the rat's choices recorded. The absolute value of the experience is kept consistent and all other factors are counterbalanced so that any bias at recall can be attributed to treatment. Replicating previous findings from studies in healthy volunteers, we observe significant positive affective biases following acute treatment with typical (fluoxetine, citalopram, reboxetine, venlafaxine, clomipramine) and atypical antidepressants (agomelatine, mirtazapine), and significant negative affective biases following treatment with drugs associated with inducing negative affective states in humans (FG7142, rimonabant, 13-cis retinoic acid). We also observed that acute psychosocial stress and environmental enrichment induce significant negative and positive affective biases, respectively, and provide evidence that these affective biases involve memory consolidation. The positive and negative affective biases induced in our test also mirror the antidepressant and pro-depressant effects of these drugs in patients suggesting our test has both translational and predictive validity. Our results suggest that cognitive affective biases could contribute to drug-or stress-induced mood changes in people and support the hypothesis that a cognitive neuropsychological mechanism contributes to antidepressant drug efficacy. © 2013 American College of Neuropsychopharmacology. All rights reserved.

Scott Obach R.,Pfizer
Pharmacological Reviews | Year: 2013

Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are converted to metabolites that can retain the intrinsic affinity of the parent drug for the pharmacological target. Drug metabolism redox reactions such as heteroatom dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations can yield active metabolites, and in rare cases even conjugation reactions can yield an active metabolite. To understand the contribution of an active metabolite to efficacy relative to the contribution of the parent drug, the target affinity, functional activity, plasma protein binding, membrane permeability, and pharmacokinetics of the active metabolite and parent drug must be known. Underlying pharmacokinetic principles and clearance concepts are used to describe the dispositional behavior of metabolites in vivo. A method to rapidly identify active metabolites in drug research is described. Finally, over 100 examples of drugs with active metabolites are discussed with regard to the importance of the metabolite(s) in efficacy and safety. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Lanas A.,University of Zaragoza | Garcia-Tell G.,University of Valencia | Armada B.,Pfizer | Oteo-Alvaro A.,Service of Orthopedics
BMC Medicine | Year: 2011

Background: Prescription of non-steroidal anti-inflammatory drugs (NSAIDs) should be based on the assessment of both gastrointestinal (GI) and cardiovascular (CV) risk for the individual patient. We aimed to assess the GI/CV risk profile and the pharmacological management of patients with osteoarthritis (OA) in clinical practice.Methods: We conducted a cross-sectional, multicentre, observational study of consecutive OA patients that visited 1,760 doctors throughout the Spanish National Health System (NHS) in a single day. The presence of GI risk factors, CV histories, hypertension and current pharmacological treatments was recorded.Results: Of the 60,868 patients, 17,105 had a diagnosis of OA and were evaluable. The majority (93.4%) had more than one GI risk factor and 60.3% were defined to be at high-GI risk. Thirty-two percent had a history of CV events, 57.6% were treated with anti-hypertensive therapy and 22.6% had uncontrolled hypertension. One-fifth of patients were treated with non-NSAID therapies, whereas the remaining patients received NSAIDs. Non-selective NSAIDs (nsNSAID) plus proton pump inhibitor (PPI) or cyclooxigenase-2 (COX-2)-selective NSAIDs alone were more frequently prescribed in patients at increased GI risk. Patients with a positive CV history received nsNSAIDs or COX-2-selective NSAIDs in 41.3% and 31.7% of cases, respectively. When both the GI and CV histories were combined, 51% of the overall population was being prescribed drugs that were either not recommended or contraindicated.Conclusions: Over 90% of patients with OA are at increased GI and/or CV risk. In over half of these patients, the prescription of NSAIDs was not in accordance with current guidelines or recommendations made by regulatory agencies. © 2011 Lanas et al; licensee BioMed Central Ltd.

Wu J.,University of Liverpool | Tang W.,University of Liverpool | Pettman A.,Pfizer | Xiao J.,University of Liverpool
Advanced Synthesis and Catalysis | Year: 2013

Promoted by iodide anion the rhodium complex dimer, [Cp RhCl 2]2, catalyzes efficiently the transfer hydrogenation of various quaternary pyridinium salts under mild conditions, affording not only piperidines but also 1,2,3,6-tetrahydropyridines in a highly chemoselective fashion, depending on the substitution pattern at the pyridinium ring. The reduction is conducted in azeotropic formic acid/triethylamine (HCOOH-Et 3N) mixture at 40 °C, with catalyst loadings as low as 0.005mol% being feasible. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Zhang X.,Pfizer | Long Q.,Emory University
Biometrical Journal | Year: 2012

In many clinical trials, the primary endpoint is time to an event of interest, for example, time to cardiac attack or tumor progression, and the statistical power of these trials is primarily driven by the number of events observed during the trials. In such trials, the number of events observed is impacted not only by the number of subjects enrolled but also by other factors including the event rate and the follow-up duration. Consequently, it is important for investigators to be able to monitor and predict accurately patient accrual and event times so as to predict the times of interim and final analyses and enable efficient allocation of research resources, which have long been recognized as important aspects of trial design and conduct. The existing methods for prediction of event times all assume that patient accrual follows a Poisson process with a constant Poisson rate over time; however, it is fairly common in real-life clinical trials that the Poisson rate changes over time. In this paper, we propose a Bayesian joint modeling approach for monitoring and prediction of accrual and event times in clinical trials. We employ a nonhomogeneous Poisson process to model patient accrual and a parametric or nonparametric model for the event and loss to follow-up processes. Compared to existing methods, our proposed methods are more flexible and robust in that we model accrual and event/loss-to-follow-up times jointly and allow the underlying accrual rates to change over time. We evaluate the performance of the proposed methods through simulation studies and illustrate the methods using data from a real oncology trial. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Wallis R.S.,Pfizer
Clinical Infectious Diseases | Year: 2013

Six new antituberculosis compounds in 4 classes are presently in clinical trials. Although these show substantial promise for drug-resistant (DR) tuberculosis, the presently planned studies of these compounds will not inform their optimal use, as each will be tested singly vs placebo with existing drugs, rather than in new regimens. Each successive regulatory approval will increase the size, cost, and complexity of trials for those that follow, causing delays during which suboptimal use will occur and resistance will emerge. This paper proposes the development of a novel regimen with the potential for use in both drug-sensitive (DS) and DR tuberculosis. Adaptive licensing for DR tuberculosis based on 2-month sputum culture would shorten time to initial approval by several years. A global outcomes registry would confirm safety and effectiveness in both DS and DR tuberculosis, making possible the second transformation of tuberculosis treatment. We should do our utmost to see it succeed. © 2012 The Author.

