Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.

Harnessing Big Data for Systems Pharmacology.

Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.

WHO guide to good prescribing is 25 years old: quo vadis?

INTRODUCTION: Twenty-five years ago, the World Health Organization (WHO) published the Guide to Good Prescribing (GGP), followed by the accompanying Teacher's Guide to Good Prescribing (TGGP). The GGP is based on a normative 6-step model for therapeutic reasoning and prescribing, and provides a six-step guide for students to the process of rational prescribing. METHOD: We reviewed the need to update both WHO publications by evaluating their use and impact, including new (theoretical) insights and demands. Based on information from literature, Internet, and other (personal) sources, we draw the following conclusions. RESULTS: 1. An update of the GGP and TGGP, both in terms of content and form, is necessary because of the current need for these tools (irrational medicine use and unavailability of medicines), the lack of similar documents, and the lack of connection with recent developments, such as Internet and modern education; 2. The basic (6-step) model of the GGP is effective in terms of rational prescribing in the undergraduate situation and is still consistent with current theories about (context) learning, clinical decision-making, and clinical practice; 3. The dissemination and introduction of the GGP and TGGP in education has been successful so far, but is still not optimal because of lack of support and cooperation. CONCLUSIONS: On the basis of the evaluation results, a plan for the revision of the GGP and TGGP is presented.

International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors--family B G protein-coupled receptors.

The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein-coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTH-related protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous system as well as in spermatogenesis. Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic "two-site" mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gα(s)/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.

The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.

International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease.

Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.

International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides.

Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gα(s), Gα(i), and Gα(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gα(s)- and Gα(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gα(i)/Gα(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and ß-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics.

[Anticancer drug research in Hungary, 1950-2000]. / Daganat-kemoterápiás kutatások Magyarországon az 1950−2000 közötti években.

The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5-fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review.

Achieving the World Health Organization's vision for clinical pharmacology.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need.

Temporal Trends in Polypharmacy and Hyperpolypharmacy in Older New Zealanders over a 9-Year Period: 2005­2013.

BACKGROUND: Polypharmacy and hyperpolypharmacy are proxy indicators for inappropriate medicine use. Inappropriate medicine use in older people leads to adverse clinical outcomes. OBJECTIVE: The objectives of this study were to investigate the prevalence and trends of polypharmacy and hyperpolypharmacy in older people in New Zealand from 2005 to 2013, analyzing the pharmaceutical collections maintained by the Ministry of Health. METHODS: A repeated cross-sectional analysis of population-level dispensing data was conducted from January 1, 2005 to December 31, 2013. Polypharmacy and hyperpolypharmacy in individuals were defined as the use of 5-9 medicines and ≥10 medicines, respectively, dispensed concurrently for a period of ≥90 days. Differences in polypharmacy and hyperpolypharmacy between 2005 and 2013 were examined. A multinomial regression model was used to predict sociodemographic characteristics associated with polypharmacy and hyperpolypharmacy. RESULTS: Polypharmacy and hyperpolypharmacy were found to be higher in 2013 compared to 2005 (polypharmacy: 29.5 vs. 23.4%, p<0.001; hyperpolypharmacy: 2.1 vs. 1.3%, p<0.001). The risk of polypharmacy and hyperpolypharmacy was higher in females, in those aged 80-84 years, in the Maori population (for polypharmacy) and the Middle Eastern, Latin American, or African population (for hyperpolypharmacy), in people living in the Southern-district health board, and in individuals with increasing deprivation. CONCLUSION: The population of New Zealand is aging and the number of older people with multiple chronic conditions is increasing. The proportion of older people exposed to polypharmacy and hyperpolypharmacy has increased in 2013 compared to 2005. Our study provides important information to alert health policy makers, researchers, and clinicians about the dire need to reduce the medication burden in older New Zealanders.

[History of clinical pharmacology in France: adaptation, evaluation, defense and illustration of drug in France 1978-1981]. / Histoire de la pharmacologie clinique en France : dans une scintillante introspective, l'adaptation, l'évaluation, la défense et l'illustration du médicament en France 1978-1981.

This text illustrates some unknown aspects of the history and beginnings of clinical pharmacology in France in the late 1970s and early 1980s From the current situation, development and objectives of clinical pharmacology are recalled as well as obstacles necessary to overcome to change the paradigm in the field of drug evaluation and appropriate use in France. The text recalls this important moment where French medicine and medical pharmacology entered the modern era.

[Clinical pharmacy and surgery: Review]. / Pharmacie clinique et chirurgie : revue de la littérature.

