220 results
Search Results
2. In Vivo Bioavailability and Therapeutic Assessment of Host-Guest Inclusion Phenomena for the Hydrophobic Molecule Etodolac: Pharmacodynamic and Pharmacokinetic Evaluation
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Amita, Honey Goel, and Vivek Ranjan Sinha
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Drug ,Bioavailability ,business.industry ,media_common.quotation_subject ,Analgesic ,Ulcerogenicity ,ETD ,β-Cyclodextrin ,Pharmaceutical Science ,Pharmacology ,Original Papers ,Pharmacokinetics ,In vivo ,Pharmacodynamics ,Spray drying ,Medicine ,Etodolac ,business ,Research Article ,Inclusion-complexes ,media_common ,medicine.drug - Abstract
The aim of present investigation was 1) to evaluate the in vivo bioavailability of an Etodolac (ETD)-β-cyclodextrin (β-CD) inclusion complex system prepared by kneading and spray drying techniques in rats, 2) to study the pharmacodynamic parameters in various animal models for analyzing the therapeutic response and, 3) to evaluate the pharmacokinetic profile of the drug administered. Inclusion complexation with β-CD enhanced the solubility of the drug, improved bioavailability and reduced ulcerogenicity of ETD in rats. Pharmacodynamic studies were carried out in normal LACA mice and pharmacokinetic evaluation was done in male Wistar rats. Pharmacokinetic parameters evaluated for the inclusion complexes revealed good correlation. The minimum dose necessary to produce analgesic or anti-arthritic activity was also decreased, indicating that the host-guest strategy that uses β-CD and ETD was very effective and could be successfully employed in the preparation of pharmaceutical formulations of anti-arthritics and analgesics.
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- 2010
3. Effect of Itraconazole on the Pharmacokinetics of Diclofenac in Beagle Dogs
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Fahad I. Al-Jenoobi
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Interaction ,business.industry ,Itraconazole ,Pharmaceutical Science ,Pharmacology ,Beagle ,Original Papers ,Absorption ,stomatognathic diseases ,Diclofenac ,Pharmacokinetics ,Blood chemistry ,Oral administration ,Pharmacokinetic parameters ,Pharmacodynamics ,Diclofenac Potassium ,medicine ,HPLC ,business ,Plasma concentration ,medicine.drug ,Research Article - Abstract
The objective of this study was to investigate the potential effect of itraconazole on the pharmacokinetics of diclofenac potassium in beagle dogs after oral coadministration. Five male beagle dogs received a single oral 50 mg dose of diclofenac potassium alone in phase I, and along with a single oral 100 mg dose of itraconazole in phase II. Blood samples obtained for 8.0 hours post dose were analysed for diclofenac concentration using a validated high performance liquid chromatography (HPLC) assay method. The area under plasma concentration-time curve (AUC0–∞), maximum plasma concentration (Cmax), time to reach Cmax (Tmax) and elimination half-life (t1/2), were calculated for diclofenac before and after itraconazole administration. The coadministration of itraconazole with diclofenac potassium has resulted in a significant reduction in AUC0–∞ and Cmax of diclofenac, which was about 31 and 42%, respectively. No statistically significant differences were observed for Tmax and t1/2 of diclofenac between the two phases. Therefore, it could be concluded that oral coadministration of itraconazole may have the potential to affect the absorption of diclofenac as indicated by the significant reduction in its AUC and Cmax in beagle dogs.
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- 2010
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4. Cyclosporine a-nanosuspension: formulation, characterization and in vivo comparison with a marketed formulation
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Subhash S. Vaghani, Mahendra P. Nakarani, Jayvadan K. Patel, P.R. Patel, Rayasa S. R. Murthy, and Pankaj Patel
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Chromatography ,Chemistry ,Scanning electron microscope ,Pharmaceutical Science ,Nanoparticle ,Nanotechnology ,Poloxamer ,Original Papers ,Osmolarity ,Cyclosporine A ,Pharmacokinetics ,Distilled water ,In vivo ,Cyclosporin a ,Poloxamer 407 ,Nanosuspension ,medicine ,Scanning electron microscopy ,medicine.drug ,Research Article - Abstract
Cyclosporine A-nanosuspensions were prepared using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and distilled water as an aqueous medium using the Pearl Milling technique. The optimized formulation was characterized in terms of particle size distribution, surface morphology, drug-surfactant interaction, drug content, saturation solubility, osmolarity, and stability. The nanoparticles consisting of Poloxamer-bound cyclosporin A with a mean diameter of 213 nm revealed a spherical shape and 5.69 fold increased saturation solubility as compared to the parent drug. The formulation was found to be iso-osmolar with blood and stable up to 3 months at 2–8°C. In-vivo studies were carried out in albino rats and the pharmacokinetic parameters were compared with a marketed formulation, which indicated better results of the prepared formulation than the marketed one.
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- 2009
5. Spatio-Temporal Simulation of First Pass Drug Perfusion in the Liver.
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Schwen, Lars Ole, Krauss, Markus, Niederalt, Christoph, Gremse, Felix, Kiessling, Fabian, Schenk, Andrea, Preusser, Tobias, and Kuepfer, Lars
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LIVER diseases ,DRUG metabolism -- Evaluation ,XENOBIOTICS ,PHARMACOKINETICS ,GASTROENTEROLOGY ,FATTY degeneration - Abstract
The liver is the central organ for detoxification of xenobiotics in the body. In pharmacokinetic modeling, hepatic metabolization capacity is typically quantified as hepatic clearance computed as degradation in well-stirred compartments. This is an accurate mechanistic description once a quasi-equilibrium between blood and surrounding tissue is established. However, this model structure cannot be used to simulate spatio-temporal distribution during the first instants after drug injection. In this paper, we introduce a new spatially resolved model to simulate first pass perfusion of compounds within the naive liver. The model is based on vascular structures obtained from computed tomography as well as physiologically based mass transfer descriptions obtained from pharmacokinetic modeling. The physiological architecture of hepatic tissue in our model is governed by both vascular geometry and the composition of the connecting hepatic tissue. In particular, we here consider locally distributed mass flow in liver tissue instead of considering well-stirred compartments. Experimentally, the model structure corresponds to an isolated perfused liver and provides an ideal platform to address first pass effects and questions of hepatic heterogeneity. The model was evaluated for three exemplary compounds covering key aspects of perfusion, distribution and metabolization within the liver. As pathophysiological states we considered the influence of steatosis and carbon tetrachloride-induced liver necrosis on total hepatic distribution and metabolic capacity. Notably, we found that our computational predictions are in qualitative agreement with previously published experimental data. The simulation results provide an unprecedented level of detail in compound concentration profiles during first pass perfusion, both spatio-temporally in liver tissue itself and temporally in the outflowing blood. We expect our model to be the foundation of further spatially resolved models of the liver in the future. [ABSTRACT FROM AUTHOR]
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- 2014
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6. Administration of a Probiotic Can Change Drug Pharmacokinetics: Effect of E. coli Nissle 1917 on Amidarone Absorption in Rats.
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Matuskova, Zuzana, Anzenbacherova, Eva, Vecera, Rostislav, Tlaskalova-Hogenova, Helena, Kolar, Milan, and Anzenbacher, Pavel
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PROBIOTICS ,PHARMACOKINETICS ,ESCHERICHIA coli disease prevention ,DRUG administration ,DRUG metabolism ,DRUG absorption ,LABORATORY rats - Abstract
The growing interest in the composition and effects of microbiota raised the question how drug pharmacokinetics could be influenced by concomitant application of probiotics. The aim of this study was to find whether probiotic E. coli strain Nissle 1917 (EcN) influences the pharmacokinetics of concomitantly taken antiarrhythmic drug amiodarone (AMI). Live bacterial suspension of probiotic EcN (or non-probiotic E. coli strain ATCC 25922) was applied orally to male Wistar rats for seven days, while a control group of rats was treated with a saline solution. On the eighth day, the amiodarone hydrochloride was administered as one single oral dose (50 mg/kg) to all rats (N = 60). After 0, 1, 2, 3, 4, 5.5, 7, 9, 14, 22, and 30 hours, blood samples were taken from the rat abdominal aorta. The plasma level of AMI and its metabolite N-desethylamiodarone (DEA) was determined using the HPLC with UV detection. Administration of EcN led to a 43% increase of AMI AUC
0-30 in comparison with control samples. However, this effect was not observed if EcN was replaced by a reference non-probiotic E. coli strain. Thus, EcN administration was most probably responsible for better drug absorption from the gastrointestinal tract. Plasma levels of DEA were also increased in plasma samples from animals treated with EcN. This change was again not found in the experiment with the reference non-probiotic strain. Higher DEA levels in samples from EcN-treated rats may be explained either by better absorption of AMI and/or by an increased activity of CYP2C forms, known to participate in metabolism of this drug, after EcN administration. In this paper, it is documented that concomitantly taken probiotic EcN may modulate pharmacokinetics of a drug; in this case, it led to an increased bioavailability of AMI. [ABSTRACT FROM AUTHOR]- Published
- 2014
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7. Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes
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Ben Busby, Sunghwan Kim, and Moamen M. Elmassry
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Male ,Enzyme Metabolism ,Gut flora ,Biochemistry ,Families ,Drug Metabolism ,Medicine and Health Sciences ,Bacteroides ,Enzyme Chemistry ,Children ,media_common ,Data Management ,Glucuronidase ,Multidisciplinary ,biology ,Microbiota ,Drugs ,Genomics ,Cheminformatics ,Medical Microbiology ,Medicine ,Female ,Metabolic Pathways ,Infants ,Research Article ,Drug ,Adult ,Science ,media_common.quotation_subject ,Mothers ,Context (language use) ,Computational biology ,Microbial Genomics ,Microbiology ,Genetics ,Xenobiotic Metabolism ,Humans ,Pharmacokinetics ,Microbiome ,Pharmacology ,Bacteria ,Gut Bacteria ,Organisms ,Infant, Newborn ,Biology and Life Sciences ,Computational Biology ,biology.organism_classification ,Gastrointestinal Microbiome ,Metabolism ,Metagenomics ,Age Groups ,People and Places ,Enzymology ,Metagenome ,Population Groupings ,Drug metabolism ,Forecasting - Abstract
Characterizing the gut microbiota in terms of their capacity to interfere with drug metabolism is necessary to achieve drug efficacy and safety. Although examples of drug-microbiome interactions are well-documented, little has been reported about a computational pipeline for systematically identifying and characterizing bacterial enzymes that process particular classes of drugs. The goal of our study is to develop a computational approach that compiles drugs whose metabolism may be influenced by a particular class of microbial enzymes and that quantifies the variability in the collective level of those enzymes among individuals. The present paper describes this approach, with microbial β-glucuronidases as an example, which break down drug-glucuronide conjugates and reactivate the drugs or their metabolites. We identified 100 medications that may be metabolized by β-glucuronidases from the gut microbiome. These medications included morphine, estrogen, ibuprofen, midazolam, and their structural analogues. The analysis of metagenomic data available through the Sequence Read Archive (SRA) showed that the level of β-glucuronidase in the gut metagenomes was higher in males than in females, which provides a potential explanation for the sex-based differences in efficacy and toxicity for several drugs, reported in previous studies. Our analysis also showed that infant gut metagenomes at birth and 12 months of age have higher levels of β-glucuronidase than the metagenomes of their mothers and the implication of this observed variability was discussed in the context of breastfeeding as well as infant hyperbilirubinemia. Overall, despite important limitations discussed in this paper, our analysis provided useful insights on the role of the human gut metagenome in the variability in drug response among individuals. Importantly, this approach exploits drug and metagenome data available in public databases as well as open-source cheminformatics and bioinformatics tools to predict drug-metagenome interactions.