Balode A.,Riga Stradins University | Punda-Polic V.,University of Split | Dowzicky M.J.,Pfizer
International Journal of Antimicrobial Agents | Year: 2013

The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) commenced in 2004 to longitudinally monitor global changes in bacterial susceptibility to a suite of antimicrobial agents. The current study examined the activity of tigecycline and comparators against isolates collected across Eastern Europe between 2004 and 2010. Minimum inhibitory concentrations were determined using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodologies. Antimicrobial susceptibility was determined using CLSI interpretive criteria, and tigecycline susceptibility was established using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. This study included 10 295 Gram-negative and 4611 Gram-positive isolates from 42 centres. Extended-spectrum β-lactamases (ESBLs) were reported among 15.3% of Escherichia coli and 39.3% of Klebsiella pneumoniae isolates; the highest rates were observed in Turkey (30.9%) and Bulgaria (53.8%), respectively. Imipenem-non-susceptible K. pneumoniae were identified only in Turkey. ESBL-positive E. coli were highly susceptible to imipenem (95.1%), meropenem (98.0%) and tigecycline (98.5%). Most antimicrobials showed poor activity against Acinetobacter baumannii and Pseudomonas aeruginosa. Vancomycin resistance was noted among 0.9% of Enterococcus faecalis and 11.7% of Enterococcus faecium isolates. High rates of susceptibility were reported for linezolid (99.7%) and tigecycline (100%) against E. faecium. One-quarter of Staphylococcus aureus isolates were meticillin-resistant S. aureus (MRSA), with the highest rate in Romania (51.5%); all MRSA were susceptible to linezolid, tigecycline and vancomycin. Antimicrobial resistance is high in much of Eastern Europe, with considerable variation seen among countries. Tigecycline and the carbapenems retain excellent activity against many pathogens from Eastern Europe; linezolid and vancomycin are active against most Gram-positive pathogens. © 2013 Elsevier B.V. and the International Society of Chemotherapy.

Currently, no serum biomarkers, including the biochemical gold standard alanine aminotransferase, can differentiate drug-induced from non-drug-related liver injury, can differentiate liver injury mediated by a specific drug or mechanism, or can accurately predict the progression and outcome of hepatic injury. Efforts have been made by veterinary clinical pathologists, toxicologists, and other scientists to address the gaps in hepatic biomarkers faced during drug development; although there have been no breakthroughs, several novel biomarker candidates have been identified. Efforts to address the gaps in translatable hepatic biomarkers and the challenges and hurdles faced during this process are highlighted in this review. © 2011 Elsevier Inc.

Zhou J.Z.,Pfizer
Methods in molecular biology (Clifton, N.J.) | Year: 2011

This chapter provides a brief overview of chemoinformatics and its applications to chemical library design. It is meant to be a quick starter and to serve as an invitation to readers for more in-depth exploration of the field. The topics covered in this chapter are chemical representation, chemical data and data mining, molecular descriptors, chemical space and dimension reduction, quantitative structure-activity relationship, similarity, diversity, and multiobjective optimization.

Offord J.,Pfizer | Offord J.,University of Michigan
Pharmacology and Therapeutics | Year: 2012

Bipolar disorder is a disease which causes major disability. The disease has both a manic and depressive component. Current standard of care consists of atypical antipsychotics for the treatment of mania, antidepressants for the treatment of depression, and mood stabilizers for the maintenance of euthymia. The molecular mechanisms which cause the disease are not well understood. Genome wide association studies have provided a set of genes which are linked to the disease. These genes show linkage to physiological and neuroanatomical alterations which are also seen in bipolar disorder. © 2011 Elsevier Inc. All rights reserved.

Cook J.A.,Pfizer
Biopharmaceutics and Drug Disposition | Year: 2012

Product development is typically challenging. There is a strong desire to understand critical performance factors early in order to optimize formulations for Phase III trials or marketing approval. However, over 90% of drugs entering development in humans do not make it to the market. Thus there is a tremendous risk that resources spent early in development will be wasted as candidates attrite. To overcome this apparent dilemma, a Bayesian approach is suggested. In 'traditional' product development, clinical study designs are typically relatively assumption free and often do not consider learning from earlier investigations. A Bayesian approach is one in which prior information is considered when interpreting the results of the current study. A candidate IVIVC can be developed at the earliest stage of clinical development. Subsequently there are multiple opportunities within a typical development program to assess the performance of the preliminary IVIVC as new formulations are introduced. With each introduction, there is an opportunity to either confirm the adequacy of the IVIVC or to identify the need for development of a more predictive dissolution test and IVIVC. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd.

Ranke M.B.,University Hospital of Tuebingen | Lindberg A.,Pfizer
BMC Medical Informatics and Decision Making | Year: 2011

Background: Mathematical models can be developed to predict growth in short children treated with growth hormone (GH). These models can serve to optimize and individualize treatment in terms of height outcomes and costs. The aims of this study were to compile existing prediction models for short children born SGA (SGA), to develop new models and to validate the algorithms. Methods. Existing models to predict height velocity (HV) for the first two and the fourth prepubertal years and during total pubertal growth (TPG) on GH were applied to SGA children from the KIGS (Pfizer International Growth Database) - 1 st year: N = 2340; 2nd year: N = 1358; 4th year: N = 182; TPG: N = 59. A new prediction model was developed for the 3 rd prepubertal year based upon 317 children by means of the all-possible regression approach, using Mallow's C(p) criterion. Results: The comparison between the observed and predicted height velocity showed no significant difference when the existing prediction models were applied to new cohorts. A model for predicting HV during the 3rd year explained 33% of the variability with an error SD of 1.0 cm/year. The predictors were (in order of importance): HV previous year; chronological age; weight SDS; mid-parent height SDS and GH dose. Conclusions: Models to predict growth to GH from prepubertal years to adult height are available for short children born SGA. The models utilize easily accessible predictors and are accurate. The overall explained variability in SGA is relatively low, due to the heterogeneity of the disorder. The models can be used to provide patients with a realistic expectation of treatment, and may help to identify compliance problems or other underlying causes of treatment failure. © 2011 Ranke et al; licensee BioMed Central Ltd.

