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Drug Discovery Today Sep 2015Measuring key pharmacokinetic and pharmacodynamic parameters in vivo at the single cell level is likely to enhance drug discovery and development. In this review, we... (Review)
Review
Measuring key pharmacokinetic and pharmacodynamic parameters in vivo at the single cell level is likely to enhance drug discovery and development. In this review, we summarize recent advances in this field and highlight current and future capabilities.
Topics: Animals; Drug Design; Drug Discovery; Humans; Models, Biological; Pharmacokinetics; Pharmacology; Single-Cell Analysis
PubMed: 26024776
DOI: 10.1016/j.drudis.2015.05.011 -
Neuropsychopharmacology : Official... Dec 2015
Topics: History, 20th Century; History, 21st Century; Humans; National Heart, Lung, and Blood Institute (U.S.); Pharmacology; United States
PubMed: 26548765
DOI: 10.1038/npp.2015.303 -
Biopharmaceutics & Drug Disposition Dec 2013Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the... (Review)
Review
Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the late-stage clinical trials. The different questions addressed during each stage of drug R&D has led to the emergence of different modeling methodologies. In the research phase, systems biology couples experimental data with elaborate computational modeling techniques to capture lifecycle and effector cellular functions (e.g. metabolism, signaling, transcription regulation, protein synthesis and interaction) and integrates them in quantitative models. These models are subsequently used in various ways, i.e. to identify new targets, generate testable hypotheses, gain insights on the drug's mode of action (MOA), translate preclinical findings, and assess the potential of clinical drug efficacy and toxicity. In the development phase, pharmacokinetic/pharmacodynamic (PK/PD) modeling is the established way to determine safe and efficacious doses for testing at increasingly larger, and more pertinent to the target indication, cohorts of subjects. First, the relationship between drug input and its concentration in plasma is established. Second, the relationship between this concentration and desired or undesired PD responses is ascertained. Recognizing that the interface of systems biology with PK/PD will facilitate drug development, systems pharmacology came into existence, combining methods from PK/PD modeling and systems engineering explicitly to account for the implicated mechanisms of the target system in the study of drug-target interactions. Herein, a number of popular system biology methodologies are discussed, which could be leveraged within a systems pharmacology framework to address major issues in drug development.
Topics: Drug Discovery; Humans; Models, Biological; Pharmacokinetics; Pharmacology, Clinical; Systems Biology
PubMed: 23983165
DOI: 10.1002/bdd.1859 -
Nature Reviews. Drug Discovery Sep 2014The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size... (Review)
Review
The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies--such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs--and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.
Topics: Animals; Biopharmaceutics; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans
PubMed: 25103255
DOI: 10.1038/nrd4363 -
Pharmaceutical Research May 2004Data visualization techniques for the pharmaceutical sciences have not been extensively investigated. The purpose of this study was to evaluate the usefulness of... (Review)
Review
PURPOSE
Data visualization techniques for the pharmaceutical sciences have not been extensively investigated. The purpose of this study was to evaluate the usefulness of VizStruct, a multidimensional visualization tool, for applications in pharmacokinetics, pharmacodynamics, and pharmacogenomics.
METHODS
The VizStruct tool uses the first harmonic of the discrete Fourier transform to map multidimensional data to two dimensions for visualization. The mapping was used to visualize several published pharmacokinetic, pharmacodynamic, and pharmacogenomic data sets. The VizStruct approach was evaluated using simulated population pharmacokinetics data sets, the data from Dalen and colleagues (Clin. PharmacoL Ther. 63:444-452, 1998) on the kinetics of nortriptyline and its 10-hydroxynortriptyline metabolite in subjects with differing number of copies of the CYP2D6, and the gene expression profiling data of Bohen and colleagues (Proc. Natl. Acad. Sci. USA 100:1926-1930, 2003) on follicular lymphoma patients responsive and nonresponsive to rituximab.
