Investigations in pharmacology and toxicology range from molecular studies to clinical care. Studies in basic and clinical pharmacology and in preclinical and clinical toxicology are all essential in bringing new knowledge and new drugs into clinical use. The 30 reviews in Volume 63 of the Annual Review of Pharmacology and Toxicology explore topics across this spectrum. Examples include "Zebrafish as a Mainstream Model for In Vivo Systems Pharmacology and Toxicology" and "Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond." Other reviews discuss components important for drug discovery and development and the use of pharmaceuticals in a variety of diseases. Air pollution continues to increase globally; accordingly, "Air Pollution-Related Neurotoxicity Across the Life Span" is a timely and forward-thinking review. Volume 63 also explores the use of contemporary technologies such as electronic health records, pharmacogenetics, and new drug delivery systems that help enhance and improve the utility of new therapies.

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The reviews in Volume 62 of the Annual Review of Pharmacology and Toxicology ( ARPT) cover a diverse range of topics. A theme that encompasses many of these reviews is their relevance to common diseases and disorders, including type 2 diabetes, heart failure, cancer, tuberculosis, Alzheimer's disease, neurodegenerative disorders, and Down syndrome. Other reviews highlight important aspects of therapeutics, including placebos and patient-centric approaches to drug formulation. The reviews with this thematic focus, as well as other reviews in this volume, emphasize new mechanistic insights, experimental and therapeutic strategies, and novel insights regarding topics in the disciplines of pharmacology and toxicology. As the editors of ARPT, we believe that these reviews help advance those disciplines and, even more importantly, have the potential to improve the health care of the world's population.

The theme of Volume 61 is “Old and New Toxicology: Interfaces with Pharmacology.” Old toxicology is exemplified by the authors of the autobiographical articles: B.M. Olivera's work on toxins and venoms from cone snails and P. Taylor's studies of acetylcholinesterase and the nicotinic cholinergic receptor, which serve as sites of action for numerous pesticides and venoms. Other articles in this volume focus on new understanding and new types of toxicology, including ( a) arsenic toxicity, which is an ancient poison that, through evolution, has caused most multicellular organisms to express an active arsenic methyltransferase to methylate arsenite, which accelerates the excretion of arsenic from the body; ( b) small molecules that react with lipid dicarbonyls, which are now considered the most toxic oxidative stress end products; ( c) immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy but have numerous immune-related adverse events, including cardiovascular complications; ( d) autoimmunity caused by the environment; ( e) idiosyncratic drug-induced liver disease, which together with the toxicity of ICIs represents new toxicology interfacing with pharmacology; and ( f) sex differences in the development of cardiovascular disease, with men more susceptible than women to vascular inflammation that initiates and perpetuates disease. These articles and others in Volume 61 reflect the interface and close integration of pharmacology and toxicology that began long ago but continues today.

"Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the Annual Review of Pharmacology and Toxicology. Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca2+ and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L -type Ca2+ channels, and AMPA receptors, as well as the aquaporin channels. Molecular identification of exactly where drugs bind in the structure not only elucidates their mechanism of action but also aids future structure -based drug discovery efforts to focus on relevant pharmacophores. The ion channels discussed here are targets for multiple nervous system diseases, including epilepsy and neuropathic pain. This theme complements several previous themes, including "New Therapeutic Targets," "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development," and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology"

“New Therapeutic Targets” is the theme of articles in the Annual Review of Pharmacology and Toxicology, Volume 59. Reviews in this volume discuss targets for a variety of conditions in need of new therapies, including type 2 diabetes, heart failure with preserved ejection fraction, obesity, thyroid-associated ophthalmopathy, tinnitus, multiple sclerosis, Parkinson's disease and other neurodegenerative diseases, pain, depression, post-traumatic stress disorder, muscle wasting diseases, cancer, and anemia associated with chronic renal disease. Numerous articles in this volume focus on the identification, validation, and utility of novel therapeutic targets, in particular, ones that involve new or unexpected molecular entities. This theme complements several previous themes, including “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development,” “Precision Medicine and Prediction in Pharmacology,” and “New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology.”