Introduction: Drug abuse is an increasing social and public health issue, putting the onus on drug developers and regulatory agencies to ensure that the abuse potential of novel drugs is adequately assessed prior to product launch.Areas covered: This review summarizes the core preclinical data that frequently contribute to building an understanding of abuse potential for a new molecular entity, in addition to highlighting models that can provide increased resolution regarding the level of risk. Second, an important distinction between abuse potential and addiction potential is drawn, with comments on how preclinical models can inform on each.Expert opinion: While the currently adopted preclinical models possess strong predictive validity, there are areas for future refinement and research. These areas include a more refined use of self-Administration models to assess relative reinforcement; and the need for open innovation in pursuing improvements. There is also the need for careful scientifically driven application of models rather than a standardization of methodologies, and the need to explore the opportunities that may exist for enhancing the value of physical dependence and withdrawal studies by focusing on withdrawal-induced drug seeking, rather than broad symptomology. © Informa UK, Ltd.

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human © 2014 Elsevier Inc.

Background: We report here on 14438 Streptococcus pneumoniae and 14770 Haemophilus influenzae isolates collected from 560 centres globally between 2004 and 2012 as a part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Methods: MIC testing was performed using broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) using CLSI-approved breakpoints; US Food and Drug Administration breakpoints were used for tigecycline as CLSI breakpoints are not available. Results: At least 99% of S. pneumoniae isolates globally were susceptible to levofloxacin, linezolid, tigecycline or vancomycin. Penicillin resistance was observed among 14.8% of S. pneumoniae and was highest in Asia/Pacific Rim (30.1%) and Africa (27.6%); 23.4% of S. pneumoniae isolates were penicillin-intermediate, which were most common in Africa (37.6%). Minocycline susceptibility among S. pneumoniae decreased by 20% between 2004-2008 and 2009-2012. High (>98.5%) susceptibility was reported among H. influenzae to all antimicrobial agents on the T.E.S.T. panel excluding ampicillin, to which only 78.3% were susceptible. β-lactamase production was observed among 20.2% of H. influenzae isolates; 1.5% of isolates were β-lactamase negative, ampicillin-resistant. Conclusions: S. pneumoniae remained highly susceptible to levofloxacin, linezolid, tigecycline and vancomycin while H. influenzae was susceptible to most antimicrobial agents in the testing panel (excluding ampicillin). © 2014 Tomic and Dowzicky.

Modi S.,University of Kentucky | Modi S.,Pfizer | Anderson B.D.,University of Kentucky
Molecular Pharmaceutics | Year: 2013

Dynamic dialysis is one of the most common methods for the determination of release kinetics from nanoparticle drug delivery systems. Drug appearance in the "sink" receiver compartment is a consequence of release from the nanoparticles into the dialysis chamber followed by diffusion across the dialysis membrane. This dual barrier nature inherent in the method complicates data interpretation and may lead to incorrect conclusions regarding nanoparticle release half-lives. Although the need to consider the barrier properties of the dialysis membrane has long been recognized, there is insufficient quantitative appreciation for the role of the driving force for drug transport across that membrane. Reversible nanocarrier binding of the released drug reduces the driving force for drug transport across the dialysis membrane leading to a slower overall apparent release rate. This may lead to the conclusion that a given nanoparticle system will provide a sustained release in vivo when it will not. This study demonstrates these phenomena using model lipophilic drug-loaded liposomes varying in lipid composition to provide variations in bilayer permeability and membrane binding affinities. Model simulations of liposomal transport as measured by dynamic dialysis were conducted to illustrate the interplay between the liposome concentration, membrane/water partition coefficient, and the apparent release rate. Reliable determination of intrinsic liposomal bilayer permeability coefficients for lipophilic drugs by dynamic dialysis requires validation of drug release kinetics at varying nanoparticle concentration and the determination of membrane binding coefficients along with appropriate mechanism-based mathematical modeling to ensure the reliability and proper interpretation of the data. © 2013 American Chemical Society.

Procopiou G.,University of Nottingham | Lewis W.,University of Nottingham | Harbottle G.,Pfizer | Stockman R.A.,University of Nottingham
Organic Letters | Year: 2013

The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented. © 2013 American Chemical Society.

Kalgutkar A.S.,Pfizer
Annual Review of Pharmacology and Toxicology | Year: 2015

Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed. ©2015 by Annual Reviews. All rights reserved.

Hamel E.J.O.,Stanford University | Grewe B.F.,Stanford University | Parker J.G.,Stanford University | Parker J.G.,Pfizer | And 2 more authors.
Neuron | Year: 2015

Fluorescence imaging offers expanding capabilities for recording neural dynamics in behaving mammals, including the means to monitor hundreds of cells targeted by genetic type or connectivity, track cells over weeks, densely sample neurons within local microcircuits, study cells too inactive to isolate in extracellular electrical recordings, and visualize activity in dendrites, axons, or dendritic spines. We discuss recent progress and future directions for imaging in behaving mammals from a systems engineering perspective, which seeks holistic consideration of fluorescent indicators, optical instrumentation, and computational analyses. Today, genetically encoded indicators of neural Ca2+ dynamics are widely used, and those of trans-membrane voltage are rapidly improving. Two complementary imaging paradigms involve conventional microscopes for studying head-restrained animals and head-mounted miniature microscopes for imaging in freely behaving animals. Overall, the field has attained sufficient sophistication that increased cooperation between those designing new indicators, light sources, microscopes, and computational analyses would greatly benefit future progress. © 2015 Elsevier Inc.