RESULTS
The VizStruct mapping preserves the key characteristics of multidimensional data in two dimensions in a manner that facilitates visualization. The mapping is computationally efficient and can be used for cluster detection and class prediction in pharmaceutical data sets. The VizStruct visualization succinctly summarized the salient similarities and differences in the nortriptyline and 10-hydroxynortriptyline pharmacokinetic profiles in subjects with increasing number of CYP2D6 gene copies. In the simulated population pharmacokinetic data sets, it was capable of discriminating the subtle differences between pharmacokinetic profiles derived from 1- and 2-compartment models with the same area under the curve. The two-dimensional VizStruct mapping computed from a subset of 102 informative genes from the Bohen and colleagues data set effectively separated the rituximab responder, rituximab nonresponder, and control subject groups.
CONCLUSIONS
The VizStruct approach is a computationally efficient and effective approach for visualizing complex, multidimensional data sets. It could have many useful applications in the pharmaceutical sciences.
Topics: Algorithms; Animals; Database Management Systems; Databases, Factual; Gene Expression Profiling; Humans; Pharmacogenetics; Pharmacokinetics; Pharmacology; Population; Software
PubMed: 15180333
DOI: 10.1023/b:pham.0000026427.30177.61 -
Molecules (Basel, Switzerland) Nov 2023Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through... (Review)
Review
Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.
Topics: Pyrazines; Chemistry, Pharmaceutical; Anti-Inflammatory Agents; Anti-Bacterial Agents; Biological Products
PubMed: 37959859
DOI: 10.3390/molecules28217440 -
British Journal of Clinical Pharmacology Jun 2017Research in clinical pharmacology covers a wide range of experiments, trials and investigations: clinical trials, systematic reviews and meta-analyses of drug usage...
Research in clinical pharmacology covers a wide range of experiments, trials and investigations: clinical trials, systematic reviews and meta-analyses of drug usage after market approval, the investigation of pharmacokinetic-pharmacodynamic relationships, the search for mechanisms of action or for potential signals for efficacy and safety using biomarkers. Often these investigations are exploratory in nature, which has implications for the way the data should be analysed and presented. Here we summarize some of the statistical issues that are of particular importance in clinical pharmacology research.
Topics: Data Interpretation, Statistical; Humans; Models, Statistical; Pharmacology, Clinical; Research; Sample Size
PubMed: 28321897
DOI: 10.1111/bcp.13254 -
Physiological Research Jun 2018On March 4, 2017 at the age of 68, Sidney George Shaw (Sid) unexpectedly died from complications following surgery, only four years after retiring from the University of...
On March 4, 2017 at the age of 68, Sidney George Shaw (Sid) unexpectedly died from complications following surgery, only four years after retiring from the University of Bern. Trained in biochemistry at Oxford University, Sid had quickly moved into molecular pharmacology and became a key investigator in the field of enzyme biochemistry, vasoactive peptide research, and receptor signaling. Sid spent half his life in Switzerland, after moving to the University of Bern in 1984. This article, written by his friends and colleagues who knew him and worked with him during different stages of his career, summarizes his life, his passions, and his achievements in biomedical research. It also includes personal memories relating to a dear friend and outstanding scientist whose intellectual curiosity, humility, and honesty will remain an example to us all.
Topics: Biochemistry; Endothelins; England; History, 20th Century; History, 21st Century; Neuropharmacology; Pharmacology; Switzerland
PubMed: 31774298
DOI: No ID Found -
Basic & Clinical Pharmacology &... Mar 2005For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma... (Review)
Review
For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma concentration and haematological toxicity is of importance in the drug development. Mechanism-based population pharmacokinetic-pharmacodynamic models have been developed for this purpose and the applications of these in candidate selection, first-in-man studies, prodrug and formulation development, dose finding, schedule optimisation, assessing influence of modifying agents, drug combination studies, subgroup identification and feedback individualisation are reviewed.
Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Drug Administration Schedule; Drug Design; Drug Therapy, Combination; Humans; Models, Biological; Prodrugs
PubMed: 15733216
DOI: 10.1111/j.1742-7843.2005.pto960310.x -
British Journal of Clinical Pharmacology Apr 2014Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While... (Review)
Review
Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy.
Topics: Brain; Cognition; Dopamine Agonists; Functional Neuroimaging; Humans; Inactivation, Metabolic; Magnetic Resonance Imaging; Pharmacogenetics; Polymorphism, Genetic; Psychomotor Performance
PubMed: 23802603
DOI: 10.1111/bcp.12197