- Published
- 2021
8. MCHP (Monte Carlo + Human Phantom): Platform to facilitate teaching nuclear radiation physics
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K.N. Yu, Dragana Krstic, Dragoslav Nikezic, Mehrdad Shahmohammadi Beni, and Hiroshi Watabe
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Statistical methods ,Light ,Adult male ,Monte Carlo method ,Social Sciences ,Scattering ,Learning and Memory ,Radiation, Ionizing ,Medicine and Health Sciences ,Psychology ,Human Body ,Radiation ,Multidisciplinary ,Physics ,Electromagnetic Radiation ,Statistics ,Brain ,Compton Scattering ,Cesium Radioisotopes ,Physical Sciences ,Medicine ,Elementary Particles ,Research Article ,Science ,Drug Absorption ,Imaging phantom ,Human Learning ,Lead shielding ,Radiation Protection ,Learning ,Humans ,Pharmacokinetics ,Particle Physics ,Radiometry ,Students ,Simulation ,Nuclear Physics ,Pharmacology ,Photons ,Light Scattering ,Cognitive Psychology ,Biology and Life Sciences ,Oak Ridge National Laboratory ,Nuclear radiation ,Visualization ,Research and analysis methods ,Ionizing Radiation ,Mathematical and statistical techniques ,Cognitive Science ,Mathematics ,Neuroscience - Abstract
Some concepts in nuclear radiation physics are abstract and intellectually demanding. In the present paper, an “MCHP platform” (MCHP was an acronym for Monte Carlo simulations + Human Phantoms) was proposed to provide assistance to the students through visualization. The platform involved Monte Carlo simulations of interactions between ionizing radiations and the Oak Ridge National Laboratory (ORNL) adult male human phantom. As an example to demonstrate the benefits of the proposed MCHP platform, the present paper investigated the variation of the absorbed photon dose per photon from a 137Cs source in three selected organs, namely, brain, spine and thyroid of an adult male for concrete and lead shields with varying thicknesses. The results were interesting but not readily comprehensible without direct visualization. Graphical visualization snapshots as well as video clips of real time interactions between the photons and the human phantom were presented for the involved cases, and the results were explained with the help of such snapshots and video clips. It is envisaged that, if the platform is found useful and effective by the readers, the readers can also propose examples to be gradually added onto this platform in future, with the ultimate goal of enhancing students’ understanding and learning the concepts in an undergraduate nuclear radiation physics course or a related course.
- Published
- 2021
9. Extracting Drug-Drug Interaction from the Biomedical Literature Using a Stacked Generalization-Based Approach.
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He, Linna, Yang, Zhihao, Zhao, Zhehuan, Lin, Hongfei, and Li, Yanpeng
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DRUG interactions , *MEDICAL literature , *PATIENT safety , *MEDICAL research , *MEDICAL informatics , *DATA extraction , *DATA mining , *PERFORMANCE evaluation - Abstract
Drug-drug interaction (DDI) detection is particularly important for patient safety. However, the amount of biomedical literature regarding drug interactions is increasing rapidly. Therefore, there is a need to develop an effective approach for the automatic extraction of DDI information from the biomedical literature. In this paper, we present a Stacked Generalization-based approach for automatic DDI extraction. The approach combines the feature-based, graph and tree kernels and, therefore, reduces the risk of missing important features. In addition, it introduces some domain knowledge based features (the keyword, semantic type, and DrugBank features) into the feature-based kernel, which contribute to the performance improvement. More specifically, the approach applies Stacked generalization to automatically learn the weights from the training data and assign them to three individual kernels to achieve a much better performance than each individual kernel. The experimental results show that our approach can achieve a better performance of 69.24% in F-score compared with other systems in the DDI Extraction 2011 challenge task. [ABSTRACT FROM AUTHOR]
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- 2013
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10. Bayesian Inference for Generalized Linear Mixed Model Based on the Multivariate t Distribution in Population Pharmacokinetic Study.
- Author
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Yan, Fang-Rong, Huang, Yuan, Liu, Jun-Lin, Lu, Tao, and Lin, Jin-Guan
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PHARMACOKINETICS ,BAYESIAN analysis ,DRUG dosage ,LINEAR statistical models ,MATHEMATICAL models ,PERFORMANCE evaluation ,EPIDEMIOLOGY ,PUBLIC health - Abstract
This article provides a fully Bayesian approach for modeling of single-dose and complete pharmacokinetic data in a population pharmacokinetic (PK) model. To overcome the impact of outliers and the difficulty of computation, a generalized linear model is chosen with the hypothesis that the errors follow a multivariate Student t distribution which is a heavy-tailed distribution. The aim of this study is to investigate and implement the performance of the multivariate t distribution to analyze population pharmacokinetic data. Bayesian predictive inferences and the Metropolis-Hastings algorithm schemes are used to process the intractable posterior integration. The precision and accuracy of the proposed model are illustrated by the simulating data and a real example of theophylline data. [ABSTRACT FROM AUTHOR]
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- 2013
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11. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
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Christopher D. Huston, Amornrat Naranuntarat Jensen, Louis Maes, Jordi Mestres, Nao Aki Watanabe, Michael Adsetts Edberg Hansen, Roberto Adelfio, Simon Townson, Didier Leroy, Kate Weatherby, Thomas Spangenberg, Manuela Carrasquilla, Kailash P. Patra, Robert E. Sinden, José Brea, Abhai K. Tripathi, W. Armand Guiguemde, Alan Y. Du, Melanie Wree, Katherine T. Andrews, Kirsten K. Hanson, Tyler B. Hughes, Sundari Suresh, Adele M. Lehane, Sangeeta N. Bhatia, Edward J. Wojcik, Andrew Hemphill, Francielly Morais Rodrigues da Costa, Worathad Chindaudomsate, Joseph M. Vinetz, Ben Gold, Sunyoung Kim, Edgar Vigil, Nuha R. Mansour, Mohamed Abdo Rizk, Patrick Valere Tsouh Fokou, Audrey Burton, Laran T. Jensen, David A. Fidock, Aishah Alsibaee, Filipe Silva Villela, Yesmalie Alemán Resto, Rajarshi Guha, Conor R. Caffrey, José A. Fernández Robledo, Thomas J. Ketas, Luke Mercer, Rob Hooft van Huijsduijnen, Maria Jose Lafuente, Wesley C. Van Voorhis, Lauve R. Y. Tchokouaha, Dee A. Carter, Anjo Theron, Benoît Laleu, Kiaran Kirk, Maurice A. Itoe, Robert P. St.Onge, Celia Quevedo, Andrea Ruecker, Paul Henri Amvam Zollo, Francisco-Javier Gamo, Nathan Lee, Alvine Ngoutane Mfopa, Paul Horrocks, Ikuo Igarashi, Nil Gural, Todd R. Golub, Gordana Panic, Jeremy N. Burrows, Phat Voong Vinh, Annette Kaiser, Fabrice Fekam Boyom, Pietro Alano, Anupam Pradhan, Sandra Duffy, Raj N. Misra, Vidya Prasanna Kumar, Aintzane Alday, Timothy N. C. Wells, María Isabel Loza, Sébastien Kicka, William J. Sullivan, Gregory M. Goldgof, Yo Suzuki, Yolanda Corbett, Sally-Ann Poulsen, Vida Ahyong, George Papadatos, Sujeevi Nawaratna, Rafaela Salgado Ferreira, Takaaki Horii, Imran Ullah, Nathalie Narraidoo, Natalie G. Robinett, Simon V. Avery, Grazia Camarda, Iset Medina Vera, Michael T. Ferdig, Fengwu Li, David Plouffe, Joseph L. DeRisi, Jasmeet Samra, Andreas Spitzmüller, Liqiong Liu, Christopher A. Rice, Thierry Soldati, Serge Maximilian Stamm, Suzanne Gokool, Beatrice L. Colon, Shimaa Abd El-Salam El-Sayed, Mark Baker, Kenneth O. Udenze, Na Le Dang, Katrin Ingram-Sieber, Dennis A. Smith, Rays H. Y. Jiang, Marian P. Brennan, Ani Galstian, Paul Willis, Dennis E. Kyle, Ainhoa Alzualde, Sarah Prats, Sheena McGowan, Vicky M. Avery, Jennifer Keiser, John P. Moore, Dalu Mancama, Gregory J. Crowther, Noemi Cowan, Maria B. Cassera, Valentin Trofimov, David Thomas, David J. Sullivan, Diana Ortiz, Nada Abla, S. Joshua Swamidass, Benjamin Blasco, Hoan Vu, Francesco Silvestrini, Anthony J. Chubb, Pamela M. White, Scott M. Landfear, Isabelle Florent, John H. Adams, Ronald J. Quinn, Andrew F. Wilks, Sandra March, Leonardo Lucantoni, Stephen Baker, Tana Bowling, Joachim Müller, Arantza Muriana, Lauren E. Boucher, Ajit Jadhav, Sukjun Lee, Elizabeth A. Winzeler, Choukri Ben Mamoun, Ulrich Schlecht, Daisy D. Colón-López, Marjorie Schmitt, Myles H. Akabas, Isabelle S Lucet, Stephen N. Hewitt, Naoaki Yokoyama, Carl Nathan, Bakela Nare, Cindy Vallières, Lotfi Bounaadja, Kayode K. Ojo, Wesley Wu, Ken Chih-Chien Cheng, Kathryn F. Tonissen, Michael J. Delves, Brian M. Suzuki, Aristea Lubar, Quentin D. Bickle, Stephan Meister, Silvia Parapini, Manuel Llinás, Ngoc Minh Pham, Seunghyun Moon, R. Kiplin Guy, Donatella Taramelli, Lawrence Ayong, Sarah D'Alessandro, Jürgen Bosch, David Little, Istituto Superiore di Sanita [Rome], Zentrum für Infektiologie [Heidelberg, Germany], Universität Heidelberg [Heidelberg]-Heidelberg University Hospital [Heidelberg], University of Nottingham, UK (UON), Eskitis Institute for Drug Discovery, Griffith University [Brisbane], Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Laboratoire de génétique moléculaire et cellulaire, Institut National de la Recherche Agronomique (INRA), Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Faculté des Sciences - Yaoundé I, Université de Yaoundé I, Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano [Milano] (UNIMI), Imperial College London, Eck Institute for Global Health, University of Notre Dame [Indiana] (UND), Columbia University Medical Center (CUMC), Columbia University [New York], Interdisciplinary Nanoscience Centre (iNANO), Institute of Parasitology, University of Bern, MS Project - Initiation (MSPRI), Apollo SSC Genève, Keele University, Swiss Tropical and Public Health Institute [Basel], University of Regina, School of Engineering and Science, University of the West of Scotland (UWS), Research School of Biology [Canberra, Australie], Australian National University (ANU), University of Pennsylvania [Philadelphia], Laboratory of Microbiology, Parasitology and Hygiene [Antwerpen] (LMPH), University of Antwerp (UA), Department of Biochemistry and Molecular Biology, Mayo Clinic, Institute for Wine Biotechnology [University of Stellenbosch - Afrique du Sud], Stellenbosch University, Oregon Health and Science University [Portland] (OHSU), Biozentrum, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Advanced Materials Research Laboratories, Department of Chemistry and Center for Optical ((COMSET), Clemson University, Université de Genève (UNIGE), Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, University of California [Santa Cruz] (UCSC), Department of sanità pubblica-microbiologia-virologia, University of California, Département Réseaux, Information, Multimédia (RIM-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre G2I, UC San Diego School of Medicine, Medicines for Malaria Venture [Geneva] (MMV), Princeton University, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, Bill & Melinda Gates Foundation, Biochemistry, Center for Drug Discovery, Kicka, Sébastien, Soldati, Thierry, Trofimov, Valentin, and Abla, Nada
