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The origin of small-molecule leads that were pursued across the independent research organizations Roche and Genentech from 2009 to 2020 is described. The identified chemical series are derived from a variety of lead-finding methods, which include public information, high-throughput screening (both full file and focused), fragment-based design, DNA-encoded library technology, use of legacy internal data, in-licensing, and de novo design (often structure-based). The translation of the lead series into in vivo tool compounds and development candidates is discussed as are the associated biological target classes and corresponding therapeutic areas. These analyses identify important trends regarding the various lead-finding approaches, which will likely impact their future application in the Roche and Genentech research groups. They also highlight commonalities and differences across the two independent research organizations. Several caveats associated with the employed data collection and analysis methodologies are included to enhance the interpretation of the presented information.

The treatment of many medical conditions requires the use of multiple drugs. A study published recently in this journal nicely illustrates the need to consider the pharmacology of potentially interacting drugs when conducting pharmacoepidemiologic studies of patient safety outcomes associated with such interactions. By examining multiple streams of data, we can piece together the risks and the mechanisms of action underlying those risks, and provide useful information for clinicians and patients to use multiple pharmacotherapies safely., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Compared with drugs from the blockbuster era, recently authorized drugs and those expected in the future present a heterogenous mix of chemicals, biologicals, and cell and gene therapies, a sizable fraction being for rare diseases, and even individualized treatments or individualized combinations. The shift in the nature of products entails secular trends for the definitions of "drugs" and "target population" and for clinical use and evidence generation. We discuss that the lessons learned from evidence generation for 20th century medicines may have limited relevance for 21st century medicines. We explain why the future is not about randomized controlled trials (RCTs) vs. real-world evidence (RWE) but RCTs and RWE-not just for the assessment of safety but also of effectiveness. Finally, we highlight that, in the era of precision medicine, we may not be able to reliably describe some small treatment effects-either by way of RCTs or RWE., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH 2 and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity.

Introduction: The SARS-CoV-2 pandemic has led to one of the most critical and boundless waves of publications in the history of modern science. The necessity to find and pursue relevant information and quantify its quality is broadly acknowledged. Modern information retrieval techniques combined with artificial intelligence (AI) appear as one of the key strategies for COVID-19 living evidence management. Nevertheless, most AI projects that retrieve COVID-19 literature still require manual tasks., Methods: In this context, we pre-sent a novel, automated search platform, called Risklick AI, which aims to automatically gather COVID-19 scientific evidence and enables scientists, policy makers, and healthcare professionals to find the most relevant information tailored to their question of interest in real time., Results: Here, we compare the capacity of Risklick AI to find COVID-19-related clinical trials and scientific publications in comparison with clinicaltrials.gov and PubMed in the field of pharmacology and clinical intervention., Discussion: The results demonstrate that Risklick AI is able to find COVID-19 references more effectively, both in terms of precision and recall, compared to the baseline platforms. Hence, Risklick AI could become a useful alternative assistant to scientists fighting the COVID-19 pandemic., (© 2021 S. Karger AG, Basel.)

Suicide is the second leading cause of death in young adults (15-24 years old). There continues to be limited access to mental health services for many patients who are in mental health crisis because of shortage of trained psychiatrist and mental health providers. Patients identified with high risk factors should get a full comprehensive psychiatric evaluation. Management should focus on preventative strategies, early identification as well as treatment with appropriate psychopharmacology and psychotherapy., (Copyright 2020 by the Missouri State Medical Association.)

The therapeutic management of cancers has undergone considerable changes due to the emergence of genomics tools and tumor molecular deciphering. In this context, a dual pharmacological approach based on pharmacogenomic analyses and therapeutic drug monitoring is now part of the routine care in cancer management for personalized therapies. First, molecular and immune profiling of tumors allows the emergence of new pharmacological targets in common as well as in rare cancers. Second, pharmacogenomic analyses coupled to therapeutic drug monitoring guide the prescription by adjusting regimen and managing drug resistance., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Advances in cancer treatment have led to dramatic increase in cancer survivors. In addition to cardiotoxicity resulting from anthracyclines and radiation therapy, the emergence of novel cancer treatment-related cardiovascular disease (CTRCD) with molecularly targeted therapies and immune checkpoint inhibitors has been recognized as an unmet medical need. Cardio-oncology is a new interdisciplinary research opportunity at the intersection of cardiovascular disease and cancer. Research priorities need to be identified for diagnosis, treatment, and prevention of previously unknown CTRCD(s), including (a) cardiac dysfunction and heart failure, (b) coronary artery disease, (c) valvular disease, (d) arrhythmias and QT-prolongation, (e) arterial hypertension, (f) thromboembolic disease, and (g) other cardiovascular disorders. In particular, understanding the fundamental mechanisms underlying CTRCD is essential for developing new methods. Applying more appropriate disease models and more effective methods for toxicity screening will help to better understand CTRCD. Although animal models have been used to predict potential problems, more advanced predictive models are also needed. Biobanks and other specimens with patient registries are expected to facilitate the validation of new biomarkers, genomic analysis, and imaging methods.

