An account on the history of pharmacology in Spain.

Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.

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.

Mapping drug-target interactions and synergy in multi-molecular therapeutics for pressure-overload cardiac hypertrophy.

Advancements in systems biology have resulted in the development of network pharmacology, leading to a paradigm shift from "one-target, one-drug" to "target-network, multi-component therapeutics". We employ a chimeric approach involving in-vivo assays, gene expression analysis, cheminformatics, and network biology to deduce the regulatory actions of a multi-constituent Ayurvedic concoction, Amalaki Rasayana (AR) in animal models for its effect in pressure-overload cardiac hypertrophy. The proteomics analysis of in-vivo assays for Aorta Constricted and Biologically Aged rat models identify proteins expressed under each condition. Network analysis mapping protein-protein interactions and synergistic actions of AR using multi-component networks reveal drug targets such as ACADM, COX4I1, COX6B1, HBB, MYH14, and SLC25A4, as potential pharmacological co-targets for cardiac hypertrophy. Further, five out of eighteen AR constituents potentially target these proteins. We propose a distinct prospective strategy for the discovery of network pharmacological therapies and repositioning of existing drug molecules for treating pressure-overload cardiac hypertrophy.

Integrating metabolomics and network pharmacology to explore Rhizoma Coptidis extracts against sepsis-associated acute kidney injury.

Sepsis remains the most common cause of acute kidney injury (AKI) in critically ill patients, increasing the risk of in-hospital and long-term death. Rhizoma Coptidis (RC), a classical traditional Chinese herb, exhibits anti-inflammatory and antioxidant properties in various diseases including sepsis. This study aimed to investigate the protective effects of RC extracts (RCE) against sepsis-associated acute kidney injury (SA-AKI) and explore the underlying mechanisms with metabolomics-based network pharmacology. The results showed that RCE improved renal function and histological injury and decreased reactive oxygen species (ROS) production in SA-AKI. Using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS), 25 differential metabolites were identified that had a close connection with the pathological processes of SA-AKI and the effects of RCE. Afterward, a compound-metabolite-target-disease network was constructed and 17 overlapping target proteins of the components of RCE, the differential metabolites, and the disease-related genes were discovered. Among these overlapping target proteins, RCE increased the nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2), the protein expression of heme oxygenase-1 (HO-1), the mRNA expression of peroxisome proliferator activated receptor α (PPARα) and reduced nitric oxide synthase 2 (NOS2) activity. In addition, molecular docking revealed that both berberine and quercetin could bond with NOS2 and PPARα, respectively. Therefore, RCE demonstrated protective effects for SA-AKI through the regulation of metabolism and different signaling pathways.

Switching from a traditional undergraduate programme in (clinical) pharmacology and therapeutics to a problem-based learning programme.

PURPOSE: The pharmacology and clinical pharmacology and therapeutics (CPT) education during the undergraduate medical curriculum of NOVA Medical School, Lisbon, Portugal, was changed from a traditional programme (i.e. discipline-based, lectures) to a problem-based learning (PBL) programme (i.e. integrated, case-based discussions) without an increase in teaching hours. The aim of this study was to investigate whether this change improved the prescribing competencies of final-year medical students. METHODS: Final-year students from both programmes (2015 and 2019) were invited to complete a validated prescribing assessment and questionnaire. The assessment comprised 24 multiple-choice questions in three subdomains (working mechanism, side-effects and interactions/contraindications), and five clinical case scenarios of common diseases. The questionnaire focused on self-reported prescribing confidence, preparedness for future prescribing task and education received. RESULTS: In total, 36 (22%) final-year medical students from the traditional programme and 54 (23%) from the PBL programme participated. Overall, students in the PBL programme had significantly higher knowledge scores than students in the traditional programme (76% (SD 9) vs 67% (SD 15); p = 0.002). Additionally, students in the PBL programme made significantly fewer inappropriate therapy choices (p = 0.023) and fewer erroneous prescriptions than did students in the traditional programme (p = 0.27). Students in the PBL programme felt more confident in prescribing, felt better prepared for prescribing as junior doctor and completed more drug prescriptions during their medical training. CONCLUSION: Changing from a traditional programme to an integrated PBL programme in pharmacology and CPT during the undergraduate medical curriculum may improve the prescribing competencies of final-year students.