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0301 basic medicine ,Plasmodium ,[SDV]Life Sciences [q-bio] ,Medizin ,Drug Evaluation, Preclinical ,Datasets as Topic ,infected erythrocytes ,stage plasmodium-falciparum ,Q1 ,Gametocytes ,Toxicology ,Pathology and Laboratory Medicine ,Drug Metabolism ,1108 Medical Microbiology ,Animal Cells ,inhibitors ,Drug Discovery ,Medicine and Health Sciences ,Biology (General) ,Genetics ,Protozoans ,biology ,630 Agriculture ,Drug discovery ,transmission ,Malarial Parasites ,Neglected Diseases ,3. Good health ,Chemistry ,1107 Immunology ,ddc:540 ,Physical Sciences ,590 Animals (Zoology) ,Identification (biology) ,Cellular Types ,Medicaments ,0605 Microbiology ,Research Article ,Drug Research and Development ,QH301-705.5 ,Immunology ,Computational biology ,in-vitro ,Microbiology ,target ,Small Molecule Libraries ,03 medical and health sciences ,Antimalarials ,blood ,Virology ,Parasite Groups ,Gametocyte ,medicine ,Parasitic Diseases ,[CHIM]Chemical Sciences ,Humans ,Pharmacokinetics ,Molecular Biology ,Biology ,theileria parasites ,Pharmacology ,Toxicity ,QH ,Malària -- Medicaments ,Organisms ,Biology and Life Sciences ,Plasmodium falciparum ,Cell Biology ,RC581-607 ,biology.organism_classification ,medicine.disease ,Tropical Diseases ,Parasitic Protozoans ,babesia ,Malaria ,030104 developmental biology ,Germ Cells ,Vector (epidemiology) ,identification ,570 Life sciences ,Parasitology ,Human medicine ,Medicinal Chemistry ,Immunologic diseases. Allergy ,Apicomplexa - Abstract
A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts., Author Summary Malaria leads to the loss of over 440,000 lives annually; accelerating research to discover new candidate drugs is a priority. Medicines for Malaria Venture (MMV) has distilled over 25,000 compounds that kill malaria parasites in vitro into a group of 400 representative compounds, called the "Malaria Box". These Malaria Box sets were distributed free-of-charge to research laboratories in 30 different countries that work on a wide variety of pathogens. Fifty-five groups compiled >290 assay results for this paper describing the many activities of the Malaria Box compounds. The collective results suggest a potential mechanism of action for over 130 compounds against malaria and illuminate the most promising compounds for further malaria drug development research. Excitingly some of these compounds also showed outstanding activity against other disease agents including fungi, bacteria, other single-cellular parasites, worms, and even human cancer cells. The results have ignited over 30 drug development programs for a variety of diseases. This open access effort was so successful that MMV has begun to distribute another set of compounds with initial activity against a wider range of infectious agents that are of public health concern, called the Pathogen Box, available now to scientific labs all over the world (www.PathogenBox.org).
- Published
- 2016
12. Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials
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Barbara Wiśniowska, Gabriela Wyszogrodzka, Sebastian Polak, and Zofia Tylutki
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Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Long QT syndrome ,QT prolongation ,030204 cardiovascular system & hematology ,Pharmacology ,030226 pharmacology & pharmacy ,QT interval ,03 medical and health sciences ,Clinical trials ,0302 clinical medicine ,Humans ,Medicine ,Drug Interactions ,Pharmacokinetics ,Drug-drug interactions ,Pharmacology (medical) ,Intensive care medicine ,media_common ,Polypharmacy ,Proarrhythmia ,Clinical Trials as Topic ,business.industry ,Mechanism (biology) ,Heart ,medicine.disease ,Clinical trial ,Long QT Syndrome ,Pharmacodynamics ,business ,Research Article - Abstract
Background Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug. Methods This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed. Results The results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation. Conclusions DDIs can play significant roles in drugs’ cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations. Electronic supplementary material The online version of this article (doi:10.1186/s40360-016-0053-1) contains supplementary material, which is available to authorized users.
- Published
- 2016
13. A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment
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Hugh A. Barton, Harvey J. Clewell, and Melvin E. Andersen
- Subjects
End point ,Dose-Response Relationship, Drug ,Computer science ,Health, Toxicology and Mutagenesis ,Pharmacokinetic modeling ,Public Health, Environmental and Occupational Health ,Cancer ,Neoplasms, Experimental ,Pharmacology ,Models, Theoretical ,medicine.disease ,Risk Assessment ,Xenobiotics ,Disease Models, Animal ,Risk analysis (engineering) ,Neoplasms ,medicine ,Dosimetry ,Animals ,Humans ,Pharmacokinetics ,Risk assessment ,Chemical risk ,Research Article - Abstract
Physiologically based pharmacokinetic modeling provides important capabilities for improving the reliability of the extrapolations across dose, species, and exposure route that are generally required in chemical risk assessment regardless of the toxic end point being considered. Recently, there has been an increasing focus on harmonization of the cancer and noncancer risk assessment approaches used by regulatory agencies. Although the specific details of applying pharmacokinetic modeling within these two paradigms may differ, it is possible to identify important elements common to both. These elements expand on a four-part framework for describing the development of toxicity: a) exposure, b) tissue dosimetry/pharmacokinetics, c) toxicity process/pharmacodynamics, and d) response. The middle two components constitute the mode of action. In particular, the approach described in this paper provides a common template for incorporating pharmacokinetic modeling to estimate tissue dosimetry into chemical risk assessment, whether for cancer or noncancer end points. Chemical risk assessments typically depend upon comparisons across species that often simplify to ratios reflecting the differences. In this paper we describe the uses of this ratio concept and discuss the advantages of a pharmacokinetic-based approach as compared to the use of default dosimetry.
- Published
- 2002
14. Integration of a physiologically-based pharmacokinetic model with a whole-body, organ-resolved genome-scale model for characterization of ethanol and acetaldehyde metabolism
- Author
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William Pei, Radhakrishnan Mahadevan, Leo Zhu, and Ines Thiele
- Subjects
Male ,Enzyme Metabolism ,Alcohol ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Metabolism ,Disulfiram ,Medicine and Health Sciences ,Metabolites ,Tissue Distribution ,Biology (General) ,Enzyme Chemistry ,0303 health sciences ,Alcohol Consumption ,Ecology ,biology ,Organic Compounds ,Aldehyde Dehydrogenase, Mitochondrial ,3. Good health ,Enzymes ,Alcoholism ,Chemistry ,Computational Theory and Mathematics ,Liver ,Modeling and Simulation ,Physical Sciences ,medicine.drug ,Research Article ,Physiologically based pharmacokinetic modelling ,QH301-705.5 ,Acetaldehyde Dehydrogenase Inhibitors ,Acetaldehyde ,Models, Biological ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Genetics ,medicine ,Humans ,Computer Simulation ,Pharmacokinetics ,Ethanol metabolism ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Alcohol dehydrogenase ,ALDH2 ,Nutrition ,Ethanol ,Organic Chemistry ,Chemical Compounds ,Computational Biology ,Biology and Life Sciences ,Proteins ,Diet ,Kinetics ,Metabolism ,chemistry ,Intestinal Absorption ,Alcohols ,biology.protein ,Enzymology ,030217 neurology & neurosurgery ,Alcohol Deterrents - Abstract
Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol’s primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. How strongly ethanol or acetaldehyde affects an individual depends highly on the genetic polymorphisms of certain genes. In particular, the genetic polymorphisms of mitochondrial aldehyde dehydrogenase, ALDH2, play a large role in the metabolism of acetaldehyde. Thus, it is important to characterize how genetic variations can lead to different exposures and responses to ethanol and acetaldehyde. While the pharmacokinetics of ethanol metabolism through alcohol dehydrogenase have been thoroughly explored in previous studies, in this paper, we combined a base physiologically-based pharmacokinetic (PBPK) model with a whole-body genome-scale model (WBM) to gain further insight into the effect of other less explored processes and genetic variations on ethanol metabolism. This combined model was fit to clinical data and used to show the effect of alcohol concentrations, organ damage, ALDH2 enzyme polymorphisms, and ALDH2-inhibiting drug disulfiram on ethanol and acetaldehyde exposure. Through estimating the reaction rates of auxiliary processes with dynamic Flux Balance Analysis, The PBPK-WBM was able to navigate around a lack of kinetic constants traditionally associated with PK modelling and demonstrate the compensatory effects of the body in response to decreased liver enzyme expression. Additionally, the model demonstrated that acetaldehyde exposure increased with higher dosages of disulfiram and decreased ALDH2 efficiency, and that moderate consumption rates of ethanol could lead to unexpected accumulations in acetaldehyde. This modelling framework combines the comprehensive steady-state analyses from genome-scale models with the dynamics of traditional PK models to create a highly personalized form of PBPK modelling that can push the boundaries of precision medicine., Author summary Alcohol is a widely used recreational drug in many parts of the world and it is often abused or misused, leading to the deaths of millions of people each year from driving under the influence and overdose. Additionally, the body breaks down alcohol into acetaldehyde, a carcinogen that has its own effects ranging from headaches and nausea to liver damage. The effects of ethanol and acetaldehyde vary due to genetic variations that create different forms of the enzymes responsible for breaking them down. Due to these differences, it is important to characterize how these changes affect the metabolism of alcohol and acetaldehyde. To capture these differences, we have created a new model that integrates the traditional pharmacokinetic model with a whole-body genome-scale model that can characterize different genetic variations. In addition, traditional models often require experimentally measured data, yet with this new framework we avoid this tedious process by mathematically solving the genome-scale model with the dynamic Flux Balance Analysis technique, allowing for gap filling. Through this model, we show that the whole-body genome-scale model demonstrates flexibility and robustness that has not been seen before in pharmacokinetic models. Our model combines advantages from both pharmacokinetic and genome-scale modelling and can be personalized to characterize individual reactions to other drugs and further precision medicine.
