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Hepatotoxicity reports in the FDA adverse event reporting system database:A comparison of drugs that cause injury via mitochondrial or other mechanisms

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3857-3868页

作者： Payal Rana Michael D.Aleo Xuerong Wen Stephen Kogut Drug Safety research&Development PfizerGrotonCT 06340USA University of Rhode Island College of PharmacyKingstonRI 02881USA

Drug-induced liver injury(DILI) is a leading reason for preclinical safety attrition and postmarket drug ***-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI,especially in idiosyncratic liver *** study examined liver injury reports submitted to the Food and Drug Administration(FDA) Adverse Event Reporting System(FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of *** frequency of hepatotoxicity was determined at a group level and individual drug level.A reporting odds ratio(ROR) was calculated as the measure of *** the two DILI groups,reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43(95% CI 1.42-1.45;P 18:benzbromarone,troglitazone,isoniazid,rifampin) were associated with mitochondrial mechanisms of *** major demographic influence for DILI risk was also *** was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1±18.33(SD)] compared to non-mitochondrial mechanisms [48±19.53(SD)](P <0.0001),suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of *** logistic regression analysis showed that reports of liver injury were 2.2(odds ratio:2.2,95% CI 2.12-2.26) times more likely to be associated with older patient age,as compared with reports involving patients less than 65 years of *** to males,female patients were 37% less likely(odds ratio:0.63,95% CI

关键词： Mitochondrial toxicity FAERS database Adverse event reporting Drug-induced liver injury Hepatotoxicity

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Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

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World Journal of Gastrointestinal Pathophysiology 2017年第4期8卷 161-175页

作者： Benjamin S Maciejewski Tara B Manion Claire M Steppan pfizer Worldwide research and Development Cardiovascular and Metabolic Diseases Research Unit pfizer Inc.

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and *** The standard experimental paradigm utilized to evaluate the incretin response was a lipid *** a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 *** hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then *** impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT ***,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological *** further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were *** DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were *** response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype ***,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid *** treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active *** contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was *** further explore this observation,GPR119 knockout mice were *** response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and ***,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype ***

关键词： Glucagon-like peptide-1 Peptide tyrosinetyrosine Glucose independent insulinotropic peptide Acyl-CoA diacylglycerol acyltransferase-1 Incretin

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An Automated,Highly Selective Reaction Monitoring Instrument Using Molecular Rotational Resonance Spectroscopy

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Precision Chemistry 2024年第2期2卷 57-62页

作者： Ann Adele Byars Khushi R.Kompally Emily Mechnick Reilly E.Sonstrom Alexander Mikhonin Justin L.Neill Ruth Boetzel James MacGregor Courtney Talicska Jian Li Yizhou Liu BrightSpec Inc.CharlottesvilleVirginia 22903United States pfizer R&D UK Limited Sandwich CT139NJUnited Kingdom Analytical research and Development Pfizer Research and DevelopmentGrotonConnecticut 06340United States

Online monitoring of chemical reactions by using analytical chemistry tools is a powerful way to maximize control over these *** this paper,we demonstrate the use of molecular rotational resonance,an emerging and extraordinarily selective spectroscopic technique,to perform automated reaction monitoring *** interface using a six-port valve with a calibrated sample loop,coupled to a temperature controlled inlet for analyte volatilization,was developed and *** reactions were chosen for initial characterization:an amine-aldehyde condensation reaction to form an imine product and an isotopic exchange reaction of aβ-ketoester with keto-enol *** spectrometer was able to provide kinetic information about the reaction and determine reaction *** the future,this system can be extended to detect and quantify impurities and characterize reaction selectivity,in addition to the reaction progress.

关键词： molecular rotational resonance spectroscopy reaction monitoring reaction kinetics isotopes process analytical technology

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AMPK promotes the survival of colorectal cancer stem cells

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Animal Models and Experimental Medicine 2018年第2期1卷 134-142页

作者： Bing Guo Xin Han Diane Tkach Shu-Guang Huang Dong Zhang pfizer research Novartis Pharmaceuticals Department of Biomedical Sciences College of Osteopathic Medicine New York Institute of Technology