[Franciscus Sylvius: A Life for Clinic, Research, Teaching And a Little Gin]. / Franciscus Sylvius: Ein Leben für Klinik, Forschung, Lehre und ein bisschen Gin.

Franciscus Sylvius, latinized from Franz de le Boë (*15 March 1614 in Hanau; † 14 November 1672 in Leiden), was a Hessian-Dutch physician, anatomist, and natural scientist of Flemish descent. He was an important clinician and iatrochemist, and is considered the founder of scientifically oriented medicine and clinical chemistry. Sylvius introduced the concept of affinity and dealt with digestive processes and body fluids. He was one of the leading exponents of the concept of blood circulation developed by William Harvey. As the person responsible for practical medicine in Leiden, Sylvius established bedside teaching as part of the medical curriculum, and he introduced his students to clinical medicine in an experimental way, both contrary to the rules of the time. He was also interested in pharmacology, herbalism and botany. For heartburn and digestive disorders, Sylvius mixed juniper berries, herbs and alcohol to create a medicine. According to legend, Sylvius marketed this medicine as Genever, for which the name Gin was later adopted in the British Isles, but not only used for medical purposes. Accordingly, the city of birth of Sylvius today calls itself a "birthplace of gin".

Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Huashi Baidu formula in the treatment of COVID-19.

PURPOSE: Huashi Baidu formula (HSBDF) was developed to treat the patients with severe COVID-19 in China. The purpose of this study was to explore its active compounds and demonstrate its mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through network pharmacology and molecular docking. METHODS: All the components of HSBDF were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using UniProt and GeneCards database. The herb-compound-target network was constructed by Cytoscape. The target protein-protein interaction network was built using STRING database. The core targets of HSBDF were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HSBDF were docked with SARS-CoV-2 and angiotensin converting enzyme II (ACE2). RESULTS: Compound-target network mainly contained 178 compounds and 272 corresponding targets. Key targets contained MAPK3, MAPK8, TP53, CASP3, IL6, TNF, MAPK1, CCL2, PTGS2, etc. There were 522 GO items in GO enrichment analysis (p < .05) and 168 signaling pathways (p < .05) in KEGG, mainly including TNF signaling pathway, PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway. The results of molecular docking showed that baicalein and quercetin were the top two compounds of HSBDF, which had high affinity with ACE2. CONCLUSION: Baicalein and quercetin in HSBDF may regulate multiple signaling pathways through ACE2, which might play a therapeutic role on COVID-19.

How can we improve the safe use of herbal medicine and other natural products? A clinical pharmacologist mission.

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually. The U.S. FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

Persea spp*: inventário de referências / Persea spp*: REFERENCE INVENTORY

Produto que inclui buscas na literatura para contabilizar e categorizar estudos.

Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review.

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.

Barrie Tan, PhD: The Importance of Geranylgeraniol.

No Abstract Available.

Network pharmacology study of traditional Chinese medicines for stroke treatment and effective constituents screening.