nique. Pour de nombreux patients, la recherche d’une médication offrant une efficacité optimale mais qui présente un moindre risque d’effets secondaires obéit souvent à une stratégie de «trial and error». Il y a donc une nécessité de mieux connaître les facteurs cités afin de cibler la thérapie et de procéder à une prescription personnalisée. En ce qui concerne les facteurs génétiques, la recherche est centrée sur l’analyse de déterminants moléculaires au niveau de la génomique, transcriptomique et protéomique. Sous sa dénomination «pharmacogénomique», cette approche devrait permettre d’identifier des biomarqueurs et des cibles de médicaments déjà disponibles, afin de développer des nouvelles molécules d’utilité thérapeutique (Squassima et al., 2010). Cette approche pluridisciplinaire nécessite la collaboration entre les firmes qui développent des outils pour le diagnostic de maladies et de celles qui développent les nouveaux médicaments, les laboratoires qui exécutent les analyses, les spécialistes et chercheurs qui analysent les «big-data», les cliniciens qui, en se basant sur la pharmacogénomique, appliquent une thérapie personnalisée. Il est donc essentiel que ces différents partenaires aient une plateforme commune pour une collaboration optimale, telle que l’offre la Société Européenne de Pharmacogénomique et Thérapie Personnalisée (European Society of Pharmacogenomics and Personalised Therapy, ESPT) (Siest, 2015).

Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e. g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e. g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Beyond their contribution to the metabolism of xenobiotics, cytochrome P450 (CYP) epoxygenases are actively involved in the metabolism of endogenous substances, like arachidonic acid (AA). The main human CYP epoxygenases, i.e. CYP2C8, CYP2C9, CYP2C19 and CYP2J2, convert AA to four regioisomer epoxyeicosatrienoic acids (EETs). EETs possess a wide range of established protective effects on the human cardiovascular system of which anti-inflammatory actions have gained great recent interest. The expression of CYP epoxygenases is regulated through an extremely complex network of nuclear receptors, microRNAs and genetic/epigenetic factors. Accordingly, a large number of biological variables as well as xenobiotics and environmental factors can influence the expression of CYP epoxygenases, resulting in a significant intra- and inter-individual variability in the expression and activity of these enzymes and subsequently in EET biosynthesis. Moreover, human CYP epoxygenases are mainly expressed in the liver; however, these enzymes are also expressed, at various extents, in most extrahepatic tissues, resulting in a marked inter-tissue variability in the expression of CYP epoxygenases. The inter-tissue, inter- and intra-individual variability in the expression of epoxygenases may lead to differences in the relative abundance of EETs among tissues, among individuals of a population and/or different ethnicities and in a given individual under various conditions. The variation in the abundance of EETs may explain, at least in part, the inter-tissue and inter-individual differences observed in the prevalence of inflammation-related disorders including cardiovascular disease, and why in a given individual, various conditions can contribute to the development of diseases with an important inflammatory component.

