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Neuropharmacology Jan 2014A major development in drug addiction research in recent years has been the discovery that immune signaling within the central nervous system contributes significantly... (Review)
Review
A major development in drug addiction research in recent years has been the discovery that immune signaling within the central nervous system contributes significantly to mesolimbic dopamine reward signaling induced by drugs of abuse, and hence is involved in the presentation of reward behaviors. Additionally, in the case of opioids, these hypotheses have advanced through to the discovery of the novel site of opioid action at the innate immune pattern recognition receptor Toll-like receptor 4 as the necessary triggering event that engages this reward facilitating central immune signaling. Thus, the hypothesis of major proinflammatory contributions to drug abuse was born. This review will examine these key discoveries, but also address several key lingering questions of how central immune signaling is able to contribute in this fashion to the pharmacodynamics of drugs of abuse. It is hoped that by combining the collective wisdom of neuroscience, immunology and pharmacology, into Neuroimmunopharmacology, we may more fully understanding the neuronal and immune complexities of how drugs of abuse, such as opioids, create their rewarding and addiction states. Such discoveries will point us in the direction such that one day soon we might successfully intervene to successfully treat drug addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Topics: Allergy and Immunology; Animals; Biomedical Research; Humans; Neuropharmacology; Substance-Related Disorders
PubMed: 23764149
DOI: 10.1016/j.neuropharm.2013.05.039 -
Zhongguo Dang Dai Er Ke Za Zhi =... Nov 2020Pharmacogenomics is an emerging tool to improve the efficacy and safety of drug treatment through the DNA analysis in the genes related to drug concentrations...
Pharmacogenomics is an emerging tool to improve the efficacy and safety of drug treatment through the DNA analysis in the genes related to drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics). Clinicians need to integrate the genomic data in their benefit-risk assessment and then provide the right drug to the right patient at the right time. This tool can help to prevent an ineffective treatment, select right dose and reduce adverse drug reactions that are common in the current practice under the trial-observation-adjustment model. Pharmacogenomics may have extensive impacts on unique paediatric patients to enhance a better relationship between medical professionals and affected children or their guardians and to improve the drug compliance. Clinicians should embrace the advancements in pharmacogenomics and actively participate in clinical research to identify the ancestor-related alleles and develop the population-specific gene panel. It will allow patients to enjoy more achievements in pharmacogenomics by implementing it in first line clinical practice.
Topics: Alleles; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Precision Medicine; Prescriptions
PubMed: 33172545
DOI: 10.7499/j.issn.1008-8830.2006032 -
Biopharmaceutics & Drug Disposition Jan 2014Advances in systems biology in conjunction with the expansion in knowledge of drug effects and diseases present an unprecedented opportunity to extend traditional... (Review)
Review
Advances in systems biology in conjunction with the expansion in knowledge of drug effects and diseases present an unprecedented opportunity to extend traditional pharmacokinetic and pharmacodynamic modeling/analysis to conduct systems pharmacology modeling. Many drugs that cause liver injury and myopathies have been studied extensively. Mitochondrion-centric systems pharmacology modeling is important since drug toxicity across a large number of pharmacological classes converges to mitochondrial injury and death. Approaches to systems pharmacology modeling of drug effects need to consider drug exposure, organelle and cellular phenotypes across all key cell types of human organs, organ-specific clinical biomarkers/phenotypes, gene-drug interaction and immune responses. Systems modeling approaches, that leverage the knowledge base constructed from curating a selected list of drugs across a wide range of pharmacological classes, will provide a critically needed blueprint for making informed decisions to reduce the rate of attrition for drugs in development and increase the number of drugs with an acceptable benefit/risk ratio.
