[The revolution of AI in drug development]. / L'intelligence artificielle, une révolution dans le développement des médicaments.

Artificial intelligence and machine learning enable the construction of predictive models, which are currently used to assist in decision-making throughout the process of drug discovery and development. These computational models can be used to represent the heterogeneity of a disease, identify therapeutic targets, design and optimize drug candidates, and evaluate the efficacy of these drugs on virtual patients or digital twins. By combining detailed patient characteristics with the prediction of potential drug-candidate properties, artificial intelligence promotes the emergence of a "computational" precision medicine, allowing for more personalized treatments, better tailored to patient specificities with the aid of such predictive models. Based on such new capabilities, a mixed reality approach to the development of new drugs is being adopted by the pharmaceutical industry, which integrates the outputs of predictive virtual models with real-world empirical studies.

Title: L'intelligence artificielle, une révolution dans le développement des médicaments. Abstract: L'intelligence artificielle (IA) et l'apprentissage automatique produisent des modèles prédictifs qui aident à la prise de décisions dans le processus de découverte de nouveaux médicaments. Cette modélisation par ordinateur permet de représenter l'hétérogénéité d'une maladie, d'identifier des cibles thérapeutiques, de concevoir et optimiser des candidats-médicaments et d'évaluer ces médicaments sur des patients virtuels, ou des jumeaux numériques. En facilitant à la fois une connaissance détaillée des caractéristiques des patients et en prédisant les propriétés de multiples médicaments possibles, l'IA permet l'émergence d'une médecine de précision « computationnelle ¼ offrant des traitements parfaitement adaptés aux spécificités des patients.

23 Congreso Nacional Farmacéutico / [23rd National Pharmaceutical Congress]

Bajo el lema Transformando la sanidad con el farmacéutico, el 23 Congreso Nacional Farmacéutico ha reunido en Valencia a más de 2.000 farmacéuticos de todos los ámbitos de la profesión, desde la óptica y la ortopedia, a la dermofarmacia, la investigación, la industria, la distribución, la alimentación, los análisis clínicos, la salud pública, la farmacia hospitalaria y, por supuesto, la farmacia comunitaria. (AU)

The nucleolus of Giardia and its ribosomal biogenesis.

Giardia duodenalis is a protozoan intestinal parasite that causes a significant number of infections worldwide each year, particularly in low-income and developing countries. Despite the availability of treatments for this parasitic infection, treatment failures are alarmingly common. As a result, new therapeutic strategies are urgently needed to effectively combat this disease. On the other hand, within the eukaryotic nucleus, the nucleolus stands out as the most prominent structure. It plays a crucial role in coordinating ribosome biogenesis and is involved in vital processes such as maintaining genome stability, regulating cell cycle progression, controlling cell senescence, and responding to stress. Given its significance, the nucleolus presents itself as a valuable target for selectively inducing cell death in undesirable cells, making it a potential avenue for anti-Giardia treatments. Despite its potential importance, the Giardia nucleolus remains poorly studied and often overlooked. In light of this, the objective of this study is to provide a detailed molecular description of the structure and function of the Giardia nucleolus, with a primary focus on its involvement in ribosomal biogenesis. Likewise, it discusses the targeting of the Giardia nucleolus as a therapeutic strategy, its feasibility, and the challenges involved.

Novel antimicrobial strategies to treat multi-drug resistant Staphylococcus aureus infections.

Antimicrobial resistance is a major obstacle for the treatment of infectious diseases and currently represents one of the most significant threats to global health. Staphylococcus aureus remains a formidable human pathogen with high mortality rates associated with severe systemic infections. S. aureus has become notorious as a multidrug resistant bacterium, which when combined with its extensive arsenal of virulence factors that exacerbate disease, culminates in an incredibly challenging pathogen to treat clinically. Compounding this major health issue is the lack of antibiotic discovery and development, with only two new classes of antibiotics approved for clinical use in the last 20 years. Combined efforts from the scientific community have reacted to the threat of dwindling treatment options to combat S. aureus disease in several innovative and exciting developments. This review describes current and future antimicrobial strategies aimed at treating staphylococcal colonization and/or disease, examining therapies that show significant promise at the preclinical development stage to approaches that are currently being investigated in clinical trials.

Machine Learning and Artificial Intelligence in Pharmaceutical Research and Development: a Review.

Over the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automated nature, predictive capabilities, and the consequent expected increase in efficiency. ML approaches have been used in drug discovery over the past 15-20 years with increasing sophistication. The most recent aspect of drug development where positive disruption from AI/ML is starting to occur, is in clinical trial design, conduct, and analysis. The COVID-19 pandemic may further accelerate utilization of AI/ML in clinical trials due to an increased reliance on digital technology in clinical trial conduct. As we move towards a world where there is a growing integration of AI/ML into R&D, it is critical to get past the related buzz-words and noise. It is equally important to recognize that the scientific method is not obsolete when making inferences about data. Doing so will help in separating hope from hype and lead to informed decision-making on the optimal use of AI/ML in drug development. This manuscript aims to demystify key concepts, present use-cases and finally offer insights and a balanced view on the optimal use of AI/ML methods in R&D.

