Small-Molecule Lead-Finding Trends across the Roche and Genentech Research Organizations.

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.

Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives.

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-NH2 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.

Utilizing Artificial Intelligence to Manage COVID-19 Scientific Evidence Torrent with Risklick AI: A Critical Tool for Pharmacology and Therapy Development.

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.

Consideraciones sobre el programa de Farmacología General en el plan de estudio D para la carrera de medicina / Considerations on the program of the General Pharmacology subject in the syllabus D for the medicine career

El plan de estudio, documento fundamental que establece la dirección general y el contenido principal de la preparación de los profesionales, se ha ido perfeccionamiento continuamente, en correspondencia con el desarrollo cientificotécnico alcanzado. El programa de la asignatura es el que refleja las características más importantes de esta, tiene validez científica y pedagógica y contribuye a la formación del médico general, según las demandas de la sociedad cubana actual. Teniendo en cuenta las consideraciones anteriores se realizó el presente estudio con el objetivo de analizar los elementos teóricos y metodológicos del programa de la asignatura Farmacología General en el plan de estudio D para la carrera de medicina.

The syllabus, fundamental document that establishes the general direction and the main content of the professionals training, has been continually improving, in correspondence with the scientific technical development achieved. The subject program is the one that reflects its most important characteristics; it has scientific and pedagogic validity and contributes to the general doctor training, according to the demands of the present Cuban society. Taking into account the previous considerations this study was carried out aimed at analyzing the theoretical and methodological elements of the General Pharmacology subject program in the syllabus D for the medicine career.

Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth.

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.

Keeping the Pharmacology in Pharmacoepidemiology.

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.

Youth Suicide: A Population Crying for Help? A System Overloaded? Who Can Help?

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.

[Clinical pharmacology of cardio-oncology: a novel interdisciplinary platform for basic and translational research].

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.

The key role of oncopharmacology in therapeutic management, from common to rare cancers: A literature review.

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.

Emergent Concepts of Receptor Pharmacology.

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.

Geriatric Pharmacology: An Update.

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.

Harnessing Human Microphysiology Systems as Key Experimental Models for Quantitative Systems Pharmacology.

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.