missing Pharmacogenetic determinants of glucocorticoid sensitivity in childhood acute lymphoblastic leukemia Dolzan Vita , Prezelj Neza, Mercun Nusa, Faganel Kotnik Barbara, Debeljak Marusa, Jazbec Janez Background: The response to glucocorticoids during the induction of remission is an important prognostic factor in childhood acute lymphoblastic leukemia (ALL). It is commonly accepted that genetic variability of drug metabolizing enzymes, transporters and drug targets may influence treatment response, but only a limited number of studies investigated genetic determinants of glucocorticoid sensitivity in ALL. Beside genetic variability of glucocorticoid receptor NR3C1 (GR) that mediates the intracellular action of glucocorticoids, genetic variability of P-glycoprotein (ABCB1) and glutathione S-transferases (GST) may influence their bioavailability and thus influence treatment response. Our aim was to investigate genetic factors that could influence the outcome of the induction treatment of childhood ALL with glucocorticoids. Methods: In total 86 Slovenian children and adolescents with ALL treated with glucocorticoids during the induction phase were genotyped for common polymorphisms in NR3C1, ABCB1, GSTM1, GSTT1 and GSTP1 genes. Logistic regression was used to assess the influence of polymorphisms on the resistance ( > 1000 blasts/ μ L on day 8) or poor response ( > 100 blasts/ μ L on day 8) to glucocorticoid treatment, and on the risk of relapse, event (relapse or death) and exitus. Cox regression was used to determine their influence on event-free survival (EFS). Results: On day 8 of prednisone treatment 6 patients (7,0 %) had > 1000 blasts/ μ L, while 26 (30,2 %) patients had > 100 blasts/ μ L The protective effect of NR3C1 rs33388 A allele against resistance to induction treatment was not statistically significant (OR 0,210; 95 % CI 0,036-1,236, p = 0,084). The carriers of GSTP1 rs1695 G allele had increased risk of poor response to prednisone treatment (OR 7,040; 95 % CI 1,826-26,618, p = 0,004), increased risk of event (relapse or death) (OR 3,75; 95 % CI 0,986-14,268; p = 0,053) and shorter EFS (HR 3,382; 95 % CI 1,028-4,172; p = 0,042). These associations remained significant in haplotype analysis. GSTP1 GC haplotype, present in 33 % of our ALL patients, increased the risk of poor response to prednisone (OR 3,963; 95 % CI 1.252-12.544; p = 0,019), the risk of event (OR 3,678; 95 % CI 1.308-10.341; p = 0,014) and exitus (OR 4,810; 95 % CI 1,157-19,988; p = 0,031). ABCB1 GT haplotypalso increased the risk of poor response to prednisone (OR 5,055; 95 % CI 1.138-22.465; p = 0,033). Conclusions: Our results suggest an important role of GSTP1 rs1695 polymorphism in glucocorticoid sensitivity and treatment outcome in childhood ALL. Genetic risk factors of anthracycline-induced cardiotoxicity – relevant polymorphisms identified in enzymes and transporters of anthracycline pharmacokinetics Kutszegi Nora , F. Semsei Agnes, Lautner-Csorba Orsolya, Hegyi Marta, Szalai Csaba, Kovacs Gabor T. Erdelyi Daniel J. Aims: The main dose limiting side-effect of anthracyclines is late cardio toxicity. Survivors of anticancer therapy have increased risk for cardiovascular problems and have higher such mortality. Subclinical changes may become crucial in case of later accompanying diseases affecting the cardiovascular system, or these changes can precede severe late onset cardiac failure. Identifying patients with altered tolerance to anthracyclines would provide great clinical benefit. Methods: We studied 164 paediatric acute lymphoblastic leukaemia (ALL) patients who had been treated with ALL BFM protocols. They had cardiac ultrasound scans with a mean follow up of 6.4 years after anthracycline therapy. Left ventricular function was assessed as fractional shortening (LVSF). Germline genotypes of 19 single nucleotide polymorphisms (SNPs) in the ABCC1, CBR1, CBR3 and AKR1A1 genes were measured. Multifactorial general linear model was used to test for associations. Results: Patients with ABCC1 rs246221CT/TT genotype had lower LVFS at the time of the latest echocardiography compared to CC patients (38.4% and 40.7% respectively, p = 0.027). Those with AKR1A1 rs2088102CC genotype had lower LVFS than those harbouring at least one T allele (36.9% and 39.1% respectively, p = 0.013). Further SNPs showed no association with left ventricular function. Conclusion: Our results suggest that the ABCC1 rs246221 and the AKR1A1 rs2088102 variations are associated with altered left ventricular function in late survivors of childhood acute lymphoblastic leukaemia. The identified early subclinical changes. Unauthenticated Download Date | 4/16/17 12:19 PM Second ESPT Conference “Pharmacogenomics: From Cell to Clinic”, Lisbon, Sep 26–28, 2013 A15 FRIDAY SEPTEMBER 27th MORNING SECOND SESSION – CLINICAL IMPLEMENTATION OF PHARMACOGENOMICS TESTS

Personalized medicine is a strategy to prevent, diagnose, and treat disease so as to achieve an optimal result for the individual. The sequencing of the human genome and other technological advances have revealed the extent of genetic diversity and the relative contribution of genetic and nongenetic factors to human health, disease, and drug response. The challenge is to translate this knowledge into tangible benefits for the patient.

Inter- und intraindividuelle Variabilitat in der Arzneimittelwirkung ist haufig. Die Ursachen dieser Unterschiede sind vielseitig und bei jedem Patienten in verschiedener Kombination vorhanden. Hauptursachen sind genetische Diversitat und wechselnde Umweltfaktoren wie Ernahrung,andere Arzneimittel und "Lifestyle". Variabilitat kann die Pharmakokinetik, z.B. den Arzneimittelabbau, oder die Pharmakodynamik, d.h. den Wirkungsmechanismus eines Medikamentes betreffen. Diese individuellen Unterschiede im Ansprechen auf ein Medikament sind ein wichtiger Teil des Konzeptes der "Personalisierten Medizin" mit dem Anspruch, fur jeden Patienten eine massgeschneiderte Therapie anzuwenden, d.h. das fur seine personliche Problematik richtige Medikament in der richtigen Dosierung. Durchbruche in den Technologien der Genomik haben dazu gefuhrt, dass vor allem die genetische Variation der Arzneimittelwirkung besser untersucht werden kann. Diese Studien haben zu molekulargenetischen Tests gefuhrt, die die Wirksamkeit oder das Risiko unerwunschter Nebenwirkungen besser voraussagen konnen. Am haufigsten wird die "Personalisierte Medizin" heute in der Krebstherapie oder bei HIV Infektionen angewandt, zunehmend aber auch in anderen therapeutischen Gebieten. Die heute bekannten Situationen, die auch fur die Praxis von Bedeutung sein konnen, werden hier zusammengefasst. Patienten der Internet-Generation sind besser informiert uber ihre Krankheit und uber die Therapie, die sie erhalten. Zunehmend werden auch Patienten in der Praxis mit bereits vorhandenen Informationen zu ihrer Gensequenz oder gewissen Gentests erscheinen.