Clinical pharmacy has been developed and evaluated in various medical hospital activities. Reviews conducted in this area reported a higher value of this discipline. In surgical services, evenly adverse drug events may occur, so clinical pharmacy activities must also help to optimize the management of drug's patient. The objectives of this literature review is to determine the profile of clinical pharmacy activities developed in surgical services and identify indicators. The research was conducted on Pubmed(®) database with the following keywords (2000-2013), "surgery", "pharmacy", "pharmacist", "pharmaceutical care", "impact" and limited to French or English papers. Studies dealing on simultaneously medical and surgical areas were excluded. Twenty-one papers were selected. The most frequently developed clinical pharmacy activities were history and therapeutic drug monitoring (antibiotics or anticoagulants). Two types of indicators were identified: activity indicators with the number of pharmaceutical interventions, their description and clinical signification, the acceptance rate and workload. Impact indicators were mostly clinical and economic impacts. The development of clinical pharmacy related to surgical patients is documented and appears to have, as for medical patients, a clinical and economical value.

Advancing pediatric drug development in South Asia: Current landscape and vision for the future.

ABSTRACT: The manuscript summarizes the outcomes of a one-day conference by the South Asian College of American College of Clinical Pharmacology (SAC-ACCP) in July 2023, at Bhopal. The theme of the conference was "Advancing pediatric drug development in South Asia." SAC-ACCP organized this event in Bhopal to foster the discipline of clinical pharmacology and to motivate researchers and physicians in the in the central part of India. The conference featured presentations on regional approaches to pediatric drug development in Asia by pediatric scientific experts from the pharmaceutical industry, regulatory agencies, as well as independent consultancies. The speakers highlighted several important aspects of the evolving regulatory landscape in India and proposed numerous actionable steps in acceleration of pediatric drug development. This commentary provides insights from presentations and the panel discussion at this conference and also makes an attempt to connect to similar discussions that occurred at the SAC-ACCP drug development conference in 2017.

The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report.

In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher-project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key.

Finding a VOICE for UK clinical pharmacology.

At a James Black Conference held in Oxford on 20-22 June 2011, a group of senior clinical pharmacologists and their junior colleagues, other medical specialists, and pharmacists discussed an agenda for UK clinical pharmacology for the next 5 years, addressing the following broad questions. How should UK clinical pharmacology be further developed and delivered as a discipline in universities, the NHS, pharmaceutical companies, and regulatory authorities? How should teaching and training in UK clinical pharmacology and therapeutics be delivered and assessed? What topics should be priorities for research in UK academic clinical pharmacology? How should clinical pharmacology contribute to UK drugs policy? How should pharmacology and clinical pharmacology be further integrated, to the benefit of both? Numerous recommendations emerged, under the collective acronym VOICE, standing for Visibility, Outreach, Integration, Coverage and Emissaries. VISIBILITY: The visibility of the discipline needs to be increased. This could be done, for example, by increased activities in acute general medicine/toxicology, through activities of Medicines and Therapeutics Committees, participation in grand rounds, teaching and training, and monitoring therapeutic interventions, and by offering bolt-on training for other specialists (for example, short courses, MSc courses, and training programmes). OUTREACH: Methods of increasing outreach include roadshows in schools/medical schools, national special study modules, public education, press coverage, and social marketing. INTEGRATION: Closer collaborations with pharmacologists, clinical pharmacists, other prescribers, and pharmaceutical companies (e.g. through joint training programmes) are desirable. COVERAGE: Attention to neglected areas, such as general practice, paediatrics, obstetrics, geriatrics, anaesthetics, cancer, and immunology. EMISSARIES: Trainees to spread the word.

The innovative crisis as a current pharmaceutical research problem: causes, consequences, responses and solutions.

The innovative crisis is a consequence of scientific stagnation in pharmaceutical research. As a result of innovative crisis the number of innovative drugs put on the market has decreased. Biopharmaceutical research methods combined with findings in molecular mechanism of diseases will allow the discovery of new innovative diagnostics and drugs.

[Clinical pharmacy and pharmacovigilance over a period of nine years in hospital]. / Pharmacie clinique et pharmacovigilance à l'hôpital : bilan et perspectives après 9 ans d'expérience.

INTRODUCTION: Underreporting is the main limit in any pharmacovigilance system relying on spontaneous notification. Available data emphasize that pharmacists report few adverse drug reactions (ADRs) in France. OBJECTIVE: To report how the integration of pharmacists in health care units contributes to reporting of ADRs and to study the validity of the reports. METHOD: Over a period of nine years we have prospectively collected and analyzed all ADRs collected by pharmacists in a university hospital setting and notified to the regional center of pharmacovigilance. RESULTS: Over the study period 2017 notifications were sent. Over the past four years the annual number of reports varied between 250 and 350. This amount is approximately ten times the number referred by physicians during the year preceding the beginning of this work. Only 8.6% of the submitted notifications were rejected by the pharmacovigilance center for various reasons: no causal link between the adverse event and taking medication, problem of timing, lack of data... CONCLUSION: The integration of the adverse reaction reporting in the daily activities of the pharmacist is a mean to increase very significantly the number of reports (factor of increase of 9.6 to 13.4).