ETHNOPHARMACOLOGICAL RELEVANCE: Stroke is one of the most frequent causes of death and disability. So far there are no effective preventives or treatments. The therapeutic system of traditional Chinese medicines (TCMs) has been in use for several thousand years and still affords a valuable resource for today's clinicians in preserving health. MATERIALS AND METHODS: We had collected the Chinese medicinal formulae and then commonly used single herbs or drug combinations were analyzed through data mining. The ingredients from the top 30 frequently used herbs which have good druggability and blood-brain barrier permeability were collected as a natural product library. Targets of the related ingredients were predicted using various databases and analyzed by GO and KEGG pathway mapping. The potential stroke targets were validated in the market or from clinical trials, and used to establish molecular docking, HipHop and SBP models to screen new compounds for multi-target activity. Lastly, in vitro experiments with models for oxygen and glucose deprivation and reperfusion (OGDR) were conducted to test the activities of compounds identified by screening. RESULTS: A total of 1679 Chinese medicinal formulas were selected and their prescription rules were analyzed. 4277 compounds were from the top 30 herbs and 3560 molecules were filtered to build the natural product library. The ingredient-target network, target-disease network and target-target interaction network were established to explain the characteristics and mechanisms of the TCMs. Thirty-one molecules were selected to have multi-target activity on targets of stroke via virtual screening. Five of these had already been reported to have therapeutic effects on stroke. Three of the eight compounds which have been examined showed protective effects on OGDR model. CONCLUSIONS: This paper details a novel strategy for exploring the characteristics and mechanisms of herbal medicines from a systematic standpoint in an attempt to identify those affecting specific target pathways related to stroke. Using this methodology on our natural products library, we found a number of lead candidates with multi-target activity.

A Brief Guide to Performing Pharmacological Studies In Vitro: Reflections from the EORTC-PAMM Course "Preclinical and Early-phase Clinical Pharmacology".

One aim of cell-based in vitro assays is to identify the best drug candidate to develop using the best tumor cell model. This is challenging in every anticancer drug discovery process. Briefly, we summarize the parameters to be taken into account when performing in vitro cell assays, in order to obtain reliable and reproducible results, which was fundamentally discussed by lecturers at the educational course on preclinical and early-phase clinical pharmacology studies, at the 40th Winter Meeting of the Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer. Moreover, specific cellular sensitivity tests are described. In addition to monolayer in vitro cell models for the screening of new potential candidate drugs, three-dimensional tumor/cell tissue models are emerging as new pre-clinical tools that more closely reflect the in vivo microenvironment. Therefore, the use of different in vitro models for drug screening can enhance the predictability and reliability of pre-clinical drug-discovery phases and target validation.

Emerging Role of Organ-on-a-Chip Technologies in Quantitative Clinical Pharmacology Evaluation.

The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals "enhancing regulatory science and expediting drug development." The key elements in "enhancing regulatory decision tools to support drug development and review" include "advancing model-informed drug development (MIDD)." This paper describes (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) how emerging novel tools, such as organ-on-a-chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically-based pharmacokinetic and pharmacodynamic evaluations. Continuous public-private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review.

Non-alcoholic Steatohepatitis (NASH) Drug Discovery - Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development.

Number of drugs with different mechanisms of actions is undergoing clinical trials for non-alcoholic steatohepatitis (NASH). Given the complexity of the disease with respect to pathophysiology in the liver and associated changes in the renal function, it becomes apparent that a clear ADME (absorption, distribution, metabolism and excretion) strategy needs to be put in place for a successful nomination of a drug candidate for NASH. This review discusses using in vitro and in vivo ADME screens to understand the properties of drugs and to establish whether or not the chosen drug(s) can overcome the challenges related hepatic and renal transporters covering both uptake and efflux mechanisms imposed by NASH. A complete panel of in vivo preclinical experiments including a 14C-labeled study are proposed in NASH animal models to delineate the problematic areas for early drug development. Furthermore, a framework is provided with respect to the clinical pharmacology studies early in clinical development to characterise in an unbiased manner, the altered pharmacokinetics of drug in NASH patients for optimizing the dose selection for late phase clinical development. Because NASH patients have other co-morbid conditions and are prescribed co-medications for treating blood pressure, type 2 diabetes mellitus, obesity, dyslipidemia and many more disorders, it is also suggested to examine the drug-drug interaction potential by performing a cocktail probe study to cover a broad range of cytochrome P450 (CYP) enzymes and transporters.