An aging worldwide population demands that anesthesiologists consider geriatrics a unique subset of patients requiring customization of practice. This article reviews the current literature investigating physiologic changes of the elderly that affect pharmacokinetics and pharmacodynamics. Changes in drug absorption, distribution, metabolism, and excretion are discussed as well as the ultimate effects of medications. Implications for practice regarding specific anesthetic and analgesic drugs are addressed. Despite the immense body of research that contributes to understanding of geriatric pharmacology, elderly patients often are excluded from rigorous research trials, and further scientific investigation to inform best practices for this group of patients is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Two technologies that have emerged in the last decade offer a new paradigm for modern pharmacology, as well as drug discovery and development. Quantitative systems pharmacology (QSP) is a complementary approach to traditional, target-centric pharmacology and drug discovery and is based on an iterative application of computational and systems biology methods with multiscale experimental methods, both of which include models of ADME-Tox and disease. QSP has emerged as a new approach due to the low efficiency of success in developing therapeutics based on the existing target-centric paradigm. Likewise, human microphysiology systems (MPS) are experimental models complementary to existing animal models and are based on the use of human primary cells, adult stem cells, and/or induced pluripotent stem cells (iPSCs) to mimic human tissues and organ functions/structures involved in disease and ADME-Tox. Human MPS experimental models have been developed to address the relatively low concordance of human disease and ADME-Tox with engineered, experimental animal models of disease. The integration of the QSP paradigm with the use of human MPS has the potential to enhance the process of drug discovery and development.

Online learning, an essential component of most traditional contact-based educational programs, must be of high quality to contribute effectively to learning. The availability of first-class web-based materials is particularly valued by both learners and educators in resource-poor nations. In this Practice article, we introduce the International Union of Basic and Clinical Pharmacology (IUPHAR) Pharmacology Education Project (PEP) (https://www.pharmacologyeducation.org/), a freely accessible online learning resource intended to support education and training in pharmacological sciences worldwide., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Pharmacology, the chemical control of physiology, emerged as an offshoot of physiology when the physiologists using chemicals to probe physiological systems became more interested in the probes than the systems. Pharmacologists were always, and in many ways still are, bound to study drugs in systems they do not fully understand. Under these circumstances, null methods were the main ways in which conclusions about biologically active molecules were made. However, as understanding of the basic mechanisms of cellular function and biochemical systems were elucidated, so too did the understanding of how drugs affected these systems. Over the past 20 years, new ideas have emerged in the field that have completely changed and revitalized it; these are described herein. It will be seen how null methods in isolated tissues gave way to, first biochemical radioligand binding studies, and then to a wide array of functional assay technologies that can measure the effects of molecules on drug targets. In addition, the introduction of molecular dynamics, the appreciation of the allosteric nature of receptors, protein X-ray crystal structures, genetic manipulations in the form of knock-out and knock-in systems and Designer Receptors Exclusively Activated by Designer Drugs have revolutionized pharmacology.

In our previous studies, vitamin C (VC) exerts potent pharmacological activities against liver injury (LI). Therefore, this report was designed to use network pharmacology-based strategy to predict therapeutic targets of VC against LI, and further to investigate the pharmacological molecular mechanisms. Pathological targets of LI were identified, followed by acquisition of verified targets of VC. After constructing target-functional protein interaction network of VC against LI, the core therapeutic targets of VC against LI were obtained. Further, biological function and pathway enrichment analyses were performed on core therapeutic targets to evaluate the biological processes and key signaling pathways of VC against LI. As revealed in network pharmacology assays, 6 key therapeutic targets for VC against LI were identified, showing tumor necrosis factor (TNF), nuclear factor-kappa-B p65 (RELA), nuclear factor-kappa-B p105 (NFKB1), TNF receptor-associated factor 2 (TRAF2), interleukin 6 (IL-6) and interleukin 1 beta (IL1B). On the basis of data analyses from DAVID database and omicshare cloud platform, bio-functional enrichment assays showed that the therapeutic effects of VC against LI were closely associated with regulating inflammatory reaction and apoptosis. Further, pathway enrichment analysis indicated the anti-LI benefits of VC were principally implicated in regulating the top 20 signaling pathways, such as inflammation-associated TNF signaling pathway, NF-κB signaling pathway. Taken together, the bioinformatics data elucidate that anti-LI pharmacological activities of VC may be predominantly related to inhibition of inflammatory stress, contributing to suppression of LI development. These resultant findings highlight the predicted therapeutic targets may be potential biomarkers for anti-LI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The National Directors of Graduate Studies biennial meeting is a forum for directors from pharmacology and physiology graduate programs to discuss challenges and best practices for programs that are preparing trainees to be successful in the biomedical workforce. The 2017 meeting was held on the campus of Stony Brook University in Stony Brook, NY. Over the course of the 3-day event, several themes evolved, including graduate education training and curricula, diversity and career development, and scientific rigor and communication. Overall, presentations and discussions highlighted the challenges and opportunities for training PhD biomedical scientists and featured best practices from across the country.