- Published
- 2021
15. Pharmacokinetic and Bioavailability Studies of Galgravin after Oral and Intravenous Administration to Rats Using HPLC-MS/MS Method
- Author
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Yuqi Fan, Xuhua Huang, Yan-xu Chang, Dongyue Yang, Songrui Wang, Lulu Zhao, Jun He, Huizi Ouyang, and Zixiang Xue
- Subjects
Male ,Analyte ,Time Factors ,Article Subject ,Formic acid ,Electrospray ionization ,Ethyl acetate ,Administration, Oral ,Biological Availability ,Schisandrin ,General Biochemistry, Genetics and Molecular Biology ,Lignans ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Drug Stability ,Liquid chromatography–mass spectrometry ,Tandem Mass Spectrometry ,Animals ,Furans ,Chromatography, High Pressure Liquid ,030304 developmental biology ,0303 health sciences ,Chromatography ,General Immunology and Microbiology ,Reproducibility of Results ,General Medicine ,Reference Standards ,Bioavailability ,chemistry ,030220 oncology & carcinogenesis ,Medicine ,Administration, Intravenous ,Research Article - Abstract
This paper presents a new high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method with a rapid analysis of 6 min to determine the concentration of galgravin in rat plasma so as to study its pharmacokinetic features and bioavailability in vivo. Schisandrin was selected as the internal standard (IS). After extracting the analyte from plasma samples with ethyl acetate, methanol-H2O (0.1% formic acid) (85 : 15, v / v ) was used as mobile phase to achieve chromatographic separation on a C18 reversed phase column. The MS detection was performed in positive ion mode using electrospray ionization (ESI) source. This method showed good linearity over the range of 1~500 ng/mL ( R 2 > 0.999 ), and the lower limit of quantitation (LLOQ) was 1.0 ng/mL. The intraday precision and interday precision were both within 8.5%, whereas the accuracies were in the range of -2.6%–6.0%. The average recoveries of galgravin in rat plasma were between 92.3% and 99.3%. Moreover, galgravin was stable throughout storage and processing with all RSDs below 12.1%. After the successful application of this optimized method, the oral bioavailability of galgravin was determined to be 8.5%. This study will be helpful to the future research and development of galgravin.
- Published
- 2021
16. Fluconazole concentrations in saliva from AIDS patients with oropharyngeal candidosis refractory to treatment with fluconazole
- Author
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L. Improvisi, F. Provost, Bertrand Dupont, Dea Garcia-Hermoso, and Françoise Dromer
- Subjects
Adult ,Male ,medicine.medical_specialty ,Saliva ,medicine.medical_treatment ,Microbial Sensitivity Tests ,Biology ,Gastroenterology ,Pharmacokinetics ,stomatognathic system ,Candidiasis, Oral ,Immunopathology ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Fluconazole ,Mycosis ,Candida ,Pharmacology ,Chemotherapy ,Acquired Immunodeficiency Syndrome ,Drug Resistance, Microbial ,Middle Aged ,Dry mouth ,medicine.disease ,Regimen ,Infectious Diseases ,Immunology ,Female ,medicine.symptom ,medicine.drug ,Research Article - Abstract
Fluconazole (FCZ) has been extensively used as a primary therapy for oropharyngeal candidosis in AIDS patients. Clinical resistance to FCZ is now encountered, often related to decreased susceptibility of the isolate in vitro. We wondered if low levels in saliva play a role in the therapeutic failure, especially in patients complaining of dry mouth. Sixteen AIDS patients treated for oropharyngeal candidosis with FCZ were studied. MICs for the isolates were determined. Serum and saliva samples were collected to measure FCZ levels with a bioassay using paper disks loaded with the clinical specimens. We showed that (i) paper disks were convenient for collecting saliva in patients with dry mouth; (ii) levels in saliva depended on the FCZ dosage regimen but did not correlate with the response to therapy; (iii) correlation between concentrations in saliva and serum was poor and independent of clinical response to treatment, other therapies, or decreased salivation; and (iv) levels in saliva were always lower than MICs in patients who failed to respond to treatment. In conclusion, therapeutic failures are more likely to be related to in vitro resistance of the isolate to FCZ or insufficient dosage regimen than to decreased salivary secretion.
- Published
- 1995
17. Literature Based Drug Interaction Prediction with Clinical Assessment Using Electronic Medical Records: Novel Myopathy Associated Drug Interactions
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Yan Jin, Xu Han, Shreyas Karnik, Abhinita Subhadarshini, Sara K. Quinney, David A. Flockhart, Marcus J. Overhage, R. Matthew Strother, J. Thomas Callaghan, Zhiping Wang, Xiaochun Li, Stephen D. Hall, Lang Li, and Jon Duke
- Subjects
Simvastatin ,Indoles ,Databases, Factual ,Text Mining ,Pharmacology ,Loratadine ,Promethazine ,030226 pharmacology & pharmacy ,0302 clinical medicine ,Drug Metabolism ,Electronic Health Records ,Medicine ,Drug Interactions ,Biology (General) ,media_common ,0303 health sciences ,Ecology ,Statistics ,Clinical Pharmacology ,Drug Information ,3. Good health ,Computational Theory and Mathematics ,Modeling and Simulation ,medicine.symptom ,Information Technology ,Research Article ,medicine.drug ,Drug ,Drugs and Devices ,CYP2D6 ,Tegaserod ,QH301-705.5 ,media_common.quotation_subject ,Thiophenes ,Biostatistics ,Duloxetine Hydrochloride ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Muscular Diseases ,Adverse Reactions ,Genetics ,Humans ,Pharmacokinetics ,Statistical Methods ,Myopathy ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Natural Language Processing ,030304 developmental biology ,Alprazolam ,business.industry ,Pharmacoepidemiology ,Drug interaction ,Ropinirole ,Computer Science ,business ,Mathematics - Abstract
Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR = 1.69); loratadine and alprazolam (RR = 1.86); loratadine and duloxetine (RR = 1.94); loratadine and ropinirole (RR = 3.21); and promethazine and tegaserod (RR = 3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms., Author Summary Drug-drug interactions are a common cause of adverse drug events. In this paper, we developed an automated search algorithm which can predict new drug interactions based on published literature. Using a large electronic medical record database, we then analyzed the correlation between concurrent use of these potentially interacting drugs and the incidence of myopathy as an adverse drug event. Myopathy comprises a range of musculoskeletal conditions including muscle pain, weakness, and tissue breakdown (rhabdomyolysis). Our statistical analysis identified 5 drug interaction pairs: (loratadine, simvastatin), (loratadine, alprazolam), (loratadine, duloxetine), (loratadine, ropinirole), and (promethazine, tegaserod). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Further investigation suggests that two major drug metabolism proteins, CYP2D6 and CYP3A4, are involved with these five drug pairs' interactions. Overall, our method is robust in that it can incorporate all published literature, all FDA approved drugs, and very large clinical datasets to generate predictions of clinically significant interactions. The interactions can then be further validated in future cell-based experiments and/or clinical studies.
- Published
- 2012
18. Design, characterization and comparison of transdermal delivery of colchicine via borneol-chemically-modified and borneol-physically-modified ethosome
- Author
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Nan Zhang, Zheng Wensheng, Yujia Zhang, Hui Song, Jin Wen, He Li, and Xiaochuan Tan
- Subjects
Male ,borneol-chemically-modified ethosome ,Pharmaceutical Science ,02 engineering and technology ,Pharmacology ,medicine.disease_cause ,030226 pharmacology & pharmacy ,Rats, Sprague-Dawley ,Mice ,Random Allocation ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Colchicine ,borneol-physically-modified ethosome ,media_common ,Transdermal ,Camphanes ,Arthritis, Gouty ,General Medicine ,021001 nanoscience & nanotechnology ,Toxicity ,Irritation ,0210 nano-technology ,Research Article ,Drug ,Cell Survival ,Skin Absorption ,media_common.quotation_subject ,macromolecular substances ,Administration, Cutaneous ,colchicine ,Cell Line ,Borneol ,03 medical and health sciences ,Organ Culture Techniques ,gout ,Pharmacokinetics ,medicine ,Animals ,Humans ,Phosphatidylethanolamines ,lcsh:RM1-950 ,medicine.disease ,equipment and supplies ,Rats ,Gout ,lcsh:Therapeutics. Pharmacology ,chemistry ,Drug Design ,transdermal delivery - Abstract
Gout is a kind of joint disease characterized by the accumulation of monosodium urate (MSU) crystals in the joint and its surrounding tissue, causing persistent hyperuricemia. Colchicine is the first choice of treatment for acute gout attacks. Due to strong toxicity of colchicines oral tablets, there are high fluctuations of blood drug concentration and serious irritation of gastrointestinal tract, and hence a transdermal preparation can help to slow down the blood drug concentration, reduce the frequency of drug taking, and improve the patients' compliance of the drug. The ethosome is a lipid carrier with high concentration of ethanol and has been proved to promote the penetration of drugs into the skin. Borneol (BO) is an excellent penetration enhancer in Chinese medicine, which can promote the entry of drugs into the skin. This paper prepared the borneol-physically-modified colchicine ethosome (COL-bpES) and used the prepared borneol-dioleoyl phosphoethanloamine (BO-DOPE) to prepare borneol-chemically-modified colchicine ethosome (COL-bcES). Compared to the free colchicine aqueous solution (free COL) and normal colchicine ethosome (COL-ES), the borneol-modified colchicine ethosome (COL-bES) demonstrated better drug penetration effect, while the particle size of the COL-bcES was lower than that of the COL-bpES. Toxicity, in vitro diffusion, pharmacokinetics and pharmacodynamics are superior to those of COL-bpES, providing a better delivery system for the treatment of small molecule inflammatory drugs.
- Published
- 2019
19. Penetration of fleroxacin and ciprofloxacin into skin blister fluid: a comparative study
- Author
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J Zhi, Charles H. Nightingale, Kevin Sweeney, Richard Quintiliani, and T J Lubowski
- Subjects
Adult ,Male ,Fleroxacin ,Administration, Oral ,Pharmacology ,Random Allocation ,Blister ,Pharmacokinetics ,Oral administration ,Interstitial fluid ,Ciprofloxacin ,medicine ,Humans ,Pharmacology (medical) ,Volunteer ,Chromatography ,integumentary system ,business.industry ,Correction ,Penetration (firestop) ,Middle Aged ,Crossover study ,Body Fluids ,Infectious Diseases ,Female ,business ,medicine.drug ,Research Article - Abstract
The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprofloxacin (500 mg every 12 h) into skin blister fluid in 12 healthy volunteers was determined in a randomized crossover study. Serum, blister fluid, and paper disk samples were analyzed by large-plate microbiologic assay. The mean areas under the concentration-time curve (AUC) for serum were 88.6 and 18.2 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. The mean AUC for blister fluid and paper disks were 71.2 and 15.0 micrograms.h/ml/70 kg and 77.8 and 15.4 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. Calculated penetration into interstitial fluid ranged from 74 to 92% for fleroxacin and 56 to 96% for ciprofloxacin; penetration was calculated by using the ratio of maximum drug concentration or AUC in blister fluid and paper disks to maximum drug concentration or AUC in serum. There was no significant difference between fleroxacin and ciprofloxacin in the percent penetration into skin blister fluid.
