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For Selected: Download Citations EndNote Ris BibTeX Toggle Thumbnails Select Quantitative pharmacology in a translational research environment Jeffrey S Barrett Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1081-1088.   Abstract （84）      PDF （1355KB）（85）       Knowledge map    Save Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury.Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies.While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative.The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research.A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships.The infrastructure of the University of Pennsylvania (Penn) Children' s Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology.A case study, NIHsponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm. Reference | Related Articles | Metrics Select Pharmacokinetic and pharmacodynamic evaluation of biologics:challenges and pitfalls Bernd Meibohm Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1089-1098.   Abstract （120）      PDF （701KB）（137）       Knowledge map    Save In recent years, biotechnologically-derived peptides and proteins have developed into mainstream therapeutic agents.Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development as well as in clinical practice.The understanding of the pharmacokinetics and pharmacodynamics, including the dose-concentration-effect relationship, is crucial to any drug-including peptides and proteins-as it lays the foundation for optimal dosing regimen design and rational clinical application.Compared to traditional small molecule-based therapeutics, pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as nutrients, by their intimate involvement in physiologic processes on the molecular level, by their macromolecule character and immunogenicity, and by analytical challenges to identify and quantify them in the presence of a myriad of similar molecules.Peptides and proteins, unlike conventional small molecule drugs, are generally not therapeutically active upon oral administration, and selection of the most appropriate route of administration requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes.Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure in order to exert the intended pharmacological response.Binding phenomena and receptor-mediated cellular uptake may further complicate this issue.Elimination processes-a critical determinant for the drug' s systemic exposure-may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. The manuscript highlights some of the major pharmacokinetic properties and processes relevant for the majority of biologics and will provide examples of well characterized pharmacodynamic relationships for peptide and protein therapeutics.Appreciation of the pharmacokinetic and pharmacodynamic differences between therapeutic biologics and traditional small molecule drugs will empower the drug development scientist as well as the healthcare provider to handle, evaluate and apply these compounds in an optimal fashion during the drug development process as well as in applied pharmacotherapy Reference | Related Articles | Metrics Select Integretion of pharmacokinetics and pharmacodynamics in antibacterial drug development and pharmacotherap SHI Jun Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1099-1113.   Abstract （97）      PDF （555KB）（88）       Knowledge map    Save There is a pressing need for new antibacterial agents due to the development of drug-resistant pathogens.Unfortunately drug development is a difficult and complicated process.The traditional approach in searching for a right dose is quite empirical, both costly and time-consuming.To enhance the ability to predict the likelihood of success for lead compound selection, in vitro pharmacodynamic and in vivo animal infection models are now extensively used.The value of these pre-clinical experiments, combined with mathematical modeling, helps to identify a pharmacokinetic (PK) -pharmacodynamic (PD) exposure measure which best predicts the therapeutic efficacy, and to quantify the magnitude of this index required for in vivo efficacy.PK-PD target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure (PK), drug potency (MIC), and in vivo exposure targets that are predictive of positive therapeutic outcomes are influencing antibacterial drug development for proof of concept, for dose and dosing interval selection, for determining susceptibility breakpoints, and for evaluating the clinical meaning of antibacterial resistance.In this article, the key concepts of antibacterial PK-PD and model based antibacterial drug development strategy and process are critically reviewed. Reference | Related Articles | Metrics Select Application of Bayesian Methods for laboratory to clinical translation and for identifying hidden subpopulations David Z. D’ Argenio, WANG Xiao-ning, ZHOU Ze-xun Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1114-1121.   Abstract （75）      PDF （299KB）（60）       Knowledge map    Save Modeling methodologies developed for studying pharmacokinetic (PK)/pharmacodynamic (PD) processes confront many challenges related in part to the severe restrictions on the number and type of measurements that are available from laboratory experiments and clinical trials, as well as the variability in the experiments and the uncertainty associated with the processes themselves.Bayesian methods have provided a framework for PK/PD modeling and drug development that can address some of the above-mentioned challenges.This paper presents two illustrations of the application of Bayesian methods :the first involves a population modeling study of the cellular kinetics of the antiretroviral compound Lamivudine in the PBMCs of HIV-1 infected adolescents ;the second uses a population mixture modeling approach to identifying hidden subpopulations that can not be identified by available measured covariates. Reference | Related Articles | Metrics Select Challenges in research and development of Traditional Chinese Medicines LIU Chang-xiao, SI Duan-yun, XIE Hai-tang Chinese Journal of Clinical Pharmacology and Therapeutics    2007, 12 (10): 1122-1129.   Abstract （110）      PDF （272KB）（95）       Knowledge map    Save In this review, the author analyzed the challenges in modern research and development of Traditional Chinese Medicine (TCM) products.Chinese traditional and herb drugs have gained interest from the international medical, biomedical and pharmaceutical institutions as potential source of valuable medicinal agents.For the researches and development of TCMs, the first challenge is to evaluate the efficacy, pharmacological properties, action mechanism and active chemical constituents. The second one is to summarize the issues for developing safety research methodologies, to improve the quality and enhance the value of research in TCM and to provide appropriate evaluation methods to facilitate the regulation and registration of TCM products, and the third is to study drug metabolism and pharmacokinetics, and the fourth is to apply new “-omics” techniques and tools in new revolution in drug discovery-development and to impact on modern research of TCM products.This interest is needed to apply modern research on the development and exploration of the promising medical potential resources of Chinese traditional and herbal drugs, especially from medicinal plants. Reference | Related Articles | Metrics