Integrative pharmacology (IP) is a discipline that studies the interaction, integration and principle of action of multiple components with the body, emphasizing the integrations of multi-level and multi-link, such as "whole and part", " in vivo and in vitro ", " in vivo process and activity evaluation". After four years of development and practice, the theory and method of IP has received extensive attention and application.In order to better promote the development of IP, this paper systematically reviews the concepts, research contents, research methods and application fields about IP., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

This article aims to understand the global and longitudinal trends of research on Panax ginseng . We used bibliometrics to analyze 3974 papers collected from the Web of Science TM Core Collection database during 1959-2016. The number of publications showed a steady growth before 2000 and exponentially increased in stage III (2000-2016, about 86% of the papers were published). Research on P. ginseng was conducted in 64 countries, mainly in Asia; in particular, 41% and 28% of the publications were from South Korea and China, respectively. The institutions from South Korea and China had high publication output and close cooperation and provided the majority of financial support. All top 10 authors and four of the top 20 journals in terms of number of publications originated from South Korea. The leading research subjects were pharmacology (39%), plant science (26%), and integrative complementary medicine (19%). The hotspot of P. ginseng research transformed from basic science to application, and multidisciplinary sciences will play a substantial role in the future. This study provides a comprehensive analysis to elucidate the global distribution, collaboration patterns, and research trends in the P. ginseng domain., Competing Interests: The authors declare no conflicts of interest.

With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the "compounds-proteins/genes-diseases" network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene-disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA-approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database.

The 23rd Scientific Conference of the Society on Neuroimmune Pharmacology (SNIP) will take place in Philadelphia, PA, USA, from March 29 to April 1, 2017. The conference will present a selection of the latest and most advanced research in the intersecting areas of neuroscience, immunology, pharmacology and its translational aspects.

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.

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

One of the cornerstones of rational drug development is the measurement of molecular parameters derived from ligand-receptor interaction, which guides therapeutic windows definition. Over the last decades, radioligand binding has provided valuable contributions in this field as key method for such purposes. However, its limitations spurred the development of more exquisite techniques for determining such parameters. For instance, safety risks related to radioactivity waste, expensive and controlled disposal of radioisotopes, radiotracer separation-dependence for affinity analysis, and one-site mathematical models-based fitting of data make radioligand binding a suboptimal approach in providing measures of actual affinity conformations from ligands and G proteincoupled receptors (GPCR). Current advances on high-throughput screening (HTS) assays have markedly extended the options of sparing sensitive ways for monitoring ligand affinity. The advent of the novel bioluminescent donor NanoLuc luciferase (Nluc), engineered from Oplophorus gracilirostris luciferase, allowed fitting bioluminescence resonance energy transfer (BRET) for monitoring ligand binding. Such novel approach named Nluc-based BRET (NanoBRET) binding assay consists of a real-time homogeneous proximity assay that overcomes radioligand binding limitations but ensures the quality in affinity measurements. Here, we cover the main advantages of NanoBRET protocol and the undesirable drawbacks of radioligand binding as molecular methods that span pharmacological toolbox applied to Drug Discovery. Also, we provide a novel perspective for the application of NanoBRET technology in affinity assays for multiple-state binding mechanisms involving oligomerization and/or functional biased selectivity. This new angle was proposed based on specific biophysical criteria required for the real-time homogeneity assigned to the proximity NanoBRET protocol., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Experimental pharmacology is undergoing fundamental changes. This article describes the challenges and opportunities associated with these changes from the perspective of the Swiss Society of Pharmacology (SSEP), the society which aims to advance experimental pharmacology in Switzerland and abroad.

Biomarkers have the potential to expedite drug development, increase patient safety, and optimize clinical response. Yet few have achieved regulatory qualification. A survey was conducted to clarify industry's perspective on biomarker qualification and identify the most promising biomarkers for drug development. The results across toxicities/clinical areas highlight challenges in regulatory qualification, although early prioritization and alignment on an evidentiary standard framework are key factors in facilitating biomarker development and qualification., (© 2015 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

There is a lack of information regarding the use of novel psychoactive substances (NPS) in Western Australia. The aim of this study was to pilot-test an online survey to obtain data on the prevalence of NPS and other drug use by young Western Australians aged between 18 and 35 years. The Young Adult Drug and Alcohol Survey (YADAS) was a questionnaire deployed online for a period of six months. Participants were recruited via a combined targeted sampling and snowball methodology. There were 472 valid responses. Overall lifetime use of NPS was relatively high (17.6%), while use in the last year was lower (6.6%). These proportions were comparable to that of cocaine use. The most popular NPS were the synthetic cannabinoids. The proportions of respondents drinking alcohol at risky levels, mixing alcohol with energy drinks, and using pharmaceuticals such as ADHD medications for non-medical reasons were high. The YADAS is the first survey to ascertain the prevalence of use of numerous types of NPS in a large sample of young Western Australian adults. The utilization of an online survey methodology yielded valid results as compared to more intensive surveys, and enables researchers greater flexibility in being able to capture current trends.