A new generation of technologies commonly named omics permits assessment of the entirety of the components of biological systems and produces an explosion of data and a major shift in our concepts of disease. These technologies will likely shape the future of health care. One aspect of these advances is that the data generated document the uniqueness of each human being in regard to disease risk and treatment response. These developments have reemphasized the concept of personalized medicine. Here we review the impact of omics technologies on one key aspect of personalized medicine: the individual drug response. We describe how knowledge of different omics may affect treatment decisions, namely drug choice and drug dose, and how it can be used to improve clinical outcomes.

A new vision of personalized medicine or personalized healthcare has evolved as a consequence of remarkable recent advances in technologies that allow to look at individual variation across the entire human genome and to identify personal risk factors behind many diseases and responses to therapy. These advances have greatly increased our understanding of how interactions between the entire genome and nongenomic factors result in health and disease and in therapeutic response. The challenge is now to translate this knowledge into benefits for the individual patient. I expect the Journal of Personalized Medicine to become the premier venue for the rapid and freely accessible publication of high quality manuscripts dealing with this vision for scientists around the world. [...].

Background Detoxification in the liver involves activation of nuclear receptors, such as the constitutive androstane receptor (CAR), which regulate downstream genes of xenobiotic metabolism. Frequently, the metabolism of endobiotics is also modulated, resulting in potentially harmful effects. We therefore used 1,4-Bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) to study the effect of CAR activation on mouse hepatic transcriptome and lipid metabolome under conditions of diet-induced hyperlipidemia. Results Using gene expression profiling with a dedicated microarray, we show that xenobiotic metabolism, PPARα and adipocytokine signaling, and steroid synthesis are the pathways most affected by TCPOBOP in normal and hyperlipidemic mice. TCPOBOP-induced CAR activation prevented the increased hepatic and serum cholesterol caused by feeding mice a diet containing 1% cholesterol. We show that this is due to increased bile acid metabolism and up-regulated removal of LDL, even though TCPOBOP increased cholesterol synthesis under conditions of hyperlipidemia. Up-regulation of cholesterol synthesis was not accompanied by an increase in mature SREBP2 protein. As determined by studies in CAR -/- mice, up-regulation of cholesterol synthesis is however CAR-dependent; and no obvious CAR binding sites were detected in promoters of cholesterogenic genes. TCPOBOP also affected serum glucose and triglyceride levels and other metabolic processes in the liver, irrespective of the diet. Conclusion Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARα and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.

The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital on gene transcription. To investigate the relative contribution of these nuclear receptors to the expression of specific genes we studied the effect of phenobarbital in livers of wild type, CAR(-/-), PXR(-/-) and CAR/PXR(-/-) knockout mice. Spotted Steroltalk v1 cDNA arrays were applied containing probes for genes involved in drug metabolism, sterol biosynthesis, steroid synthesis/transport and heme synthesis. In the absence of CAR and PXR, phenobarbital unexpectedly induced mRNAs of several nuclear receptors, including PPARalpha and its target genes Cyp4a10 and Cyp4a14. Interestingly, in primary cultures of hepatocytes isolated from CAR/PXR(-/-) knockout mice, phenobarbital increased HNF-4alpha levels. In further experiments in these hepatocyte cultures we provide evidence that phenobarbital directly induces transcription of the PPARalpha gene via its HNF-4alpha response element, and indirectly by lack of inhibitory crosstalk of AMPK, CAR and PXR with HNF-4alpha. Our results provide further insight into CAR and PXR-independent effects of phenobarbital and the crosstalk between different nuclear receptor signaling pathways.

Warfarin is a challenging drug to accurately dose, both initially and for maintenance, because of its narrow therapeutic range, wide interpatient variability, and long list of factors that can influence dosing. Two million people in the United States are initiated on warfarin therapy annually, and this number is steadily increasing because of the increase in number of eligible patients. Recently, warfarin was reported to be the fourth leading cause of adverse events. The U.S. Food and Drug Administration recognizes that the adverse event rate of warfarin can be improved through better initial dosing, because many of the serious adverse events of warfarin occur soon after starting treatment. A substantial number of studies demonstrate that common variants of two genes, VKORC1 and CYP2C9, along with other nongenetic factors, correlate significantly with warfarin dosing. The genotypes of VKORC1 and CYP2C9 alone account for nearly 3 times more of the variability (∼30%) in warfarin dosing than do age, weight, gender, and other clinical factors combined (∼12%). Therefore, the purpose of this report is to review the current recommendations for warfarin therapy that involve genetic testing.