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Lancet (London, England) Aug 2019Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be... (Review)
Review
Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.
Topics: Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Pharmacogenomic Variants
PubMed: 31395440
DOI: 10.1016/S0140-6736(19)31276-0 -
Trends in Pharmacological Sciences Feb 2022For complex diseases, most drugs are highly ineffective, and the success rate of drug discovery is in constant decline. While low quality, reproducibility issues, and... (Review)
Review
For complex diseases, most drugs are highly ineffective, and the success rate of drug discovery is in constant decline. While low quality, reproducibility issues, and translational irrelevance of most basic and preclinical research have contributed to this, the current organ-centricity of medicine and the 'one disease-one target-one drug' dogma obstruct innovation in the most profound manner. Systems and network medicine and their therapeutic arm, network pharmacology, revolutionize how we define, diagnose, treat, and, ideally, cure diseases. Descriptive disease phenotypes are replaced by endotypes defined by causal, multitarget signaling modules that also explain respective comorbidities. Precise and effective therapeutic intervention is achieved by synergistic multicompound network pharmacology and drug repurposing, obviating the need for drug discovery and speeding up clinical translation.
Topics: Drug Discovery; Humans; Network Pharmacology; Pharmacology; Reproducibility of Results
PubMed: 34895945
DOI: 10.1016/j.tips.2021.11.004 -
Genes Jun 2020Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several...
Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the uptake in clinical practice is still poor. Many coordinated international efforts are ongoing in order to overcome the existing barriers to pharmacogenomic implementation. On the other hand, existing validated pharmacogenomic markers can explain only a minor part of the observed clinical variability in the therapeutic outcome. New investigational approaches are warranted, including the study of the pharmacogenomic role of the immune system genetics and of previously neglected rare genetic variants, reported to account for a large part of the inter-individual variability in drug metabolism. In this Special Issue, we collected a series of articles covering many aspects of pharmacogenomics. These include clinical implementation of pharmacogenomics in clinical practice, development of tools or infrastractures to support this process, research of new pharmacogenomics markers to increase drug efficacy and safety, and the impact of rare genetic variants in pharmacogenomics.
Topics: Biomarkers; Humans; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32580376
DOI: 10.3390/genes11060679 -
Seminars in Perinatology Apr 2020
Topics: Biomedical Research; Congresses as Topic; Female; Humans; Information Dissemination; Pharmacoepidemiology; Pharmacogenetics; Pharmacokinetics; Pharmacological Phenomena; Pregnancy
PubMed: 32197796
DOI: 10.1016/j.semperi.2020.151220 -
Signal Transduction and Targeted Therapy Oct 2023Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and... (Review)
Review
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
Topics: Humans; Precision Medicine; Microbiota; Gastrointestinal Microbiome; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37806986
DOI: 10.1038/s41392-023-01619-w -
Paediatric Drugs Jun 2020Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with... (Review)
Review
Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.
Topics: Adolescent; Adult; Arginine; Child; Citrulline; Female; Humans; Male; Pharmacology, Clinical; Young Adult
PubMed: 32140997
DOI: 10.1007/s40272-020-00384-5 -
Pharmacological Reviews Jan 20215-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function... (Review)
Review
5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
Topics: Humans; Ligands; Pharmacology, Clinical; Receptors, Serotonin; Serotonin
PubMed: 33370241
DOI: 10.1124/pr.118.015552 -
Therapeutic Drug Monitoring Apr 2023Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have greatly benefitted from computational and mathematical advances over the past 60 years.... (Review)
Review
BACKGROUND
Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have greatly benefitted from computational and mathematical advances over the past 60 years. Furthermore, the use of artificial intelligence (AI) and machine learning (ML) approaches for supporting clinical research and support is increasing. However, AI and ML applications for precision dosing have been evaluated only recently. Given the capability of ML to handle multidimensional data, such as from electronic health records, opportunities for AI and ML applications to facilitate TDM and MIPD may be advantageous.
METHODS
This review summarizes relevant AI and ML approaches to support TDM and MIPD, with a specific focus on recent applications. The opportunities and challenges associated with this integration are also discussed.
RESULTS
Various AI and ML applications have been evaluated for precision dosing, including those related to concentration or exposure prediction, dose optimization, population pharmacokinetics and pharmacodynamics, quantitative systems pharmacology, and MIPD system development and support. These applications provide an opportunity for ML and pharmacometrics to operate in an integrated manner to provide clinical decision support for precision dosing.
CONCLUSIONS
Although the integration of AI with precision dosing is still in its early stages and is evolving, AI and ML have the potential to work harmoniously and synergistically with pharmacometric approaches to support TDM and MIPD. Because data are increasingly shared between institutions and clinical networks and aggregated into large databases, these applications will continue to grow. The successful implementation of these approaches will depend on cross-field collaborations among clinicians and experts in informatics, ML, pharmacometrics, clinical pharmacology, and TDM.
Topics: Humans; Artificial Intelligence; Machine Learning; Models, Biological; Precision Medicine; Pharmacology, Clinical
PubMed: 36750470
DOI: 10.1097/FTD.0000000000001078 -
Chemical & Pharmaceutical Bulletin 2020
Topics: Chemistry, Pharmaceutical; Congresses as Topic; Drug Discovery; Societies, Scientific
PubMed: 32115523
DOI: 10.1248/cpb.c20-ctf6803 -
Biomolecules Jan 2021The use of remedies based on medicinal plants continues to expand rapidly around the world, with many people now resorting to this type of product for the treatment and...
The use of remedies based on medicinal plants continues to expand rapidly around the world, with many people now resorting to this type of product for the treatment and prevention of several pathologies [...].
Topics: Animals; Cell Line, Tumor; Humans; Mice; Pharmacology; Phytochemicals; Phytotherapy; Plants, Medicinal
PubMed: 33466709
DOI: 10.3390/biom11010101