Background: Colorectal cancer(CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main culprit of cancer metastasis,chemotherapy resistance, and ***: To further understand the unique biological properties of cancer stem cells and uncover novel molecular targets to eradicate them, we first established a panel of patient-derived xenograft(PDX) tumor models using tumors surgically removed from human colorectal cancer patients. We then isolated CRC cancer stem cells based on their ALDH activity using fluorescent-activated cell sorting(FACS)and characterized their metabolic ***: Interestingly, we found that the CRC cancer stem cells(ie, CRC cells with higher ALDH activity, or ALDH+) express higher level of antioxidant genes and have lower level of reactive oxygen species(ROS) than non-CRC cancer stem cells(ie, CRC cells with lower ALDH activity, or ALDHà). The CRC cancer stem cells also possess more mitochondria mass and show higher mitochondrial activity. More intriguingly,we observed higher AMP-activated protein kinase(AMPK) activities in these CRC cancer stem cells. Inhibition of the AMPK activity using 2 AMPK inhibitors, Compound C and Iodotubercidin, preferentially induces cell death in CRC cancer stem ***: We propose that AMPK inhibitors may help to eradicate the CRC cancer stem cells and prevent the relapse of CRCs.

关键词： AMP-activated protein kinase cancer metabolism colorectal cancer stem cells patient-derived xenograft

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Identification of HCV Inhibitors from a Cell-Based Sub-Genomic Replicon Screen

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Open Journal of Medicinal Chemistry 2013年第1期3卷 16-25页

作者： David C. Pryde Thien-Duc Tran Mark Gardner Chris Pickford Stephen M. Shaw Mike Westby Tanya Parkinson Caroline Smith-Burchnell Rob Webster Satish Dayal Anti-Infectives research Unit Pfizer Global Research and Develoapment Sandwich UK Anti-Infectives research Unit Pfizer Global Research and Development Sandwich UK Pharmacokinetics Dynamics and Metabolism Pfizer Global Research and Development Sandwich UK Worldwide Medicinal Chemistry Pfizer Global Research and Development Sandwich UK

A high throughput screen of the pfizer compound collection was carried out using a hepatitis C virus (HCV) genotype 1b subgenomic replicon cell line. Those confirmed hits that demonstrated broad spectrum activity without overt cytotoxicity were further evaluated, leading to the identification of a series of pyrrolopyridines with excellent antiviral activity in a fully infectious HCV cell-based assay and pharmacokinetic properties.

关键词： HCV Replicon Antiviral Cell-Based Screen

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Leptin signaling and leptin resistance

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Frontiers of Medicine 2013年第2期7卷 207-222页

作者： Yingjiang Zhou Liangyou Rui Cambridge Laboratories Pfizer Worldwide Research&DevelopmentCambridgeMA 02139USA Department of Molecular and Integrative Physiology University of Michigan Medical SchoolAnn ArborMI 48109USA

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body *** deficiency or genetic defects in the components of the leptin signaling pathways cause *** controls energy balance and body weight mainly through leptin receptor b(LEPRb)-expressing neurons in the brain,particularly in the *** 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 *** factors,including inflammation and endoplasmic reticulum(ER)stress,contribute to leptin *** resistance is the key risk factor for *** review is focused on recent advance about leptin action,leptin signaling,and leptin resistance.

关键词： leptin signaling leptin receptor energy balance leptin resistance obesity

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Safety and Efficacy of Cefovecin (Convenia<sup>®</sup>) as an Adjunctive Treatment of Periodontal Disease in Dogs

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Open Journal of Veterinary Medicine 2012年第3期2卷 89-97页

作者： Henry Giboin Csilla Becskei Jacky Civil Michael R. Stegemann Veterinary Medicine research & Development Pfizer Animal Health Zaventem Belgium

This study was designed to determine the safety and efficacy of cefovecin (Convenia?;pfizer Animal Health) when compared to clindamycin (Antirobe?;pfizer Animal Health) as an adjunctive therapy to periodontal scaling or surgery for severe periodontal disease in dogs. A multi-centre, double-masked, randomised study was conducted in 299 dogs with severe periodontal disease. Clindamycin, administered once daily at 11 mg/kg bodyweight orally for 10 days following dental surgery was compared with a single, subcutaneous injection of cefovecin (8 mg/kg bodyweight) administered at the time of dental surgery. The primary efficacy parameter assessed was percentage of tooth-root sites bleeding when probed (an indicator of gingival inflammation) 42 days after surgery. Two-hundred and ninety-one (291) dogs were included in the efficacy assessments. Cefovecin was shown to be non-inferior to clindamycin. The percentage of sites bleeding on probing was reduced from 54.3% to 20.3% for the cefovecin group (53.1% reduced to 17.4% for the clindamycin group). There were no suspected adverse drug experiences attributed to treatment with cefovecin or clindamycin. Cefovecin was shown to be as effective and safe adjunctive treatment for severe periodontal disease in dogs undergoing periodontal scaling and surgery as clindamycin.

