[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.

Antibiotic Development: Lessons from the Past and Future Opportunities.

The challenge of antimicrobial resistance is broadly appreciated by the clinical and scientific communities. To assess progress in the development of medical countermeasures to combat bacterial infections, we deployed information gleaned from clinical trials conducted from 2000 to 2021. Whereas private sector interest in cancer grew dramatically over this period, activity to combat bacterial infections remained stagnant. The comparative ambivalence to antimicrobial resistance is reflected in the number of investigative drugs under clinical investigation, their stage of development and most troublingly, a declining number of organizations that are actively involved in the development of new products to treat bacterial infections. This drop reflects the exits of many companies that had previously developed antibacterial agents.

Exploring future perspectives and pipeline progression in vaccine research and development.

Introduction: The COVID-19 pandemic had a profound impact on vaccines' Research and Development, on vaccines' market, and on immunization programmes and policies. The need to promptly respond to the health emergency boostered resources' al-location and innovation, while new technologies were made available. Regulatory procedures were revised and expedited, and global production and distribution capacities significantly increased. Aim of this review is to outline the trajectory of research in vaccinology and vaccines' pipeline, highlighting major challenges and opportunities, and projecting future perspectives in vaccine preventables diseases' prevention and control. Study Design: Narrative review. Methods: We comprehensively consulted key biomedical databases including "Medline" and "Embase", preprint platforms, including"MedRxiv" and "BioRxiv", clinical trial registries, selected grey literature sources and scientific reports. Further data and insights were collected from experts in the field. We first reflect on the impact that the COVID-19 had on vaccines' Research and Development, regulatory frameworks, and market, we then present updated figures of vaccines pipeline, by different technologies, comparatively highlighting advantages and disadvantages. We conclude summarizing future perspectives in vaccines' development and immunizations strategies, outlining key challenges, knowledge gaps and opportunities for prevention strategies. Results: COVID-19 vaccines' development has been largely supported by public funding. New technologies and expetited autho-rization and distribution processes allowed to control the pandemic, leading vaccines' market to grow exponentially. In the post-pandemic era investments in prevention are projected to decrease but advancements in technology offer great potential to future immunization strategies. As of 2023, the vaccine pipeline include almost 1,000 candidates, at different Research and Development phase, including innovative recombinant protein vaccines, nucleic acid vaccines and viral vector vaccines. Vaccines' technology platforms development varies by disease. Overall, vaccinology is progressing towards increasingly safe and effective products that are easily manufacturable and swiftly convertible. Conclusions: Vaccine research is rapidly evolving, emerging technologies and new immunization models offer public health new tools and large potential to fight vaccines preventables diseases, with promising new platforms and broadened target populations. Real-life data analysis and operational research is needed to evaluate how such potential is exploited in public health practice to improve population health.

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.

Why do we not have more drugs approved for MDS? A critical viewpoint on novel drug development in MDS.

Approval of new agents to treat higher risk (HR) myelodysplastic syndrome (MDS) has stalled since the approval of DNA methyltransferase inhibitors (DNMTi). In addition, the options for patients with lower risk (LR) MDS who have high transfusion needs and do not harbor ring sideroblasts or 5q- syndrome are limited. Here, we review the current treatment landscape in MDS and identify areas of unmet need, such as treatment after failure of erythropoiesis-stimulating agents or DNMTis, TP53-mutated disease, and MDS with potentially targetable mutations. We discuss how our understanding of MDS pathogenesis can inform therapy development, including treating HR-MDS similarly to AML and pursuing therapies to address splicing factor mutations and dysregulated inflammation. We then bring a critical lens to current methodology of MDS studies and propose solutions to improve the efficiency and yield of these clinical trials, including using the most meaningful response metrics and expanding enrollment.

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).

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.