Mendes R.E.,JMI Laboratories | Hogan P.A.,Pfizer | Streit J.M.,JMI Laboratories | Jones R.N.,JMI Laboratories | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives To summarize the activity and spectrum of linezolid and comparators tested against 7972 Gram-positive clinical isolates as part of the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) Program for 2012. Moreover, to provide molecular characterization for associated resistance mechanisms and epidemiological typing. Methods A total of 7972 isolates were collected from 73 medical centres (33 countries) on five continents. Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 document. MIC interpretations were based on CLSI and EUCAST criteria. Results Linezolid showed MIC50 and MIC90 results of 1 and 2 mg/L, respectively, when tested against Staphylococcus aureus. These isolates were inhibited by linezolid at ≤2 mg/L, except for four S. aureus exhibiting higher MIC values (4-8 mg/L), which had cfr and/or target site mutations, including a first detection of cfr in an isolate from Brazil. Coagulase-negative staphylococci (CoNS) were susceptible to linezolid (MIC50/90, 0.5/1 mg/L), with only eight isolates exhibiting high MIC results (16-32 mg/L). These CoNS had cfr and/or single or multiple target site alterations in 23S rRNA and/or ribosomal proteins (L3, L4). The same species of linezolid-resistant CoNS collected from the same hospital were clonally related to those observed in previously surveyed years. Linezolid exhibited stable modal MIC and MIC50 results when tested against enterococci, regardless of the species or vancomycin resistance phenotype; in addition, linezolid inhibited all streptococci at ≤2 mg/L. Conclusions This surveillance report documents stable linezolid activity and susceptibility rates against a large and longitudinal collection of clinical isolates worldwide. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Lovering F.,Pfizer
MedChemComm | Year: 2013

Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A number of molecular descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compounds as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic. © 2013 The Royal Society of Chemistry.

Chorghade R.,University of Cambridge | Battilocchio C.,University of Cambridge | Hawkins J.M.,Pfizer | Ley S.V.,University of Cambridge
Organic Letters | Year: 2013

A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 C. © 2013 American Chemical Society.

Ehlers M.D.,Pfizer
Biochemical Society Transactions | Year: 2013

Among the largest cells in the body, neurons possess an immense surface area and intricate geometry that poses many unique cell biological challenges. This morphological complexity is critical for neural circuit formation and enables neurons to compartmentalize cell-cell communication and local intracellular signalling to a degree that surpasses other cell types. The adaptive plastic properties of neurons, synapses and circuits have been classically studied by measurement of electrophysiological properties, ionic conductances and excitability. Over the last 15 years, the field of synaptic and neural electrophysiology has collided with neuronal cell biology to produce a more integrated understanding of how these remarkable highly differentiated cells utilize common eukaryotic cellular machinery to decode, integrate and propagate signals in the nervous system. The present article gives a very brief and personal overview of the organelles and trafficking machinery of neuronal dendrites and their role in dendritic and synaptic plasticity. © 2013 Biochemical Society.

Choy E.,Massachusetts General Hospital | Allen Jacobs I.,Pfizer
Seminars in Oncology | Year: 2014

Biologics are important treatments for a number of cancers. Patents for several biologics will expire over the next decade, removing a barrier to the development and commercialization of biosimilars. As biologics differ from small-molecule drugs due to their size and complexity, multifaceted manufacturing process, and their potential for immunogenicity, biosimilars cannot be considered "generic versions" of currently approved biologics. In highly regulated markets, biosimilars can be authorized only if they are demonstrated to be highly similar to the original drug from an analytical and clinical perspective. Any differences must be justified and shown to have no clinically meaningful effect on the safety and efficacy of the biosimilar. The European Medicines Agency has approved a number of biosimilars and the recent approval of the biosimilar infliximab monoclonal antibody is another regulatory milestone. This article will provide context regarding key safety issues addressed in biosimilar development, approval, and delivery, as well as inform oncologists on matters of safety to consider when prescribing biosimilars. Pertinent issues about safety from countries or regions where biosimilars are currently in use also will be reviewed. © 2014 Elsevier Inc.

Bui L.A.,Inc. GCRI for Personalized Oncology | Taylor C.,Pfizer
Seminars in Oncology | Year: 2014

Biosimilars offer the prospect of providing efficacious and safe treatment options for many diseases, including cancer, while potentially increasing accessibility with greater affordability relative to biologics. Because biologics are large, complex molecules that cannot be exactly duplicated, biosimilars cannot be considered "generic" versions of biologic drugs. This review will examine important considerations for biosimilar clinical trials. Since the aim of biosimilar manufacturing is to produce a molecule highly similar to the reference biologic, a comparability exercise is needed to demonstrate similarity with the reference biologic product based on physicochemical characterization. In vitro analytical studies and in vivo studies as well as pharmacokinetic/pharmacodynamic (PK/PD) assessments also are conducted. Lastly, because it may not be possible to fully characterize a biosimilar in relation to its reference biologic, robust pharmacovigilance strategies are utilized to ensure that any matters in regard to safety can be monitored. Other key topics will be discussed, including regulatory guidance for the evaluation of biosimilars, clinical trial design considerations, and whether data submitted for the approval of a biosimilar for one indication can be extrapolated to other indications for which the reference biologic is approved. European and Canadian experiences in biosimilar development will be reviewed. © 2014 Published by Elsevier Inc.

Background/Aims: The aim was to describe the factors determining total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD), Turner syndrome (TS), who were small for gestational age (SGA) or had idiopathic short stature (ISS). Methods: The patients were documented within KIGS (Pfizer International Growth Database). TPG was defined as growth from puberty onset - spontaneous (>B1 or testes >3 ml) or induced with sex steroids to adult height in idiopathic GHD (n = 639; males 399), TS (n = 463), SGA (n = 59; males 35), and ISS (n = 130; males 87). Algorithms to predict TPG at puberty onset were developed by multiple linear regression analysis. Results: In GHD (males, females) and TS TPG could be explained with the same four predictors: (1) age (years) at puberty onset (neg.), (2) age - bone age at puberty onset (pos.), (3) height - midparental height (SDS) at puberty onset (neg.), and (4) mean dose of growth hormone (GH) during puberty (pos.). The algorithms explained 66, 65 and 68%, respectively, of the variability with total errors of 4.5, 3.8 and 2.9 cm, in spontaneous and induced TPG. Conclusions: TPG is determined by the same factors at puberty onset in adolescents with GHD, TS, SGA or ISS treated with GH. Thus, TPG depends mostly on the outcomes achieved at the end of prepubertal growth and less so on the dose of GH. Copyright © 2011 S. Karger AG, Basel.