关键词： Canine Antibiotics Dentistry Porphyromonas gulae Prevotella intermedia

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East meets West:ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians

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Chinese Journal of Cancer 2011年第5期30卷 287-292页

作者： Wei Zhou David C. Christiani Molecular Epidemiology research Global Outcomes Research Pfizer Oncology Collegeville PA 19426 USA Departments of Epidemiology and Environmental Health Harvard School of Public Health Boston MA 02115 USA Department of Medicine Massachusetts General Hospital Harvard Medical School Boston MA 02115 USA

Lung cancer is the leading cause of cancer death worldwide,with large variation of the incidence and mortality across *** the mortality of lung cancer has been decreasing,or steady in the US,it has been increasing in Asia for the past two *** 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 *** median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients,particularly among *** and Caucasians may have different genetic susceptibilities to lung cancer,as evidenced from candidate polymorphisms and genome-wide association *** 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 *** 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 *** ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations.

关键词：非小细胞肺癌临床试验种族差异流行病学亚洲人中西文化行为白种人

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Pharmacological Assessment of <i>γ</i>-Secretase Activity from Rodent and Human Brain

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Neuroscience & Medicine 2012年第2期3卷 149-161页

作者： Christine E. Oborski Rathna Iyer Bruce A. Maguire Gary Bora Kevin Atchison Nikolay Pozdnyakov Kathleen Wood Christine Parker Timothy A. Subashi Martin Pettersson Douglas S. Johnson Kelly R. Bales Neuroscience Medicinal Chemistry Pfizer Inc. Groton Connecticut USA Neuroscience research Unit Pfizer Inc. Groton Connecticut USA Primary Pharmacology Group Pfizer Inc. Groton Connecticut USA

γ-Secretase is involved in the final processing of the amyloid precursor protein into a heterogeneous pool of β-amyloid (Aβ) peptides. Current Alzheimer’s disease drug discovery efforts include targeting γ-secretase activity in brain to attenuate production of the neurotoxic Aβ species. The resulting pharmacology may be affected by species-specific differences in the γ-secretase core complex or its associated proteins. Therefore, we utilized partially purified γ-secretase membranes derived from the brains of different species, including human cortex, to quantitatively assess the de novo production of both Aβ42 and Aβ40 following treatment with known γ-secretase inhibitors and modulators. We determined that the inhibitory activity of a Notch-1 sparing γ-secretase inhibitor and the modulatory activity of two classes of γ-secretase modulators were equipotent at affecting the production of Aβ across rodent and human brain membrane preparations. Additionally, the observed modulator-specific Aβ profile in isolated brain membranes across species was similar to that observed in HeLa cell membranes, and the brain and CSF of guinea pigs following oral administration. By utilizing rapidly purified γ-secretase, we were able to probe and compare the complex pharmacology of γ-secretase in the brain across common rodent species and human cortex.

关键词： Alzheimer’s Disease Amyloid Precursor Protein Aβ γ-Secretase Pharmacology

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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line

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Frontiers of Medicine 2013年第4期7卷 462-476页

作者： Douglas D.Fang Joan Cao Jitesh P.Jani Konstantinos Tsaparikos Alessandra Blasina Jill Kornmann Maruja E.Lira Jianying Wang Zuzana Jirout Justin Bingham Zhou Zhu Yin Gu Gerrit Los Zdenek Hostomsky Todd VanArsdale Oncology research Unit PfizerInc.10777 Science Center DriveSan DiegoCA 92121USA WuXi AppTec(Shanghai)Co. Ltd.288 Fute Zhong RdWaigaoqiao Free Trade ZoneShanghai 200131China

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell(CSC)*** this study,we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell *** these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell ***,the CSC-like cells exhibited resistance to gemcitabine-induced ***,the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

关键词： drug resistance cancer stem cell checkpoint kinase 1(CHK1) PF-00477736 lung cancer tumorigenicity

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