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Development of a Quantitative Systems Pharmacology (QSP) model is a long process with many iterative steps. Lack of standard practices for publishing QSP models has resulted in limited model reproducibility within the field. Multiple studies have identified that model reproducibility is a large challenge, especially for QSP models. This work aimed to investigate the causes of QSP model reproducibility issues and suggest standard practices as a potential solution to ensure QSP models are reproducible. In addition, a protocol is suggested as a guidance towards better publication strategy across journals, hoping to enable QSP knowledge preservation., Competing Interests: Declarations Competing interests J.W. and A.Y. are employees of Astellas. A.G. was an employee of Astellas at the time of this work, is presently employed at Merck & Co. Inc. and owns its stocks. As an Associate Editor for JPKPD, A.G. was not involved in the review or decision process for this paper., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As medical care advances, there is a growing number of adult patients with cerebral palsy. The spastic form is characterized by muscle hypertonicity, hyperreflexia, and spasticity, which are associated with worse quality of life, poor functionality, and pain. This literature review attempts to explore the existing treatments for spasticity in cerebral palsy to provide insight into potential treatments in the adult population. The types of treatments are broadly categorized into physical therapy, pharmacologic treatments, botulinum toxin, surgical treatments, and alternative options.

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., (Copyright 2020 by the Missouri State Medical Association.)

In pharmacology teaching, pharmacokinetics (PK) and pharmacodynamics (PD) may be defined as part of the 'general pharmacology' domain, whereas effects of drugs on the autonomic nervous system and clinical trial design might be defined as part of the 'medical' and 'clinical' pharmacology domain, respectively. We recently designed a pharmacology course covering these domains for second year Health and Life Sciences students at the Vrije Universiteit Amsterdam (VU). We used a combination of lectures, problem-based learning and practicals to transfer knowledge to students in order for them to acquire sufficient knowledge and insight to solve real-world pharmacological problems. To evaluate whether we 1) successfully aligned our course objectives with both our teaching strategy and assessment, and 2) to identify topics in our course that would benefit from improvement in teaching strategy and/or effort, we determined success rate of the exam questions in above-defined pharmacology domains. We analyzed 3 consecutive second year cohorts (n = 377) of students enrolled in our course, and found a statistically significant reduction in success rate in exam questions of the general pharmacology domain (especially in PK), compared to domains covering 'medical' and 'clinical' pharmacology. In addition, we found lower success rates for 'knows how' questions compared to 'knows' questions in the combined PK/PD domain. Our data show that we overall succeeded in aligning our course objectives with both our teaching strategy and assessment, but that outcomes on the PK domain might benefit from additional attention., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The American Society for Pharmacology and Experimental Therapeutics has revised the Instructions to Authors for Drug Metabolism and Disposition , Journal of Pharmacology and Experimental Therapeutics , and Molecular Pharmacology These revisions relate to data analysis (including statistical analysis) and reporting but do not tell investigators how to design and perform their experiments. Their overall focus is on greater granularity in the description of what has been done and found. Key recommendations include the need to differentiate between preplanned, hypothesis-testing, and exploratory experiments or studies; explanations of whether key elements of study design, such as sample size and choice of specific statistical tests, had been specified before any data were obtained or adapted thereafter; and explanations of whether any outliers (data points or entire experiments) were eliminated and when the rules for doing so had been defined. Variability should be described by S.D. or interquartile range, and precision should be described by confidence intervals; S.E. should not be used. P values should be used sparingly; in most cases, reporting differences or ratios (effect sizes) with their confidence intervals will be preferred. Depiction of data in figures should provide as much granularity as possible, e.g., by replacing bar graphs with scatter plots wherever feasible and violin or box-and-whisker plots when not. This editorial explains the revisions and the underlying scientific rationale. We believe that these revised guidelines will lead to a less biased and more transparent reporting of research findings., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Terminal delirium is a distressing irreversible process that occurs frequently in the dying phase, often misdiagnosed and undertreated. A previous study in our organization revealed that terminal delirium was a poorly managed symptom at end of life. Pharmacological options are available in an existing order set to manage this symptom. The management plans of 41 patients identified as having terminal delirium were further evaluated. Elements extracted included medications prescribed to manage terminal delirium, whether medication changes occurred, and whether they were administered and effective. Patients with the order set were more comfortable as compared with the group without. Both groups had several changes made by the palliative care team. Nurses did not administer prescribed as-needed medication to more than one-third of patients. Modifications will be made to the existing order set, and additional education for staff will be organized.