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis.

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011-2020): Current Status and Future Prospects.

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).

Antiprotozoal agents: How have they changed over a decade?

Neglected tropical diseases are a diverse group of communicable diseases that are endemic in low- or low-to-middle-income countries located in tropical and subtropical zones. The number and availability of drugs for treating these diseases are low, the administration route is inconvenient in some cases, and most of them have safety, efficacy, or adverse/toxic reaction issues. The need for developing new drugs to deal with these issues is clear, but one of the most drastic consequences of this negligence is the lack of interest in the research and development of new therapeutic options among major pharmaceutical companies. Positive changes have been achieved over the last few years, although the overall situation remains alarming. After more than one decade since the original work reviewing antiprotozoal agents came to light, now it is time to question ourselves: How has the scenario for the treatment of protozoal diseases such as malaria, leishmaniasis, human African trypanosomiasis, and American trypanosomiasis changed? This review covers the last decade in terms of the drugs currently available for the treatment of these diseases as well as the clinical candidates being currently investigated.

Catalyzing momentum in male contraceptive development†.

Globally, nearly half of all pregnancies are unplanned. Male contraceptives offer the potential to decrease unintended pregnancy and introduce contraceptive equity, but decades of research have yet to bring a novel product to market. New funding avenues from the philanthropic sector seek to stimulate research in male contraceptives through investments, grants, and support for trainees alongside other programs that encourage product development and ultimately commercialization. This Forum outlines the purpose of and funding opportunities provided by Male Contraceptive Initiative, a funding agency and non-profit focused on the advancement of non-hormonal, reversible contraceptive technologies for those who produce sperm.

Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019.

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making.

Small molecule drugs for atopic dermatitis, rheumatoid arthritis, and hereditary angioedema.

OBJECTIVE: To review recent trends in the development of targeted small molecule drugs (SMDs) for the treatment of immunologically driven disorders, including atopic dermatitis, rheumatoid arthritis, and hereditary angioedema. DATA SOURCES: Data sources included peer-reviewed published literature from the PubMed database, published abstracts from scientific and medical meetings, and medication information from the Drugs@FDA database. STUDY SELECTIONS: Articles with primary or retrospective trial results, articles with patient or physician survey results, articles providing expert perspectives, and commentary on chronic immunologic disorders, Food and Drug Administration package inserts, and abstracts from scientific meetings were selected. RESULTS: Targeted biological therapies have greatly improved response rates and symptom relief for patients with long-term immunologically driven disorders over the past 2 decades. However, recent advances in the understanding of molecular pathways involved in the pathogenesis of these disorders have led to the development of novel targeted SMDs, such as tofacitinib and berotralstat, that can be delivered orally or topically. Few head-to-head studies that compare the safety and efficacy of biologics to SMDs in immunologically driven disorders exist, although some studies suggest that oral and topical modes of administration are preferred by patients and may improve patient quality of life over time. CONCLUSION: Scientific advances have led to an increase in the development of targeted SMDs for the treatment of chronic immunologic disorders, which may revolutionize the management of these diseases. Head-to-head studies and real-world evidence are needed to fully compare treatment attributes between biologics and SMDs, including safety, efficacy, adherence, impact on quality of life, and cost-effectiveness.

Opportunities for overcoming tuberculosis: Emerging targets and their inhibitors.

Tuberculosis (TB), an airborne infectious disease mainly caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of human morbidity and mortality worldwide. Given the alarming rise of resistance to anti-TB drugs and latent TB infection (LTBI), new targets and novel bioactive compounds are urgently needed for the treatment of this disease. We provide an overview of the recent advances in anti-TB drug discovery, emphasizing several newly validated targets for which an inhibitor has been reported in the past five years. Our review presents several attractive directions that have potential for the development of next-generation therapies.

A Round Trip: The Japanese Contribution to the Development of Sevoflurane.

Sevoflurane was first synthesized independently by Richard Wallin and Bernard Regan at Travenol Laboratories Incorporated and Ross Terrell and Louise Croix at Airco, Inc in the late 1960s, and subsequent animal studies and a phase-1 human trial of the agent published in 1981 showed promising results. Further research in the United States was halted, however, because of concerns regarding potential nephrotoxicity and the introduction of less degradable alternatives. Interest in sevoflurane resumed in Japan when Maruishi Pharmaceutical Company, Limited (Ltd) (Maruishi) decided to continue its development in 1982. They secured approval by the Japanese Ministry of Health, Labor and Welfare for its clinical use in January 1990. Because of its low blood:gas partition coefficient and resulting rapid action, sevoflurane quickly became the anesthetic of choice of Japanese anesthesiologists. In 1992 Abbott Laboratories, now AbbVie, Inc (Abbott, North Chicago, IL) finalized a licensing agreement with Maruishi to seek the US Food and Drug Administration approval for sevoflurane sales in the United States. Approved in June 1995, sevoflurane is now marketed by Abbott in 120 countries and has been administered >120 million times. This report details the Japanese contribution to the development of sevoflurane.