Bobes J.,University of Oviedo | Arango C.,Hospital General Universitario Gregorio Maranon | Garcia-Garcia M.,Biometria Clinica CRO | Rejas J.,Pfizer
Schizophrenia Research | Year: 2010

Aim: We analysed the impact of tobacco smoking over several healthy lifestyle habits along with the impact on 10-years cardiovascular event (CVE) risk in the CLAMORS schizophrenia cohort. Methods: This analysis was performed within the scope of the CLAMORS study which included consecutive outpatients meeting DSM-IV criteria for schizophrenia spectrum disorder. Beside smoking history, data on usual healthy lifestyle habits included current exercise, saturated fat sparing diet, low-caloric diet, and daily dietary fibre, salt, caffeine and alcohol consumption were recorded. The 10-year CVE risk was calculated with Framingham function. Results: 1704 patients (61.1% male), 18 to 74. years were examined. Prevalence of smoking was 54.54% (95% CI: 52.16%-56.90%) significantly higher than in age and sex matched general population subjects, 31.51% (31.49%-31.52%); OR=2.61 (2.37-2.87, p<0.0001). After controlling by confounders smokers showed a 10-year CVE risk excess versus non-smokers of 2.63 (2.16-3.09), p<0.001. Smoking cessation would reduce the likely of high/very high 10-year CVE risk (above 10%) by near 90% [OR=0.10 (0.06-0.18), p<0.0001]. Also, smokers were more likely to consume alcohol daily [4.13 (3.07-5.54), p<0.0001] and caffeine [3.39 (2.72-4.23), p<0.0001] than non-smoker patients with schizophrenia, and less likely to avoid daily consumption of salt [0.58 (0.43-0.78), p<0.0001], saturated fat [0.71 (0.56-0.91), p=0.006], high fibre diet [0.67 (0.53-0.84), p=0.001], or to follow a low-caloric diet [0.63 (0.48-0.81), p<0.0001]. Smokers also were less likely to do exercise habitually [0.62 (0.48-0.82, p=0.001]. Conclusion: Compared with the general population, patients with schizophrenia showed significant higher prevalence of smoking. Smokers who stop smoking would benefit by a near 90% reduction in the likely of 10-year cardiovascular event risk above 10%. © 2010 Elsevier B.V.

This perspective examines the environmental impact which is the result of variable global approval times in the pharmaceutical industry. In the first part of the paper several case histories are presented demonstrating the positive environmental benefits of second generation chemistry. This positive benefit is partially negated by the variable approval times from regulatory agencies and in the second part of the paper the results of a survey of approval times in the US, EU and globally are presented. © 2013 The Royal Society of Chemistry.

Mico J.-A.,University of Cadiz | Prieto R.,University of Cadiz | Prieto R.,Pfizer
CNS Drugs | Year: 2012

This review provides a brief summary of what is known about the anxiolytic mechanism of action of pregabalin, a highly selective, high-affinity ligand of the PQ type of voltage-gated calcium channel (CaV). Evidence from in vivo models of neuronal hyperexcitability suggests that pregabalin reduces synaptic release of neurotransmitters in selected CNS regions including the cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum and dorsal horn of the spinal cord. Release of neurotransmitters from the synaptic vesicle, and propagation of neurotransmission, requires the vesicle to fuse with the presynaptic membrane. Pregabalin binding to the α2δ type 1 protein of the PQ type CaV reduces the availability of Ca2 required for membrane fusion and exocytosis of neurotransmitters. Evidence that the anxiolytic mechanism of action of pregabalin is mediated by binding to the α2δ type 1 protein comes from animal models, which have demonstrated a structure-activity relationship between the affinity of ligands for the α2δ type 1 protein and their potency in models of anxiety such as the Vogel conflict test. Furthermore, the anxiolytic activity of pregabalin is lost in transgenic mice with specific point mutations in the CaV α2δ type 1 protein. Pregabalin-mediated reduction in calcium currents has also been shown to result in a significant inhibition of the release of neurotransmitters implicated in pathological anxiety such as glutamate and monoamine neurotransmitters. However, further research is needed to confirm that these effects contribute to the anxiolytic mechanism of action of pregabalin. Finally, pregabalin may also act by inhibiting synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of CaV to the plasma membrane. © 2012 Springer International Publishing AG. All rights reserved.

Liu P.,Pfizer | Mould D.R.,Projections Research Inc.
Antimicrobial Agents and Chemotherapy | Year: 2014

To assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC 0-12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479). Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Porteous D.J.,University of Edinburgh | Millar J.K.,University of Edinburgh | Brandon N.J.,Pfizer | Sawa A.,Johns Hopkins University
Trends in Molecular Medicine | Year: 2011

Psychiatric genetics research, as exemplified by the DISC1 gene, aspires to inform on mental health etiology and to suggest improved strategies for intervention. DISC1 was discovered in 2000 through the molecular cloning of a chromosomal translocation that segregated with a spectrum of major mental illnesses in a single large Scottish family. Through in vitro experiments and mouse models, DISC1 has been firmly established as a genetic risk factor for a spectrum of psychiatric illness. As a consequence of its protein scaffold function, the DISC1 protein impacts on many aspects of brain function, including neurosignaling and neurodevelopment. DISC1 is a pathfinder for understanding psychopathology, brain development, signaling and circuitry. Although much remains to be learnt and understood, potential targets for drug development are starting to emerge, and in this review, we will discuss the 10 years of research that has helped us understand key roles of DISC1 in psychiatric disease. © 2011 Elsevier Ltd.