Topics: Biomarkers; Drug-Related Side Effects and Adverse Reactions; Humans; Models, Biological; Pharmacology, Clinical; Phenotype; Systems Biology
PubMed: 24136298
DOI: 10.1002/bdd.1871 -
Basic & Clinical Pharmacology &... May 2019Toxicological and pharmacological information from human cells and tissues provides knowledge readily applicable to human safety assessment and to the efficacy... (Review)
Review
Toxicological and pharmacological information from human cells and tissues provides knowledge readily applicable to human safety assessment and to the efficacy assessment of pharmaceuticals. The 3R principle in animal studies includes the use of human material in the R of Replacement. The Reduction and Refinement Rs are related to animal use. Knowledge of the 3Rs and successful 3R methods are a prerequisite for the Reduction of animal experiments in the future. More collaboration among researchers using experimental animals and those working in vitro is necessary with mutual respect. The OECD Guidelines for the Testing of Chemicals have included the animal-free part of the 3Rs in guidances for the development and reporting of Adverse Outcome Pathways (AOPs), which is to be part of the Integrated Approaches to Testing and Assessment (IATA). The 3R centres established to help fulfil the Directive 2010/63/EU play an important role to promote the 3Rs and in the development of animal-free toxicology. Research centres in each Nordic country are founded upon solid research activities in cell and organ toxicity, including major EU programmes to promote 3Rs and implementation of good practices and methods broadly in all stakeholders of industry, regulators and academia. In the light of this, the Nordic Symposium on Toxicology and Pharmacology without Animal Experiments addressed more adopted/modified test guidelines or new test guidelines for new end-points, or hazard challenges, new in vitro 3D models, speeding up transfer of knowledge from research to regulation to understand AOP and towards IATA.
Topics: Animal Experimentation; Animals; Drug Evaluation, Preclinical; Pharmacology; Scandinavian and Nordic Countries; Toxicology
PubMed: 30561843
DOI: 10.1111/bcpt.13193 -
British Journal of Clinical Pharmacology Dec 2022Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the... (Review)
Review
Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper.
Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.
Topics: Humans; Child; Infant, Newborn; Models, Biological; Research Design; Data Collection; Pharmacokinetics; Pharmacology
PubMed: 34180088
DOI: 10.1111/bcp.14958 -
The AAPS Journal Oct 2020Graphical Abstract.
Graphical Abstract.
Topics: Female; History, 20th Century; History, 21st Century; Humans; Pharmacology; Research Personnel; Women
PubMed: 33098055
DOI: 10.1208/s12248-020-00526-0 -
CPT: Pharmacometrics & Systems... Jun 2022
Topics: Humans; Pharmacology; Pharmacology, Clinical
PubMed: 35388628
DOI: 10.1002/psp4.12783 -
Journal of Clinical Pharmacology Oct 2018Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are... (Review)
Review
Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are crucial to optimizing trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and noninvasive matrices, and microvolume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically based models that individualize pediatric dosing recommendations and support drug approval. Last, given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.
Topics: Biomedical Research; Child; Clinical Trials as Topic; Humans; Infant; Models, Biological; Pharmacology, Clinical; Research Design
PubMed: 30248192
DOI: 10.1002/jcph.1053 -
Molecules (Basel, Switzerland) Nov 2021Medicinal chemistry is facing new challenges in approaching precision medicine. Several powerful new tools or improvements of already used tools are now available to... (Review)
Review
Medicinal chemistry is facing new challenges in approaching precision medicine. Several powerful new tools or improvements of already used tools are now available to medicinal chemists to help in the process of drug discovery, from a hit molecule to a clinically used drug. Among the new tools, the possibility of considering folding intermediates or the catalytic process of a protein as a target for discovering new hits has emerged. In addition, machine learning is a new valuable approach helping medicinal chemists to discover new hits. Other abilities, ranging from the better understanding of the time evolution of biochemical processes to the comprehension of the biological meaning of the data originated from genetic analyses, are on their way to progress further in the drug discovery field toward improved patient care. In this sense, the new approaches to the delivery of drugs targeted to the central nervous system, together with the advancements in understanding the metabolic pathways for a growing number of drugs and relating them to the genetic characteristics of patients, constitute important progress in the field.
Topics: Chemistry, Pharmaceutical; Drug Design; Drug Discovery; Humans; Machine Learning; Precision Medicine
PubMed: 34834152
DOI: 10.3390/molecules26227061 -
Integrative Biology : Quantitative... Apr 2015Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug... (Review)
Review
Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are μOrgans-on-a-chip and μHuman-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery.
Topics: Biological Assay; Drug Design; Equipment Design; Equipment Failure Analysis; Flow Injection Analysis; Humans; Lab-On-A-Chip Devices; Models, Biological; Organ Culture Techniques; Pharmacokinetics; Pharmacology
PubMed: 25739725
DOI: 10.1039/c4ib00292j