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Pharmacological Research Jan 20193D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue... (Review)
Review
3D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue models have been developed. In parallel, microfluidic organ-on-a-chip tissue cultures have gained increasing interest for their ability to house several organ models on a single device and interlink these within a human-like environment. In contrast to these advancements, the development of human disease models is still in its infancy. Although major advances have recently been made, efforts still need to be intensified. Human disease models have proven valuable for their ability to closely mimic disease patterns in vitro, permitting the study of pathophysiological features and new treatment options. Although animal studies remain the gold standard for preclinical testing, they have major drawbacks such as high cost and ongoing controversy over their predictive value for several human conditions. Moreover, there is growing political and social pressure to develop alternatives to animal models, clearly promoting the search for valid, cost-efficient and easy-to-handle systems lacking interspecies-related differences. In this review, we discuss the current state of the art regarding 3D organ as well as the opportunities, limitations and future implications of their use.
Topics: Animals; Biomedical Research; Epithelium; Humans; Liver; Models, Biological; Pharmacology; Printing, Three-Dimensional; Tissue Engineering
PubMed: 30395949
DOI: 10.1016/j.phrs.2018.11.002 -
British Journal of Clinical Pharmacology Aug 2021
Topics: Humans; Pharmacology; Pharmacology, Clinical
PubMed: 33835508
DOI: 10.1111/bcp.14789 -
Naunyn-Schmiedeberg's Archives of... Aug 2021
Topics: Editorial Policies; Humans; Periodicals as Topic; Pharmacology; Probiotics
PubMed: 34169335
DOI: 10.1007/s00210-021-02110-5 -
Therapeutic Advances in Respiratory... 2023Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly... (Review)
Review
Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.
Topics: Humans; Pharmacology, Clinical; Idiopathic Pulmonary Fibrosis; Biopsy; Fibrosis; Disease Progression
PubMed: 37392011
DOI: 10.1177/17534666231181537 -
International Journal of Molecular... Mar 2023Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules.... (Review)
Review
Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates-equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.
Topics: Humans; Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Stereoisomerism
PubMed: 36982753
DOI: 10.3390/ijms24065679 -
Indian Journal of Pharmacology 2021
Topics: Global Health; Humans; Pharmacology, Clinical
PubMed: 34975130
DOI: 10.4103/ijp.ijp_867_21 -
Annual Review of Pharmacology and... Jan 2017Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is... (Review)
Review
Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.
Topics: Animals; Data Interpretation, Statistical; Databases, Factual; High-Throughput Screening Assays; Humans; Pharmacology, Clinical; Systems Biology
PubMed: 27814027
DOI: 10.1146/annurev-pharmtox-010716-104659 -
Pharmacogenomics Aug 2020Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to... (Review)
Review
Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice.
Topics: Analgesics, Opioid; Animals; Genetic Variation; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pharmacogenetics
PubMed: 32705966
DOI: 10.2217/pgs-2020-0040 -
British Journal of Clinical Pharmacology Jan 2022
Topics: Humans; Pharmacology, Clinical; Trust
PubMed: 34773656
DOI: 10.1111/bcp.15118 -
Nucleic Acids Research Jan 2017ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 and 2014 Nucleic Acids Research Database Issues....
ChEMBL is an open large-scale bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012 and 2014 Nucleic Acids Research Database Issues. Since then, alongside the continued extraction of data from the medicinal chemistry literature, new sources of bioactivity data have also been added to the database. These include: deposited data sets from neglected disease screening; crop protection data; drug metabolism and disposition data and bioactivity data from patents. A number of improvements and new features have also been incorporated. These include the annotation of assays and targets using ontologies, the inclusion of targets and indications for clinical candidates, addition of metabolic pathways for drugs and calculation of structural alerts. The ChEMBL data can be accessed via a web-interface, RDF distribution, data downloads and RESTful web-services.
Topics: Computational Biology; Crop Protection; Databases, Chemical; Databases, Nucleic Acid; Drug Discovery; Gene Ontology; Humans; Molecular Sequence Annotation; Pharmacology; Search Engine; User-Computer Interface; Web Browser
PubMed: 27899562
DOI: 10.1093/nar/gkw1074