The Antibody Drug Conjugate (ADC) is a therapeutic modality consisting of a monoclonal antibody attached to a cytotoxic, small-molecule payload. The antibody portion of the ADC serves as a transport vehicle that recognizes and binds to a protein antigen expressed in tumor tissues. The localized delivery and release of the payload within or near malignant cells allows for targeted delivery of a potent cytotoxic agent to diseased tissue, while reducing damage to antigen-negative, normal tissues. Recent years have witnessed an explosive increase in ADC-based therapies, due mainly to clinical reports of activity in both hematologic and epithelial cancers. Accompanying this upsurge in ADC development is a renewed interest in natural product cytotoxins, which are typically highly potent cell-killing agents, but suffer from poor drug-like properties and narrow safety margins when systemically administered as conventional chemotherapeutics. In this review, we discuss recent advances related to the construction of ADCs, the optimization of ADC safety and efficacy, and the increasingly pivotal roles of natural product payloads in the current and future landscape of ADC therapy.

Non-inferiority trials are experimental models designed to determine whether a new treatment or procedure is not less effective than an established one, which is considered as standard. They are especially important in the assessment of treatments in which the use of placebo is impracticable. They differ substantially from the classical superiority trials and require different approach, especially in the planning and the data analysis. This paper is a review of the key differences between non-inferiority and traditional clinical studies. There is a considerable amount of misunderstanding on the correct use of this experimental design, which certainly compromises the credibility of some clinical assessments.

Multiple-active anthelmintic formulations (combinations of anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance) are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (i) to enable the effective control of nematodes in the presence of single or multiple drug resistance and (ii) to slow development of resistance to the component anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the anthelmintics in the combination. The question then becomes whether these criteria are likely to be fulfilled under field conditions. Concerns include the potential to select for resistance to multiple anthelmintic classes concurrently if there are insufficient parasites in refugia, the potential for shared mechanisms of resistance between chemical classes of anthelmintics, the need for further empirical validation of computer simulations, the pre-existing frequency of resistance alleles which may be too high on some farms to warrant introduction of certain combinations and the potential encouragement of farmers to prepare their own mixtures and/or neglect other management principles for sustainable parasite control. In conclusion, multiple-active formulations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable anthelmintic use. © 2012 Elsevier B.V.

Brandon N.J.,Pfizer | Sawa A.,Johns Hopkins University
Nature Reviews Neuroscience | Year: 2011

Recent advances in our understanding of the underlying genetic architecture of psychiatric disorders has blown away the diagnostic boundaries that are defined by currently used diagnostic manuals. The disrupted in schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of an inherited chromosomal translocation, which segregates with major mental illnesses. In addition, many biological studies have indicated a role for DISC1 in early neurodevelopment and synaptic regulation. Given that DISC1 is thought to drive a range of endophenotypes that underlie major mental conditions, elucidating the biology of DISC1 may enable the construction of new diagnostic categories for mental illnesses with a more meaningful biological foundation. © 2011 Macmillan Publishers Limited. All rights reserved.

To characterize the in vitro binding and effector function properties of CD20-directed small modular immunopharmaceutical (SMIP) 2LM20-4, and to compare its in vivo B-cell depletion activity with the mutated 2LM20-4 P331S [no in vitro complement-dependent cytotoxicity (CDC)] and rituximab in cynomolgus monkeys. Direct binding is examined in flow cytometry, confocal microscopy, scatchard and lipid raft assays. Effector function assays include CDC and Fc-mediated cellular toxicity. In the 6-month-long in vivo B-cell depletion study, single i.v. dosages of 1 or 10 mg/kg of anti-CD20 proteins were administered to monkeys and B-cell counts were monitored in peripheral blood, bone marrow and lymph nodes. 2LM20-4 has lower saturation binding to human primary B cells and recruits fewer CD20 molecules into lipid rafts compared with rituximab; however, it induces higher in vitro CDC. In competitive binding, 2LM20-4 only partially displaces rituximab, suggesting that it binds to a fraction of CD20 molecules within certain locations of the plasma membrane as compared with rituximab. In monkeys, 2LM20-4 had more sustained B-cell depletion activity than rituximab in peripheral blood and had significantly more profound and sustained activity than 2LM20-4 P331S and rituximab in the lymph nodes. SMIP 2LM20-4, which binds to a fraction of CD20 molecules as compared with rituximab, has more potent in vitro CDC, and more potent and sustained B-cell depletion activity in cynomolgus monkeys. Our work has considerable clinical relevance since it provides novel insights related to the emerging B-cell depletion therapies in autoimmune diseases.

Certain idiosyncratic adverse drug reactions (IADRs) can be triggered by electrophilic protein-reactive metabolites that are formed in the process of drug metabolism. While methodologies (e.g., structural alert concept in drug design, glutathione (GSH) trapping, and protein covalent binding) for examining reactive metabolite (RM) formation are available, predicting the IADR potential applying these parameters remains a significant challenge. The present work examines toxicity trends associated with the aniline structural alert in the top 200 prescribed drugs of 2011 and recently approved (2009-2013) small molecule drugs, in relation with 30 aniline-based drugs withdrawn from commercial use or associated with a black box warning for IADRs. The aniline sub-structure was found in several drugs from the toxic, mostprescribed, and recently approved category. RMs resulting from the bioactivation of the aniline alert was also noted in the three categories chosen for comparison. A major discriminator between the toxic drugs and the majority of drugs in the most-prescribed list, however, was the daily dose - drugs most frequented associated with IADRs were the ones with higher daily doses (exceeding hundreds of milligrams). A greater tolerance for IADRs was also noted with certain drugs intended to treat rare, unmet medical needs (e.g., cancer). Overall, the analysis suggests that optimization of pharmacologic potency and pharmacokinetics that would lead to a lower daily dose, and therefore, a lower body burden of parent drug/metabolites, should be taken into consideration in drug discovery. © 2015 Bentham Science Publishers.