Quantitative translation of information on drug absorption, disposition, receptor engagement, and drug-drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies to in vivo outcomes. To predict in vivo outcomes, biochemical data from experimental systems are routinely scaled using protein quantity in these systems and relevant tissues. Although several laboratories have generated useful quantitative proteomic data using state-of-the-art mass spectrometry, no harmonized guidelines exit for sample analysis and data integration to in vivo translation practices. To address this gap, a workshop was held on September 27 and 28, 2018, in Cambridge, MA, with 100 experts attending from academia, the pharmaceutical industry, and regulators. Various aspects of quantitative proteomics and its applications in translational pharmacology were debated. A summary of discussions and best practices identified by this expert panel are presented in this "White Paper" alongside unresolved issues that were outlined for future debates., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Toxicological and pharmacological information from human cells and tissues provides knowledge readily applicable to human safety assessment and to the efficacy assessment of pharmaceuticals. The 3R principle in animal studies includes the use of human material in the R of Replacement. The Reduction and Refinement Rs are related to animal use. Knowledge of the 3Rs and successful 3R methods are a prerequisite for the Reduction of animal experiments in the future. More collaboration among researchers using experimental animals and those working in vitro is necessary with mutual respect. The OECD Guidelines for the Testing of Chemicals have included the animal-free part of the 3Rs in guidances for the development and reporting of Adverse Outcome Pathways (AOPs), which is to be part of the Integrated Approaches to Testing and Assessment (IATA). The 3R centres established to help fulfil the Directive 2010/63/EU play an important role to promote the 3Rs and in the development of animal-free toxicology. Research centres in each Nordic country are founded upon solid research activities in cell and organ toxicity, including major EU programmes to promote 3Rs and implementation of good practices and methods broadly in all stakeholders of industry, regulators and academia. In the light of this, the Nordic Symposium on Toxicology and Pharmacology without Animal Experiments addressed more adopted/modified test guidelines or new test guidelines for new end-points, or hazard challenges, new in vitro 3D models, speeding up transfer of knowledge from research to regulation to understand AOP and towards IATA., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pharmacological nomenclature has been continuously developed over the last century and taught to generations of medical, pharmacy, and science students. Many pharmacological terms coined decades ago remain in textbooks and the scientific literature. With the advancement in the field and the identification of molecular drug targets, rethinking the pharmacological terms in the context of these new findings has become imperative. Some examples of such terms are antihistamine, beta blocker, calcium antagonist, disease-modifying antirheumatic drug (DMARD), and non-steroidal anti-inflammatory drug (NSAID). This opinion article is an attempt to generate discussion in the community that the better way forward to name/rename pharmacological terms would be according to their mechanism of action. A mechanism-based nomenclature provides important information about therapeutic and adverse effects of drugs. Abbreviations for drug classes have also been suggested. A parsimonious, practical, and mechanism-oriented pharmacological nomenclature will ultimately improve quality and safety of drug therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background The Journal Citation Reports (JCR) Pharmacology and Pharmacy subject category is heterogeneous. The inclusion of journals with basic and clinical scopes, which have different citation patterns, compromises comparability of impact factors among journals within the category. Objective To subdivide the Pharmacology and Pharmacy category into basic pharmacology, clinical pharmacology, and pharmacy based on the analyses of Medical Subject Headings (MeSH) as a proxy of journals' scopes. Setting JCR. Method All articles, and respective MeSH, published in 2013, 2014, and 2015 in all journals included in the 2014 JCR Pharmacology and Pharmacy category were retrieved from PubMed. Several models using a combination of the 14 MeSH categories and specific MeSH tree branches were tested using hierarchical cluster analysis. Main outcome measure Distribution of journals across the subcategories of the JCR Pharmacology and Pharmacy subject category. Results A total of 107,847 articles from 214 journals were included. Nine different models combining the MeSH categories M (Persons) and N (Health Care) with specific MeSH tree branches (selected ad-hoc) and Pharmacy-specific MeSH (identified in previous research) consistently grouped 142 journals (66.4%) in homogeneous groups reflecting their basic and clinical pharmacology, and pharmacy scopes. Ultimately, journals were clustered into: 150 in basic pharmacology, 43 in clinical pharmacology, 16 in basic pharmacology and clinical pharmacology, and 5 in pharmacy. Conclusion The reformulation of the Pharmacology and Pharmacy category into three categories was demonstrated by the consistent results obtained from testing nine different clustering models using the MeSH terms assigned to their articles.

