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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 -
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 -
Journal of Nuclear Medicine Technology Sep 2018Pharmacology principles provide a key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a... (Review)
Review
Pharmacology principles provide a key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a series of articles that aims to enhance the understanding of pharmacologic principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology, and principles of pharmacodynamics explored in the first article in the series. Specifically, this article will focus on the basic principles associated with pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications used in general nuclear medicine; article 4, pharmacology relevant to pharmaceutical interventions and adjunctive medications used in nuclear cardiology; article 5, pharmacology relevant to contrast media associated with CT and MRI; and article 6, drugs in the emergency cart.
Topics: Animals; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology
PubMed: 29724803
DOI: 10.2967/jnmt.117.199638 -
Journal of Nuclear Medicine Technology Jun 2018There is an emerging need for greater understanding of pharmacology principles among technical staff. Indeed, the responsibility of dose preparation and administration,... (Review)
Review
There is an emerging need for greater understanding of pharmacology principles among technical staff. Indeed, the responsibility of dose preparation and administration, under any level of supervision, demands a foundational understanding of pharmacology. This is true for radiopharmaceuticals, contrast media, and pharmaceutical interventions or adjunctive medications. Regulation around the same might suggest a need to embed pharmacology theory in undergraduate education programs, and there is a need to disseminate that same foundational understanding to practicing clinicians. Moreover, pharmacology foundations can provide a key understanding of the principles that underpin quantitative techniques (e.g., pharmacokinetics). This article is the first in a series that aims to enhance the understanding of pharmacologic principles relevant to nuclear medicine. This article will deal with the introductory concepts, terminology, and principles that underpin the concepts to be discussed in the remainder of the series. The second article will build on the pharmacodynamic principles examined in this article with a treatment of pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications used in general nuclear medicine, article 4 will cover pharmacology relevant to pharmaceutical interventions and adjunctive medications used in nuclear cardiology, and article 5 will discuss the pharmacology related to contrast media associated with CT and MRI. The final article (6) in the series will examine the pharmacology of drugs associated with the crash cart/emergency trolley.
Topics: Animals; Drug Interactions; Humans; Pharmaceutical Preparations; Pharmacology; Receptors, Cell Surface; Terminology as Topic
PubMed: 29599397
DOI: 10.2967/jnmt.117.199588 -
Cell Sep 2014The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and...
The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.
Topics: Culture Techniques; Heterografts; Humans; Male; Neoplasm Metastasis; Organoids; Pharmacology; Prostatic Neoplasms; Tumor Suppressor Proteins
PubMed: 25201530
DOI: 10.1016/j.cell.2014.08.016 -
Drugs Mar 2016Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important... (Review)
Review
Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.
Topics: Amphotericin B; Animals; Chemistry, Pharmaceutical; Clinical Trials as Topic; Deoxycholic Acid; Drug Combinations; Half-Life; Humans; Tissue Distribution
PubMed: 26818726
DOI: 10.1007/s40265-016-0538-7 -
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 -
European Journal of Pharmacology Sep 2015Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G... (Review)
Review
Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery.
Topics: Animals; Drug Design; Humans; Ligands; Pharmacology; Protein Multimerization; Receptors, Opioid; Signal Transduction
PubMed: 25981301
DOI: 10.1016/j.ejphar.2015.05.012 -
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 -
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