- Published
- 1992
20. Correction: Tissue expression of antigens of ABH blood groups in species of New World Monkeys (Aotus infulatus, Callithrix jacchus, Sapajus apella and Saimiri sciureus)
- Author
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Klena Sarges Marruaz da Silva, Gyselly de Cássia Bastos de Matos, Rosane do Socorro Pompeu de Loiola, Délia Cristina Figueira Aguiar, Washington Luiz Assunção Pereira, and Tereza Cristina de Oliveira Corvelo
- Subjects
Physiology ,030204 cardiovascular system & hematology ,Monkeys ,Biochemistry ,Epithelium ,Salivary Glands ,0302 clinical medicine ,Immune Physiology ,Medicine and Health Sciences ,Primate ,Tissue Distribution ,Saimiri ,chemistry.chemical_classification ,Mammals ,Immune System Proteins ,Multidisciplinary ,biology ,Eukaryota ,Callithrix ,Body Fluids ,Platyrrhini ,Phenotypes ,Blood ,Organ Specificity ,Sapajus apella ,Vertebrates ,Aotidae ,Medicine ,Anatomy ,Aotus infulatus ,Research Article ,Primates ,Science ,030231 tropical medicine ,Immunology ,ABO Blood-Group System ,03 medical and health sciences ,Exocrine Glands ,Antigen ,Species Specificity ,biology.animal ,Genetic model ,Genetics ,Animals ,Pharmacokinetics ,Antigens ,Pharmacology ,New World monkeys ,Biology and life sciences ,Organisms ,Saimiri sciureus ,Proteins ,Correction ,biology.organism_classification ,Molecular biology ,Enzyme ,Biological Tissue ,chemistry ,Tissue expression ,Amniotes ,Zoology ,Digestive System ,Blood Groups - Abstract
ABH antigens are histo-antigens, but were first described on the surface of human erythrocytes. They are found in those cells only in great apes and humans, while in more primitive animals they are found in tissues and body fluids. ABH antigens are mainly distributed in tissues that are in contact with the external environment and may serve as ligands for pathogens in tissues or block their connection. Description of the distribution of these molecules in non-human primate tissues is restricted to a few tissues and species. This paper describes the expression of human A, B and H type antigens in different organs from four species of New World Primates, obtained from the Centro Nacional de Primatas, as well as comparing that expression with what has been described for humans. In this study, although the tissue description of the antigens is similar to the genetic model for humans, some differences in expression between some organs from those species and those of humans were found. The differences occurred mainly in endodermal organs that have secretory functions and are probably under the control of the human-type FUT-2 enzyme. In the mesodermal-origin organs there was a reduction or absence of A and B antigen marking, particularly in the H precursor substance, indicating that those organs are under the control of the human-type FUT-1 enzyme. These findings have demonstrated that there is similar ABH antigen reactivity in tissue distribution between the species, although there are some species-specific cases.
- Published
- 2021
21. Lower Corticosteroid Skin Blanching Response Is Associated with Severe COPD.
- Author
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Hoonhorst, Susan J. M., ten Hacken, Nick H. T., Lo Tam Loi, Adèle T., Koenderman, Leo, Lammers, Jan Willem J., Telenga, Eef D., Boezen, H. Marike, van den Berge, Maarten, and Postma, Dirkje S.
- Subjects
CORTICOSTEROIDS ,HORMONE therapy ,BLANCHING of skin ,OBSTRUCTIVE lung diseases ,INFLAMMATION ,DRUG resistance ,AIRWAY (Anatomy) - Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by ongoing inflammatory and remodeling processes of the airways and lung tissue. Inflammation can be targeted by corticosteroids. However, airway inflammation is generally less responsive to steroids in COPD than in asthma. The underlying mechanisms are yet unclear. This study aimed to assess whether skin corticosteroid insensitivity is associated with COPD and COPD severity using the corticosteroid skin blanching test. Methods: COPD patients GOLD stage I–IV (n = 27, 24, 22, and 16 respectively) and healthy never-smokers and smokers (n = 28 and 56 respectively) were included. Corticosteroid sensitivity was assessed by the corticosteroid skin blanching test. Budesonide was applied in 8 logarithmically increasing concentrations (0–100 μg/ml) on subject's forearm. Assessment of blanching was performed after 7 hours using a 7-point scale (normal skin to intense blanching). All subjects performed spirometry and body plethysmography. Results: Both GOLD III and GOLD IV COPD patients showed significantly lower skin blanching responses than healthy never-smokers and smokers, GOLD I, and GOLD II patients. Their area under the dose-response curve values of the skin blanching response were 586 and 243 vs. 1560, 1154, 1380, and 1309 respectively, p<0.05. Lower FEV
1 levels and higher RV/TLC ratios were significantly associated with lower skin blanching responses (p = 0.001 and p = 0.004 respectively). GOLD stage I, II, III and IV patients had similar age and packyears. Conclusions: In this study, severe and very severe COPD patients had lower skin corticosteroid sensitivity than mild and moderate COPD patients and non-COPD controls with comparable age and packyears. Our findings together suggest that the reduced skin blanching response fits with a subgroup of COPD patients that has an early-onset COPD phenotype. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
22. The Effects of LPM570065, a Novel Triple Reuptake Inhibitor, on Extracellular Serotonin, Dopamine and Norepinephrine Levels in Rats.
- Author
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Zhang, Renyu, Li, Xiang, Shi, Yanan, Shao, Yufeng, Sun, Kaoxiang, Wang, Aiping, Sun, Fengying, Liu, Wanhui, Wang, Di, Jin, Jingji, and Li, Youxin
- Subjects
NEUROTRANSMITTER uptake inhibitors ,EXTRACELLULAR signal-regulated kinases ,SEROTONIN ,DOPAMINE ,NORADRENALINE ,DRUG administration - Abstract
Triple reuptake inhibitors (TRIs) are currently being developed as a new class of promising antidepressants that block serotonin (5-HT), dopamine (DA) and norepinephrine (NE) transporters, thereby increasing extracellular monoamine concentrations. The purpose of this study was to investigate the effects of LPM570065, a novel TRI and a desvenlafaxine prodrug, on extracellular 5-HT, DA and NE levels in the rat striatum after acute and chronic administration relative to desvenlafaxine, using High Performance Liquid Chromatography (HPLC) and microdialysis. Acute administration was performed by providing rodents with oral solutions (0.06 mmol·kg
−1 p.o.), oral suspensions (0.06 mmol·kg−1 p.o.) and intravenous solutions (0.04 mmol·kg−1 i.v.) of LPM570065 and desvenlafaxine. Oral suspensions (0.06 mmol·kg−1 ·day−1 ) of the two drugs were also administered for a 14-day chronic period. HPLC analysis revealed that LPM570065 rapidly penetrated the rat striatum, converted into desvenlafaxine and exhibited larger total exposure compared with the administration of desvenlafaxine. Microdialysis revealed that acute and chronic administration of oral suspension of LPM570065 increased the 5-HT, DA and NE levels more than the relative administration of desvenlafaxine. Unlike desvenlafaxine, acute administration of an intravenous LPM570065 solution did not induce the undesirable 90% decrease in extracellular 5-HT levels. In contrast to the fully dose-dependent elevation of 5-HT induced by desvenlafaxine, the acute administration of LPM570065 showed a capped increase in extracellular 5-HT levels when combined with WAY-100635. Additionally, forced swim test demonstrated that acute and chronic administration of LPM570065 reduced the immobility time more than the relative administration of desvenlafaxine. These data suggest that LPM570065 may have greater efficacy and/or a more rapid onset of antidepressant action than desvenlafaxine and also counterbalance the harmful effects of desvenlafaxine on 5-HT neurotransmission related to 5-HT1A autoreceptors. Thus, this new class of drugs, TRIs has the potential to provide a new therapeutic mechanism for treating depression. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
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23. Efficient Human Breast Cancer Xenograft Regression after a Single Treatment with a Novel Liposomal Formulation of Epirubicin Prepared Using the EDTA Ion Gradient Method.
- Author
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Gubernator, Jerzy, Lipka, Dominik, Korycińska, Mariola, Kempińska, Katarzyna, Milczarek, Magdalena, Wietrzyk, Joanna, Hrynyk, Rafał, Barnert, Sabine, Süss, Regine, and Kozubek, Arkadiusz
- Subjects
BREAST cancer treatment ,XENOGRAFTS ,LIPOSOMES ,EPIRUBICIN ,ETHYLENEDIAMINETETRAACETIC acid ,DRUG carriers ,CANCER chemotherapy - Abstract
Liposomes act as efficient drug carriers. Recently, epirubicin (EPI) formulation was developed using a novel EDTA ion gradient method for drug encapsulation. This formulation displayed very good stability and drug retention in vitro in a two-year long-term stability experiment. The cryo-TEM images show drug precipitate structures different than ones formed with ammonium sulfate method, which is usually used to encapsulate anthracyclines. Its pharmacokinetic properties and its efficacy in the human breast MDA-MB-231 cancer xenograft model were also determined. The liposomal EPI formulation is eliminated slowly with an AUC of 7.6487, while the free drug has an AUC of only 0.0097. The formulation also had a much higher overall antitumor efficacy than the free drug. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
24. Selectivity and Potency of Microcystin Congeners against OATP1B1 and OATP1B3 Expressing Cancer Cells.
- Author
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Niedermeyer, Timo H. J., Daily, Abigail, Swiatecka-Hagenbruch, Monika, and Moscow, Jeffrey A.
- Subjects
CANCER cells ,MICROCYSTINS ,GENE expression ,PHOSPHATASE inhibitors ,TOXINS ,ACTIVE biological transport ,DRUG absorption ,CANCER treatment - Abstract
Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC
50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
25. Controlled Delivery of Zoledronate Improved Bone Formation Locally In Vivo.
- Author
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Gou, Wenlong, Wang, Xin, Peng, Jiang, Lu, Qiang, Wang, Yu, Wang, Aiyuan, Guo, Quanyi, Gao, Xupeng, Xu, Wenjing, and Lu, Shibi
- Subjects
BONE resorption ,ZOLEDRONIC acid ,DIPHOSPHONATES ,BONE diseases ,COMPUTED tomography ,OSTEOBLASTS - Abstract
Bisphosphonates (BPs) have been widely used in clinical treatment of bone diseases with increased bone resorption because of their strong affinity for bone and their inhibition of bone resorption. Recently, there has been growing interest in their improvement of bone formation. However, the effect of local controlled delivery of BPs is unclear. We used polylactide acid-glycolic acid copolymer (PLGA) as a drug carrier to deliver various doses of the bisphosphonate zoledronate (Zol) into the distal femur of 8-week-old Sprague-Dawley rats. After 6 weeks, samples were harvested and analyzed by micro-CT and histology. The average bone mineral density and mineralized bone volume fraction were higher with medium- and high-dose PLGA-Zol (30 and 300 µg Zol, respectively) than control and low-dose Zol (3 µg PLGA-Zol; p<0.05). Local controlled delivery of Zol decreased the numbers of osteoclast and increased the numbers of osteoblast. Moreover, local controlled delivery of medium- and high-dose Zol accelerated the expression of bone-formation markers. PLGA used as a drug carrier for controlled delivery of Zol may promote local bone formation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
26. Evaluation of Fentanyl Disposition and Effects in Newborn Piglets as an Experimental Model for Human Neonates.
- Author
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Rey-Santano, Carmen, Mielgo, Victoria, Valls-i-Soler, Adolfo, Encinas, Esther, Lukas, John C., Vozmediano, Valvanera, and Suárez, Elena
- Subjects
FENTANYL ,PHARMACOKINETICS ,ARTIFICIAL respiration ,OXYGENATION (Chemistry) ,HEART beat ,PATHOLOGICAL physiology ,NEONATOLOGY - Abstract
Background: Fentanyl is widely used off-label in NICU. Our aim was to investigate its cerebral, cardiovascular and pulmonary effects as well as pharmacokinetics in an experimental model for neonates. Methods: Fentanyl (5 µg/kg bolus immediately followed by a 90 minute infusion of 3 µg/kg/h) was administered to six mechanically ventilated newborn piglets. Cardiovascular, ventilation, pulmonary and oxygenation indexes as well as brain activity were monitored from T = 0 up to the end of experiments (T = 225–300 min). Also plasma samples for quantification of fentanyl were drawn. Results: A “reliable degree of sedation” was observed up to T = 210–240 min, consistent with the selected dosing regimen and the observed fentanyl plasma levels. Unlike cardiovascular parameters, which were unmodified except for an increasing trend in heart rate, some of the ventilation and oxygenation indexes as well as brain activity were significantly altered. The pulmonary and brain effects of fentanyl were mostly recovered from T = 210 min to the end of experiment. Conclusion: The newborn piglet was shown to be a suitable experimental model for studying fentanyl disposition as well as respiratory and cardiovascular effects in human neonates. Therefore, it could be extremely useful for further investigating the drug behaviour under pathophysiological conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. In Silico Prediction of Inhibition of Promiscuous Breast Cancer Resistance Protein (BCRP/ABCG2).