Lamoureux F.,University of British Columbia | Thomas C.,University of British Columbia | Yin M.-J.,Pfizer | Fazli L.,University of British Columbia | And 2 more authors.
European Urology | Year: 2014

Background Although prostate cancer responds initially to androgen ablation therapies, progression to castration-resistant prostate cancer (CRPC) frequently occurs. Heat shock protein (Hsp) 90 inhibition is a rational therapeutic strategy for CRPC that targets key proteins such as androgen receptor (AR) and protein kinase B (Akt); however, most Hsp90 inhibitors trigger elevation of stress proteins like Hsp27 that confer tumor cell survival and treatment resistance. Objective We hypothesized that cotargeting the cytoprotective chaperone Hsp27 and Hsp90 would amplify endoplasmic reticulum (ER) stress and treatment-induced cell death in cancer. Design, setting, and participants Inducible and constitutive Hsp27 and other HSPs were measured by real-time reverse transcription-polymerase chain reaction and immunoblot assays. The combinations of OGX-427 with Hsp90 inhibitors were evaluated in vitro for LNCaP cell growth and apoptosis and in vivo in CRPC LNCaP xenograft models. Outcome measurements and statistical analysis Tumor volumes were compared using the Kruskal-Wallis test. Overall survival was analyzed using Kaplan-Meier curves, and statistical significance was assessed with the log-rank test. Results and limitations Hsp90 inhibitors induced expression of HSPs in tumor cells and tissues in a dose- and time-dependent manner; in particular, Hsp27 mRNA and protein levels increased threefold. In vitro, OGX-427 synergistically enhanced Hsp90 inhibitor-induced suppression of cell growth and induced apoptosis by 60% as measured by increased sub-G1 fraction and poly(ADP-ribose) polymerase cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR, and prostate-specific antigen, and induction of ER stress markers (cleaved activating transcription factor 6, glucose-regulated protein 78, and DNA-damage-inducible transcript 3). In vivo, OGX-427 potentiated the anticancer effects of Hsp90 inhibitor PF-04929113 (orally, 25 mg/kg) to inhibit tumor growth and prolong survival in CRPC LNCaP xenografts. Conclusions HSP90 inhibitor-mediated induction of Hsp27 expression can be attenuated by OGX-427, resulting in increased ER stress and apoptosis, and synergistic inhibition of CRPC tumor growth. Patient summary This study supports the development of targeted strategies using OGX-427 in combination with Hsp90 inhibitors to improve patient outcome in CRPC. © 2013 European Association of Urology.

Kemp M.I.,Pfizer
Progress in Medicinal Chemistry | Year: 2010

Publisher Summary The chapter examines the second-generation voltage-gated sodium (Nav) channel blockers and patent applications of the past decade and highlights structural trends by clustering compounds with similar structures. The term 'second generation' refers to compounds identified in the search for Nav subtype selectivity, as opposed to compounds whose Nav activity was characterized subsequent to their use in the clinic. Nav channels are transmembrane proteins that control the flow of sodium ions across cell membranes. They are important regulators of cellular excitability, contributing to the initiation and propagation of action potentials in neurons, heart and muscle. The term 'structural trends' refers to two-dimensional substructure motifs shared between compounds. This chapter discusses small-molecule Nav channel blockers. Blockers act as channel modulators, stabilizing one of the non-conducting states. An examination of structural trends among Nav channel blockers showed that the structure-activity relationships (SAR) are subtle and unpredictable. Small structural changes switch the selectivity between TTX-sensitive and TTX-resistant members, however these changes are often highly scaffold specific. Further developments in understanding the fine structure of Nav channels will help to rationalize these findings and facilitate the next round of drug design for these clinically important targets. © 2010 Elsevier B.V.

Jones H.M.,Pfizer | Rowland-Yeo K.,Simcyp Ltd
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

The aim of this tutorial is to introduce the concept of physiologically based pharmacokinetic (PBPK) modeling to individuals in the pharmaceutical industry who may be relatively new to this area and to demonstrate application of this approach in a preclinical and clinical setting. The tutorial provides some background on PBPK models and their data requirements, introduces strategies for PBPK modeling in drug development, and includes a discussion on regulatory considerations and potential resource issues. © 2013 ASCPT All rights reserved.

Lycopene, a carotenoid produced by some commonly consumed plants such as tomatoes, is not synthesized by animals. Thus, the levels of lycopene found in the breast milk of lactating females reflect the dietary lycopene supply. Lycopene has potent antioxidant activity but has also been implicated in modulating immune function. Therefore, lycopene in breast milk has the potential to affect the development and/or function of the immune system in the suckling pups. Here, we have investigated the impact of breast milk lycopene on systemic and mucosal immunity in mouse neonates. Diets containing 0.3 g/kg lycopene (Lyc) or control (Con) diets were fed to mouse dams beginning at late gestation and continuing throughout lactation. Seven-day-old female BALB/c pups were parenterally immunized with a model vaccine antigen dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) and then reimmunized as adults. The levels of DNP-KLH-specific IgG in the sera as well as keyhole limpet hemocyanin-specific IFNγ and IL-4 production by splenic CD4 + cells were similar in the Lyc and Con pups. In addition, female neonatal (d7) C57BL/6 Lyc and Con pups were infected orally with the enteropathogen Yersinia enterocolitica. Breast milk lycopene had no effect on the recruitment of neutrophils to intestinal lymphoid tissues or on bacterial tissue colonization of the intestines, spleens, and livers. Thus, suckling pups exposed to lycopene in breast milk appear to develop normal innate and adaptive responses both systemically and at intestinal mucosal surfaces. © 2011 American Society for Nutrition.

Huang L.-M.,National Taiwan University Hospital | Lin T.-Y.,Chang Gung University | Juergens C.,Pfizer
Vaccine | Year: 2012

Immunogenicity and safety of 13-valent and 7-valent pneumococcal conjugate vaccines (PCV13; PCV7) were compared in Taiwanese children.In this double-blind, multicenter study, healthy children were randomly assigned to receive PCV13 (n= 84) or PCV7 (n= 84) at 2, 4, 6 and 15 months with routine pediatric vaccines.For the 7 PCV13/PCV7 common serotypes, serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) were high 1 month postinfant series, with ≥95.0% in both groups achieving IgG levels ≥0.35 μg/mL, with a trend to lower IgG GMCs for PCV13 compared with PCV7 (PCV13:PCV7 GMC ratios 0.59-0.91). For the 6 additional serotypes unique to PCV13, GMCs were notably higher after PCV13 than PCV7 (PCV13:PCV7 GMC ratios 1.50-202.58). Immune responses generally increased posttoddler dose. Safety was similar between groups.PCV13 was safe and immunogenic in this Taiwanese population. PCV13 should offer broader protection than PCV7 against pneumococcal disease.Clinical trials registration number: NCT00688870. © 2012 Elsevier Ltd.