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Ding, Yi-Lung, Shih, Yu-Hsuan, Tsai, Fu-Yuan, and Leong, Max K.
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BREAST cancer ,DRUG resistance in cancer cells ,P-glycoprotein ,ACTIVE biological transport ,XENOBIOTICS ,BLOOD-brain barrier ,SUPPORT vector machines - Abstract
Background: Breast cancer resistant protein has an essential role in active transport of endogenous substances and xenobiotics across extracellular and intracellular membranes along with P-glycoprotein. It also plays a major role in multiple drug resistance and permeation of blood-brain barrier. Therefore, it is of great importance to derive theoretical models to predict the inhibition of both transporters in the process of drug discovery and development. Hitherto, very limited BCRP inhibition predictive models have been proposed as compared with its P-gp counterpart. Methodology/Principal Findings: An in silico BCRP inhibition model was developed in this study using the pharmacophore ensemble/support vector machine scheme to take into account the promiscuous nature of BCRP. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those molecules in the training set (n = 22, r
2 = 0.82, = 0.73, RMSE = 0.40, s = 0.24), test set (n = 97, q2 = 0.75–0.89, RMSE = 0.31, s = 0.21), and outlier set (n = 16, q2 = 0.72–0.91, RMSE = 0.29, s = 0.17). When subjected to a variety of statistical validations, the developed PhE/SVM model consistently met the most stringent criteria. A mock test by HIV protease inhibitors also asserted its predictivity. Conclusions/Significance: It was found that this accurate, fast, and robust PhE/SVM model can be employed to predict the BCRP inhibition of structurally diverse molecules that otherwise cannot be carried out by any other methods in a high-throughput fashion to design therapeutic agents with insignificant drug toxicity and unfavorable drug–drug interactions mediated by BCRP to enhance clinical efficacy and/or circumvent drug resistance. [ABSTRACT FROM AUTHOR]- Published
- 2014
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28. Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma.
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Morris, John C., Tan, Antoinette R., Olencki, Thomas E., Shapiro, Geoffrey I., Dezube, Bruce J., Reiss, Michael, Hsu, Frank J., Berzofsky, Jay A., and Lawrence, Donald P.
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TRANSFORMING growth factors-beta ,MONOCLONAL antibodies ,MELANOMA ,RENAL cell carcinoma ,PHARMACOKINETICS ,BIOMARKERS ,SKIN cancer ,PATIENTS - Abstract
Background: In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods: In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results: Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions: GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration: Clinicaltrials.gov NCT00356460 [ABSTRACT FROM AUTHOR]
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- 2014
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29. Semi-Quantitative Parameter Analysis of DCE-MRI Revisited: Monte-Carlo Simulation, Clinical Comparisons, and Clinical Validation of Measurement Errors in Patients with Type 2 Neurofibromatosis.
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Jackson, Alan, Li, Ka-Loh, and Zhu, Xiaoping
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MAGNETIC resonance imaging ,MONTE Carlo method ,MEASUREMENT errors ,NEUROFIBROMATOSIS ,PHARMACOKINETICS ,ACOUSTIC neuroma ,MENINGIOMA ,PATIENTS - Abstract
Purpose: To compare semi-quantitative (SQ) and pharmacokinetic (PK) parameters for analysis of dynamic contrast enhanced MR data (DCE-MRI) and investigate error-propagation in SQ parameters. Methods: Clinical data was collected from five patients with type 2-neurofibromatosis (NF2) receiving anti-angiogenic therapy for rapidly growing vestibular schwannoma (VS). There were 7 VS and 5 meningiomas. Patients were scanned prior to therapy and at days 3 and 90 of treatment. Data was collected using a dual injection technique to permit direct comparison of SQ and PK parameters. Monte Carlo modeling was performed to assess potential measurement errors in SQ parameters in persistent, washout, and weakly enhancing tissues. The simulation predictions for five semi-quantitative parameters were tested using the clinical DCE-MRI data. Results: In VS, SQ parameters and K
trans showed close correlation and demonstrated similar therapy induced reductions. In meningioma, only the denoised Signal Enhancement Ratio (Rse1/se2(DN) ) showed a significant therapy induced reduction (p<0.05). Simulation demonstrated: 1) Precision of SQ metrics normalized to the pre-contrast-baseline values (MSErel and ∑MSErel ) is improved by use of an averaged value from multiple baseline scans; 2) signal enhancement ratio Rmse1/mse2 shows considerable susceptibility to noise; 3) removal of outlier values to produce a new parameter, Rmse1/mse2(DN) , improves precision and sensitivity to therapy induced changes. Direct comparison of in-vivo analysis with Monte Carlo simulation supported the simulation predicted error distributions of semi-quantitative metrics. Conclusion: PK and SQ parameters showed similar sensitivity to anti-angiogenic therapy induced changes in VS. Modeling studies confirmed the benefits of averaging baseline signal from multiple images for normalized SQ metrics and demonstrated poor noise tolerance in the widely used signal enhancement ratio, which is corrected by removal of outlier values. [ABSTRACT FROM AUTHOR]- Published
- 2014
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30. Long-Term Implanted cOFM Probe Causes Minimal Tissue Reaction in the Brain.
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Birngruber, Thomas, Ghosh, Arijit, Hochmeister, Sonja, Asslaber, Martin, Kroath, Thomas, Pieber, Thomas R., and Sinner, Frank
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PERFUSION ,LONG-term care facilities ,CEREBROSPINAL fluid ,FRONTAL lobe ,LABORATORY rats ,DIFFUSION barriers ,HISTOLOGY - Abstract
This study investigated the histological tissue reaction to long-term implanted cerebral open flow microperfusion (cOFM) probes in the frontal lobe of the rat brain. Most probe-based cerebral fluid sampling techniques are limited in application time due to the formation of a glial scar that hinders substance exchange between brain tissue and the probe. A glial scar not only functions as a diffusion barrier but also alters metabolism and signaling in extracellular brain fluid. cOFM is a recently developed probe-based technique to continuously sample extracellular brain fluid with an intact blood-brain barrier. After probe implantation, a 2 week healing period is needed for blood-brain barrier reestablishment. Therefore, cOFM probes need to stay in place and functional for at least 15 days after implantation to ensure functionality. Probe design and probe materials are optimized to evoke minimal tissue reaction even after a long implantation period. Qualitative and quantitative histological tissue analysis revealed no continuous glial scar formation around the cOFM probe 30 days after implantation and only a minor tissue reaction regardless of perfusion of the probe. [ABSTRACT FROM AUTHOR]
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- 2014
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31. Approaches to Improve the Oral Bioavailability and Effects of Novel Anticancer Drugs Berberine and Betulinic Acid.
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Godugu, Chandraiah, Patel, Apurva R., Doddapaneni, Ravi, Somagoni, Jaganmohan, and Singh, Mandip
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DRUG bioavailability ,ORAL drug administration ,ANTINEOPLASTIC agents ,BERBERINE ,TRITERPENES ,PHARMACOKINETICS - Abstract
Background: The poor bioavailability of Berberine (BBR) and Betulinic acid (BA) limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD) mucoadhesive microparticle formulations were prepared. Methods: A patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI) permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations. Results: Pharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma C
max concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549) tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1α, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity. Conclusions: Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA. [ABSTRACT FROM AUTHOR]- Published
- 2014
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32. MRI-Based Computational Model of Heterogeneous Tracer Transport following Local Infusion into a Mouse Hind Limb Tumor.
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Magdoom, Kulam Najmudeen, Pishko, Gregory L., Rice, Lori, Pampo, Chris, Siemann, Dietmar W., and Sarntinoranont, Malisa
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MAGNETIC resonance imaging ,EXTREMITIES (Anatomy) ,COMPUTATIONAL biology ,LABORATORY mice ,DRUG delivery systems ,THREE-dimensional imaging ,BIOENGINEERING ,CANCER - Abstract
Systemic drug delivery to solid tumors involving macromolecular therapeutic agents is challenging for many reasons. Amongst them is their chaotic microvasculature which often leads to inadequate and uneven uptake of the drug. Localized drug delivery can circumvent such obstacles and convection-enhanced delivery (CED) - controlled infusion of the drug directly into the tissue - has emerged as a promising delivery method for distributing macromolecules over larger tissue volumes. In this study, a three-dimensional MR image-based computational porous media transport model accounting for realistic anatomical geometry and tumor leakiness was developed for predicting the interstitial flow field and distribution of albumin tracer following CED into the hind-limb tumor (KHT sarcoma) in a mouse. Sensitivity of the model to changes in infusion flow rate, catheter placement and tissue hydraulic conductivity were investigated. The model predictions suggest that 1) tracer distribution is asymmetric due to heterogeneous porosity; 2) tracer distribution volume varies linearly with infusion volume within the whole leg, and exponentially within the tumor reaching a maximum steady-state value; 3) infusion at the center of the tumor with high flow rates leads to maximum tracer coverage in the tumor with minimal leakage outside; and 4) increasing the tissue hydraulic conductivity lowers the tumor interstitial fluid pressure and decreases the tracer distribution volume within the whole leg and tumor. The model thus predicts that the interstitial fluid flow and drug transport is sensitive to porosity and changes in extracellular space. This image-based model thus serves as a potential tool for exploring the effects of transport heterogeneity in tumors. [ABSTRACT FROM AUTHOR]
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- 2014
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33. Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin.
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Reddy, Cheruku Apoorva, Somepalli, Venkateswarlu, Golakoti, Trimurtulu, Kanugula, Anantha KoteswaraRao, Karnewar, Santosh, Rajendiran, Karthikraj, Vasagiri, Nagarjuna, Prabhakar, Sripadi, Kuppusamy, Periannan, Kotamraju, Srigiridhar, and Kutala, Vijay Kumar
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MITOCHONDRIAL physiology ,CURCUMINOIDS ,TARGETED drug delivery ,DRUG efficacy ,BIOAVAILABILITY ,CURCUMIN ,ANTINEOPLASTIC agents - Abstract
Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC
50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers. [ABSTRACT FROM AUTHOR]- Published
- 2014
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34. Engineering a Segmented Dual-Reservoir Polyurethane Intravaginal Ring for Simultaneous Prevention of HIV Transmission and Unwanted Pregnancy.
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Clark, Justin T., Clark, Meredith R., Shelke, Namdev B., Johnson, Todd J., Smith, Eric M., Andreasen, Andrew K., Nebeker, Joel S., Fabian, Judit, Friend, David R., and Kiser, Patrick F.
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POLYURETHANES ,VAGINAL contraceptives ,HIV prevention ,HIV infection transmission ,UNWANTED pregnancy ,DRUG dosage ,DRUG delivery systems - Abstract
The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems. [ABSTRACT FROM AUTHOR]
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- 2014
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35. Optimization and In Vivo Toxicity Evaluation of G4.5 Pamam Dendrimer-Risperidone Complexes.
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Prieto, Maria Jimena, del Rio Zabala, Nahuel Eduardo, Marotta, Cristian Hernán, Carreño Gutierrez, Hector, Arévalo Arévalo, Rosario, Chiaramoni, Nadia Silvia, and Alonso, Silvia del Valle
- Subjects
DENDRIMERS ,RISPERIDONE ,ANTIPSYCHOTIC agents ,AQUEOUS solutions ,PROTEIN binding ,METABOLISM ,CHLOROFORM - Abstract
Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). Since new strategies to improve efficient treatments are needed, we studied the efficiency of anionic G4.5 PAMAM dendrimers as nanocarriers for this therapeutic drug. To this end, we explored dendrimer-risperidone complexation dependence on solvent concentration, pH and molar relationship. The best dendrimer-risperidone incorporation (46 risperidone molecules per dendrimer) was achieved with a mixture of chloroform:methanol 50∶50 v/v solution pH 3. In addition, to explore the possible effects of this complex, in vivo studies were carried out in the zebrafish model. Changes in the development of dopaminergic neurons and motoneurons were studied using tyrosine hydroxylase and calretinin, respectively. Physiological changes were studied through histological sections stained with hematoxylin-eosin to observe possible morphological brain changes. The most significant changes were observed when larvae were treated with free risperidone, and no changes were observed when larvae were treated with the complex. [ABSTRACT FROM AUTHOR]
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- 2014
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36. Metabotyping of Docosahexaenoic Acid - Treated Alzheimer’s Disease Cell Model.
- Author
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Bahety, Priti, Tan, Yee Min, Hong, Yanjun, Zhang, Luqi, Chan, Eric Chun Yong, and Ee, Pui-Lai Rachel
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DOCOSAHEXAENOIC acid ,ALZHEIMER'S disease ,AMYLOID beta-protein precursor ,PHENOTYPES ,GAS chromatography ,TRICARBOXYLIC acids ,NEUROPROTECTIVE agents - Abstract
Background: Despite the significant amount of work being carried out to investigate the therapeutic potential of docosahexaenoic acid (DHA) in Alzheimer’s disease (AD), the mechanism by which DHA affects amyloid-β precursor protein (AβPP)-induced metabolic changes has not been studied. Objective: To elucidate the metabolic phenotypes (metabotypes) associated with DHA therapy via metabonomic profiling of an AD cell model using gas chromatography time-of-flight mass spectrometry (GC/TOFMS). Methods: The lysate and supernatant samples of CHO-wt and CHO-AβPP
695 cells treated with DHA and vehicle control were collected and prepared for GC/TOFMS metabonomics profiling. The metabolic profiles were analyzed by multivariate data analysis techniques using SIMCA-P+ software. Results: Both principal component analysis and subsequent partial least squares discriminant analysis revealed distinct metabolites associated with the DHA-treated and control groups. A list of statistically significant marker metabolites that characterized the metabotypes associated with DHA treatment was further identified. Increased levels of succinic acid, citric acid, malic acid and glycine and decreased levels of zymosterol, cholestadiene and arachidonic acid correlated with DHA treatment effect. DHA levels were also found to be increased upon treatment. Conclusion: Our study shows that DHA plays a role in mitigating AβPP-induced impairment in energy metabolism and inflammation by acting on tricarboxylic acid cycle, cholesterol biosynthesis pathway and fatty acid metabolism. The perturbations of these metabolic pathways by DHA in CHO-wt and CHO-AβPP695 cells shed further mechanistic insights on its neuroprotective actions. [ABSTRACT FROM AUTHOR]- Published
- 2014
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37. Metronidazole or Cotrimoxazole Therapy Is Associated with a Decrease in Intestinal Bioavailability of Common Antiretroviral Drugs.
- Author
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Dossou-Yovo, Flore, Mamadou, Godefroy, Soudy, Imar Djibrine, Limas-Nzouzi, Nicolas, Miantezila, Joe, Desjeux, Jehan-François, and Eto, Bruno
- Subjects
METRONIDAZOLE ,CO-trimoxazole ,BIOAVAILABILITY ,ANTIRETROVIRAL agents ,HIV infections ,ANTIBIOTICS ,ANIMAL models in research - Abstract
Metronidazole (MTZ) and Cotrimoxazole (CTX) are used in HIV/AIDS patients eligible for antiretroviral treatment. The objective of this animal study was to determine whether pre-treatment with antibiotics affects the intestinal bioavailability of Atazanavir (ATV) and Ritonavir (RTV). After oral administration of 1 mg MTZ and CTX for 7 days, the rat colonic mucosa were analyzed for mucus thickness or placed in Ussing chambers to measure ATV and RTV net transepithelial fluxes (J
net ). 1. In control rats, the mucus thickness was 43.3±7.6 µm and 40.7±6.9 µm, in proximal and distal colon, respectively. In proximal colon, the thickness was 57.2±8.8 and 58.2±6.9 µm after MTZ and CTX, respectively whereas in distal colon, the thickness was 121.1±38.4 and 170.5±35.0 µm (P<0.05) respectively. 2. Transepithelial conductance was reduced after MTZ or CTX in the proximal and distal colon. 3. In control, net ATV secretion was observed both in proximal (−0.36±0.02 µg.hr−1 cm−2 ) and distal colon (−0.30±0.08 µg.hr−1 cm−2 ). After MTZ and CTX, it was increased in the proximal colon by two 2 fold and 4 fold, respectively and in the distal colon by 3 fold and 5 fold, respectively. 4. In control, there was no net active RTV transport either in proximal (+0.01±0.01 µg.hr−1 cm−2 ) or distal colon (+0.04±0.01 µg.hr−1 cm−2 ). After MTZ and CTX, secretion was increased 5 fold and 10 fold, respectively, in the proximal colon and two fold and 5 fold, respectively in the distal colon (p<0.001). In conclusion, after MTZ and CTX therapy, the mucus layer was enlarged, passive permeability was decreased and ATV and RTV were actively secreted by the colonic epithelium suggesting that, in rat, the intestinal bioavailability of ATV and RTV is impaired after antibiotic therapy. [ABSTRACT FROM AUTHOR]- Published
- 2014
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38. Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats.
- Author
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Gao, Na, Qi, Bing, Liu, Fang-jun, Fang, Yan, Zhou, Jun, Jia, Lin-jing, and Qiao, Hai-ling
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LIVER enzymes ,FLAVONES ,PHENACETIN ,MICROSOMES ,LABORATORY rats ,PHARMACOKINETICS - Abstract
Baicalin has been used as mainly bioactive constituent of about 100 kinds of traditional Chinese medicines in Chinese pharmacopoeia. The effect of baicalin on cytochrome P450 should be paid more attention because baicalin was used widely. The aim of this study was to investigate whether baicalin could inhibit CYP1A2 in pooled human liver microsomes (HLMs) and in rats in vivo and the gene polymorphisms could affect inter-individual variation in IC
50 in 28 human livers. Phenacetin was used as probe of CYP1A2. Kinetic parameter of CYP1A2 and IC50 of baicalin on CYP1A2 to each sample were measured and the common CYP1A2 polymorphisms (−3860G>A and −163C>A) were genotyped. The results showed that baicalin exhibited a mixed-type inhibition in pooled HLMs, with a Ki value of 25.4 µM. There was substantial variation in Km , Vmax , CLint of CYP1A2 and IC50 of baicalin on CYP1A2 (3∼10-fold). The range was from 26.6 to 114.8 µM for Km , from 333 to 1330 pmol·min−1 ·mg−1 protein for Vmax and from 3.8 to 45.3 µL·min−1 ·mg−1 protein for CLint in HLMs (n = 28). The Mean (range) value of IC50 in 28 HLMs was 36.3 (18.9 to 56.1) µM. The genotypes of −3860G>A and −163C>A had no significant effect on the inhibition of baicalin on CYP1A2. The animal experiment results showed that baicalin (450 mg/kg, i.v.) significantly decreased the Cmax and CL of phenacetin, and increased C60 min , t1/2 , Vd and AUC (P<0.05). There were significant correlations between percentage of control in C60 min , t1/2 , CL, AUC of phenacetin and Cmax of baicalin in 11 rats (P<0.05). Protein binding experiments in vitro showed that baicalin (0–2000 mg/L) increased the unbound phenacetin from 14.5% to 28.3%. In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism. Baicalin can change the pharmacokinetics of phenacetin in rats. [ABSTRACT FROM AUTHOR]- Published
- 2014
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39. Therapeutic Drug Monitoring and Pharmacogenetic Study of HIV-Infected Ethnic Chinese Receiving Efavirenz-Containing Antiretroviral Therapy with or without Rifampicin-Based Anti-Tuberculous Therapy.
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Lee, Kuan-Yeh, Lin, Shu-Wen, Sun, Hsin-Yun, Kuo, Ching-Hua, Tsai, Mao-Song, Wu, Bing-Ru, Tang, Sue-Yo, Liu, Wen-Chun, Chang, Sui-Yuan, and Hung, Chien-Ching
- Subjects
DRUG monitoring ,PHARMACOGENOMICS ,HIV infections ,EFAVIRENZ ,ANTIRETROVIRAL agents ,TUBERCULOSIS patients ,CHINESE people ,ETHICS ,DISEASES - Abstract
Objectives: Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese. Methods: HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively. Results: From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33–0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97–9.59) in multivariate analysis. Conclusions: Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations. [ABSTRACT FROM AUTHOR]
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- 2014
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40. Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes.
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Jensen, Henrik Sindal, Nichol, Kathryn, Lee, Deborah, and Ebert, Bjarke
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GABA receptors ,TRANQUILIZING drugs ,METABOLITES ,FEBRILE seizures ,LENNOX-Gastaut syndrome ,ALLOSTERIC regulation ,JUVENILE diseases ,THERAPEUTICS - Abstract
Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABA
A receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α1 -subunit–selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α2 subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA -receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α1 , α2 , α3 , or α5 ), β2 , and γ2 subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α2 - vs. α1 -receptor complexes, a difference not observed for CLN, for which no distinction between α2 and α1 receptors was observed. Our experiments with ZOL confirmed the high preference for α1 receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB. [ABSTRACT FROM AUTHOR]- Published
- 2014
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41. Infrared-Transparent Gold Nanoparticles Converted by Tumors to Infrared Absorbers Cure Tumors in Mice by Photothermal Therapy.
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Hainfeld, James F., O'Connor, Michael J., Lin, Ping, Qian, Luping, Slatkin, Daniel N., and Smilowitz, Henry M.