Gualberto A.,Pfizer
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Figitumumab is being developed as a highly potent and specific fully human IgG2 monoclonal antibody against the IGF Type 1 receptor (IGF-IR) for the treatment of cancer. Areas covered in this review: This manuscript reviews the rationale, preclinical data and early clinical results of the figitumumab development program. Early trials were initiated in 2003 and initial reports appeared in 2006. What the reader will gain: Figitumumab has an effective half life of approximately 20 days and has been generally well tolerated in clinical trials. Initial pharmacodynamic studies suggested that IGF-IR overexpression and increased bioactivity of IGFs constitute independent mechanisms of tumor sensitivity to figitumumab. Single-agent activity has been noted in Ewing's sarcoma and a recently completed proof-of-concept study suggested that figitumumab may be active in NSCLC. Take home message: The strong biologic rationale for IGF-IR targeting in multiple types of human cancer and the feasibility of combination with full doses of therapies that constitute the standard of care in a variety of oncology indications have justified an expanded clinical program in multiple areas of unmet medical need in oncology. © 2010 Informa UK Ltd.

Hellio Le Graverand-Gastineau M.-P.,Pfizer
Current Drug Targets | Year: 2010

Osteoarthritis (OA) is a slowly, progressive, ultimately degenerative disorder of movable joints, mainly characterized by joint pain and functional limitation and affecting all joint structures not just articular cartilage, but also the subchondral bone, ligaments, capsule, synovial membrane, and menisci. OA occurs when the equilibrium between breakdown and repair of the joint tissues becomes unbalanced. There are currently no pharmacological interventions available to patients for modifying the underlying disease (DMOADs) in relation to major drug development challenges. The current regulatory draft guidances for clinical development programs for DMOAD agents suggest radiographic joint space narrowing (JSN) as a primary endpoint. However, research efforts must continue to characterize imaging alternatives with greater sensitivity to change to enable development of new DMOADs. Past experience with DMOAD clinical trials indicate that pharmacologic agents must demonstrate pristine safety, and that consideration for special populations is important to avoid failed studies. More research is needed to determine what constitutes clinically meaningfulness for DMOAD activity in particular as it relates to OA progression. Current research pursues a variety of molecular targets including anti-catabolic agents to slow or halt OA progression and anabolic drugs to induce cartilage regrowth. © 2010 Bentham Science Publishers Ltd.

Zganjer V.,Pfizer
Acta medica (Hradec Králové) / Universitas Carolina, Facultas Medica Hradec Králové | Year: 2011

There are many ways how children with mental illness have actually tried to hurt themselves. Suicidal thinking or attempts always indicate that professional help is needed (2). Every object which can be potential dangerous should be removed but this is very difficult to do. Some of children with these symptoms had Pica diseases. Pica is a medical disorder characterized by an appetite for substances largely non-nutritive (e.g. metal, coal, soil, feces, paper, soap, gum, etc.) or an abnormal appetite for some things that may be considered foods. The patient swallow sponge from a pillow over a long period of time and she came into our hospital with abdominal pain. She was 16 years old and had abdominal distension, vomiting, abdominal cramping and failure to pass gas or stool. Immediately we suspected mechanical blockade of the intestine. Diagnosis was clinically confirmed by X-rays of the abdomen and with ultrasound. The operative treatment was indicated and we found the proximal bowel distended and the distal segment collapsed. The part of bowel necrosis was removed and anastomosis was done. When patients are determined to attempt suicide or have Pica disorder it is very difficult to prevent.

Wei R.,Pfizer
Current Drug Metabolism | Year: 2011

Metabolomics is emerging as a promising systems biology approach for many research fields including functional genomics, disease diagnosis, nutrition science, and drug discovery. Following rapid development in academic and research institutes, metabolomics is drawing an attention in the pharmaceutical industry. This review aims to highlight the practical value of metabolomics in (a) potentially validating more novel therapeutic targets and indications, (b) facilitating decision-making on the advancement of therapeutics in the drug development process, and (c) leading to better patient stratification and cost-effective clinical trials, through the application of LC/MS/MRM-based targeted metabolomics studies at a relatively low cost in pharmaceutical companies. This paper provides a brief history of the development of metabolomics and common strategies for conducting metabolomics studies. The pros and cons of the most important technologies and the major components of metabolomics studies are reviewed and discussed. Finally, selected metabolomics study examples are reviewed to illustrate how metabolomics can be used to simultaneously capture underlying biochemical changes associated with pharmaceutical interventions, and effectively produce more accurate and/or alternative efficacy and ADR biomarkers, thereby, greatly extending our knowledge of disease, protein function and drug action and maximally benefiting the pharmaceutical industry. © 2011 Bentham Science Publishers Ltd.

Forkel N.V.,Imperial College London | Henderson D.A.,Pfizer | Fuchter M.J.,Imperial College London
Green Chemistry | Year: 2012

Development of a calcium-mediated regioselective 1,2-reduction of challenging α,β-unsaturated ketones, such as 2-cyclopententone, is reported. The corresponding allylic alcohols are obtained in very good regioselectivities using Ca(OTf)2 and NaBH4. Furthermore, we have shown that our method can stereoselectively reduce aziridinyl ketones. © 2012 The Royal Society of Chemistry.

Holloway C.A.,University of Manchester | Muratore M.E.,University of Oxford | Storer R.L.,Pfizer | Dixon D.J.,University of Oxford
Organic Letters | Year: 2010

A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to perform, atom-efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee). © 2010 American Chemical Society.