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IMAGING of cancer ,GOLD nanoparticles ,PHOTOTHERMAL effect ,ANTINEOPLASTIC agents ,LIGHT absorption ,EPIDERMAL growth factor receptors ,LABORATORY mice ,CANCER cells - Abstract
Gold nanoparticles (AuNPs) absorb light and can be used to heat and ablate tumors. The “tissue window” at ∼800 nm (near infrared, NIR) is optimal for best tissue penetration of light. Previously, large, 50–150 nm, gold nanoshells and nanorods that absorb well in the NIR have been used. Small AuNPs that may penetrate tumors better unfortunately barely absorb at 800 nm. We show that small AuNPs conjugated to anti-tumor antibodies are taken up by tumor cells that catalytically aggregate them (by enzyme degradation of antibodies and pH effects), shifting their absorption into the NIR region, thus amplifying their photonic absorption. The AuNPs are NIR transparent until they accumulate in tumor cells, thus reducing background heating in blood and non-targeted cells, increasing specificity, in contrast to constructs that are always NIR-absorptive. Treatment of human squamous cell carcinoma A431 which overexpresses epidermal growth factor receptor (EGFr) in subcutaneous murine xenografts with anti-EGFr antibodies conjugated to 15 nm AuNPs and NIR resulted in complete tumor ablation in most cases with virtually no normal tissue damage. The use of targeted small AuNPs therefore provides a potent new method of selective NIR tumor therapy. [ABSTRACT FROM AUTHOR]
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- 2014
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42. Differential In Vitro Inhibition of Thrombin Generation by Anticoagulant Drugs in Plasma from Patients with Cirrhosis.
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Potze, Wilma, Arshad, Freeha, Adelmeijer, Jelle, Blokzijl, Hans, van den Berg, Arie P., Meijers, Joost C. M., Porte, Robert J., and Lisman, Ton
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TREATMENT of cirrhosis of the liver ,ANTITHROMBINS ,ANTICOAGULANTS ,BLOOD plasma ,THROMBOSIS complications ,THROMBOSIS ,CARDIOVASCULAR disease treatment - Abstract
Background: Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known. Objectives: We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis. Patients/Methods: Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs. Results: Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma. Conclusions: The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis. [ABSTRACT FROM AUTHOR]
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- 2014
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43. Drug-Induced Trafficking of P-Glycoprotein in Human Brain Capillary Endothelial Cells as Demonstrated by Exposure to Mitomycin C.
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Noack, Andreas, Noack, Sandra, Hoffmann, Andrea, Maalouf, Katia, Buettner, Manuela, Couraud, Pierre-Olivier, Romero, Ignacio A., Weksler, Babette, Alms, Dana, Römermann, Kerstin, Naim, Hassan Y., and Löscher, Wolfgang
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DRUG traffic ,GLYCOPROTEINS ,ENDOTHELIAL cells ,MITOMYCIN C ,BLOOD-brain barrier ,CELL membranes ,CONFOCAL fluorescence microscopy - Abstract
P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid rafts to gain its full functionality. [ABSTRACT FROM AUTHOR]
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- 2014
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44. Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis.
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Rakesh, Bruhn, David F., Scherman, Michael S., Woolhiser, Lisa K., Madhura, Dora B., Maddox, Marcus M., Singh, Aman P., Lee, Robin B., Hurdle, Julian G., McNeil, Michael R., Lenaerts, Anne J., Meibohm, Bernd, and Lee, Richard E.
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NITROFURANS ,MYCOBACTERIUM tuberculosis ,NITROAROMATIC compounds ,ANTI-infective agents ,NITROIMIDAZOLES ,ANTITUBERCULAR agents ,PHARMACOKINETICS - Abstract
The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo,9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis. [ABSTRACT FROM AUTHOR]
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- 2014
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45. Differential Effects of Methoxy Group on the Interaction of Curcuminoids with Two Major Ligand Binding Sites of Human Serum Albumin.
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Sato, Hiroki, Chuang, Victor Tuan Giam, Yamasaki, Keishi, Yamaotsu, Noriyuki, Watanabe, Hiroshi, Nagumo, Kohei, Anraku, Makoto, Kadowaki, Daisuke, Ishima, Yu, Hirono, Shuichi, Otagiri, Masaki, and Maruyama, Toru
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METHOXY group ,CURCUMINOIDS ,LIGANDS (Biochemistry) ,BINDING sites ,SERUM albumin ,CHEMICAL structure ,BLOOD plasma - Abstract
Curcuminoids are a group of compounds with a similar chemical backbone structure but containing different numbers of methoxy groups that have therapeutic potential due to their anti-inflammatory and anti-oxidant properties. They mainly bind to albumin in plasma. These findings influence their body disposition and biological activities. Spectroscopic analysis using site specific probes on human serum albumin (HSA) clearly indicated that curcumin (Cur), demethylcurcumin (Dmc) and bisdemethoxycurcumin (Bdmc) bind to both Site I (sub-site Ia and Ib) and Site II on HSA. At pH 7.4, the binding constants for Site I were relatively comparable between curcuminoids, while the binding constants for Site II at pH 7.4 were increased in order Cur < Dmc < Bdmc. Binding experiments using HSA mutants showed that Trp214 and Arg218 at Site I, and Tyr411 and Arg410 at Site II are involved in the binding of curcuminoids. The molecular docking of all curcuminoids to the Site I pocket showed that curcuminoids stacked with Phe211 and Trp214, and interacted with hydrophobic and aromatic amino acid residues. In contrast, each curcuminoid interacted with Site II in a different manner depending whether a methoxy group was present or absent. A detailed analysis of curcuminoids-albumin interactions would provide valuable information in terms of understanding the pharmacokinetics and the biological activities of this class of compounds. [ABSTRACT FROM AUTHOR]
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- 2014
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46. Identification of Cinnabarinic Acid as a Novel Endogenous Aryl Hydrocarbon Receptor Ligand That Drives IL-22 Production.
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Lowe, Margaret M., Mold, Jeff E., Kanwar, Bittoo, Huang, Yong, Louie, Alexander, Pollastri, Michael P., Wang, Cuihua, Patel, Gautam, Franks, Diana G., Schlezinger, Jennifer, Sherr, David H., Silverstone, Allen E., Hahn, Mark E., and McCune, Joseph M.
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LIGANDS (Biochemistry) ,HALOCARBONS ,ENVIRONMENTAL toxicology ,T cells ,IMMUNE response ,ENZYME metabolism - Abstract
The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions. [ABSTRACT FROM AUTHOR]
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- 2014
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47. Cardiovascular Risks in Relation to Daidzein Metabolizing Phenotypes among Chinese Postmenopausal Women.
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Liu, Zhao-min, Ho, Suzanne C., Chen, Yu-ming, Liu, Jun, and Woo, Jean
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POSTMENOPAUSE ,CARDIOVASCULAR diseases risk factors ,DAIDZEIN ,PHENOTYPES ,METABOLISM ,ISOFLAVONES ,DRUG metabolism ,DISEASES in women ,CHINESE women - Abstract
Background: Studies suggested that the inter-individual differences in metabolizing isoflavone daidzein to equol or O-desmethylangolensin (ODMA) might explain the inconsistency of the soy/isoflavones efficacy on cardiovascular health. Objectives: The study aims to evaluate the relationship between equol and ODMA phenotypes and cardiovascular risks with habitual isoflavone consumption in Chinese postmenopausal women. Methods: This is a cross-sectional study among 726 prehypertensive postmenopal women who were screened for a randomized controlled trial. 648 women returned a daidzein-challenged urine samples for determination of equol and O-DMA production. 595 attended clinic visits for assessment of cardiovascular risks including body composition, blood pressure (BP), serum lipids, uric acid, high sensitivity C-reactive protein (hs-CRP), fasting glucose and free fatty acid (FFA). Results: The prevalences of equol and O-DMA producers were 53.2% and 60.9% respectively. Equol producers had higher fat free mass (p = 0.001), lower systolic (p = 0.01) and diastolic (p = 0.01) BP, serum triglyceride (p = 0.023), hs-CRP (p = 0.015) and FFA (p = 0.001) than non-producers. O-DMA producers had lower body fat% (p = 0.032), SBP (p = 0.02), total cholesterol (p = 0.002) than non-producers. The significant differences remained after further adjustment for potential confounders. The habitual soy isoflavones intake had little relation to cardiovascular risk factors in either equol/O-DMA producer phenotypes. Conclusion: Equol/O-DMA producers had more favorable cardiovascular risk profiles than non-producers in prehypertensive postmenopausal women. [ABSTRACT FROM AUTHOR]
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- 2014
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48. Novel Exenatide Analogs with Peptidic Albumin Binding Domains: Potent Anti-Diabetic Agents with Extended Duration of Action.
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Levy, Odile E., Jodka, Carolyn M., Ren, Shijun Steven, Mamedova, Lala, Sharma, Abhinandini, Samant, Manoj, D’Souza, Lawrence J., Soares, Christopher J., Yuskin, Diane R., Jin, Li Jenny, Parkes, David G., Tatarkiewicz, Krystyna, and Ghosh, Soumitra S.
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METABOLIC disorder treatment ,PEPTIDE drugs ,ALBUMINS ,HYPOGLYCEMIC agents ,DRUG design ,DRUG synthesis ,PHARMACOKINETICS ,DRUG receptors ,THERAPEUTICS - Abstract
The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu
14 ]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu14 ]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu14 ]exenatide-ABD and [Leu14 ]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu14 ]exenatide-ABD was compared to exenatide in a Lepob/ob mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu14 ]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu14 ]exenatide-ABD as compared to [Leu14 ]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2014
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49. The Effect of a Diiodothyronine Mimetic on Insulin Sensitivity in Male Cardiometabolic Patients: A Double-Blind Randomized Controlled Trial.
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van der Valk, Fleur, Hassing, Carlijne, Visser, Maartje, Thakkar, Purav, Mohanan, Anookh, Pathak, Kaushal, Dutt, Chaitanya, Chauthaiwale, Vijay, Ackermans, Mariette, Nederveen, Aart, Serlie, Mireille, Nieuwdorp, Max, and Stroes, Erik
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METABOLIC syndrome ,DIIODOTHYRONINES ,INSULIN resistance ,OBESITY ,NUCLEAR magnetic resonance spectroscopy ,CARBOHYDRATE metabolism ,RANDOMIZED controlled trials ,PATIENTS - Abstract
Background and aims: Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic. Materials and Methods: This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1∶1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and
1 H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment. Results: At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg−1 min−1 , p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered. Conclusion: Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia. Trial Registration: clinicaltrials.gov NCT01408667 [ABSTRACT FROM AUTHOR]- Published
- 2014
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50. Use of Positron Emission Tomography for Real-Time Imaging of Biodistribution of Green Tea Catechin.
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Shimizu, Kosuke, Asakawa, Tomohiro, Harada, Norihiro, Fukumoto, Dai, Tsukada, Hideo, Asai, Tomohiro, Yamada, Shizuo, Kan, Toshiyuki, and Oku, Naoto
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PLANT polyphenols ,POSITRON emission tomography ,GREEN tea ,CATECHIN ,ANIMAL models in research - Abstract
The aim of this study was to achieve real-time imaging of the in vivo behavior of a green tea polyphenol, catechin, by positron emission tomography (PET). Positron-labeled 4″ -[
11 C]methyl-epigallocatechin gallate ([11 C]Me-EGCG) was orally administered to rats, and its biodistribution was imaged for 60 min by using a small animal PET system. As the result, images of [11 C]Me-EGCG passing through the stomach into the small intestines were observed; and a portion of it was quantitatively detected in the liver. On the other hand, intravenous injection of [11 C]Me-EGCG resulted in a temporal accumulation of the labeled catechin in the liver, after which almost all of it was transferred to the small intestines within 60 min. In the present study, we succeeded in obtaining real-time imaging of the absorption and biodistribution of [11 C]Me-EGCG with a PET system. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
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