Voltage gated ion channels are central in defining the fundamental properties of the ventricular cardiac action potential (AP), and are also involved in the development of drug-induced arrhythmias. Many drugs can inhibit cardiac ion currents, including the Na + current (I Na ), L-type Ca 2+ current (Ica-L), and K + currents (I to , I K1 , I Ks , and I Kr ), and thereby affect AP properties in a manner that can trigger or sustain cardiac arrhythmias. Since publication of ICH E14 and S7B over a decade ago, there has been a focus on drug effects on QT prolongation clinically, and on the rapidly activating delayed rectifier current (I Kr ), nonclinically, for evaluation of proarrhythmic risk. This focus on QT interval prolongation and a single ionic current likely impacted negatively some drugs that lack proarrhythmic liability in humans. To rectify this issue, the Comprehensive in vitro proarrhythmia assay (CiPA) initiative has been proposed to integrate drug effects on multiple cardiac ionic currents with in silico modelling of human ventricular action potentials, and in vitro data obtained from human stem cell-derived ventricular cardiomyocytes to estimate proarrhythmic risk of new drugs with improved accuracy. In this review, we present the physiological functions and the molecular basis of major cardiac ion channels that contribute to the ventricle AP, and discuss the CiPA paradigm in drug development., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The present study is an attempt to standardize and establish validity and reliability of objective structured practical examination (OSPE) as a tool of assessment in pharmacology., Methods: The individual stations were standardized by establishing the blueprint of assessment, checklists for individual OSPE stations, and a review and revision of existing OSPE stations through intensive focus group discussions. Face and content validity was established by subject nonexperts and experts, respectively. Internal construct reliability was assessed using Cronbach's alpha. The scores obtained by the students during their formative sessional examinations were analyzed to calculate Cronbach's alpha, a measure of internal construct reliability and Pearson's coefficient of correlation was used to analyze test-retest reliability and interexaminer reliability. Student and faculty feedback were taken using an open-ended questionnaire., Results: The Pearson's coefficient of correlation for inter-rater reliability was 0.985, P = 0.0001. The Pearson's coefficient of correlation for test-retest reliability was 0.967, P = 0.0001. Cronbach's alpha values for first, second, and third sessional examinations were 0.825, 0.724, and 0.798, respectively., Conclusion: The faculty and student feedback received was constructive and enabled a systematic review of the existing method and also served as a means to revise the existing curricula., Competing Interests: There are no conflicts of interest.

Background: The Learner-Centered Student-run Clinic (LC-SRC) was designed to teach and train prescribing skills grounded in a real-life context, to provide students with early clinical experience and responsibility. The current studies' theoretical framework was based on the Self-determination Theory. According to the Self-determination Theory, early involvement in clinical practice combined with a high level of responsibility makes the LC-SRC an environment that can stimulate intrinsic motivation. We investigated the different types of motivation and the proficiency in CanMEDS competencies of the participating students., Method: Type of motivation was measured using the Academic Motivation Scale and Intrinsic Motivation Inventory. CanMEDS competencies were evaluated by faculty using a mini-clinical examination and by the students themselves using a post-participation questionnaire., Results: The 29 participating students were highly intrinsic motivated for this project on all subscales of the Intrinsic Motivation Inventory. Motivation for medical school on the Academic Motivation Scale was high before and was not significantly changed after participation. Students considered that their CanMEDS competencies "Collaborator", "Communicator", "Academic", and "Medical expert" had improved. Their actual clinical team competence was judged by faculty to be at a junior doctor level., Conclusion: Students showed a high level of intrinsic motivation to participate in the LC-SRC and perceived an improvement in competence. Furthermore their actual clinical competence was at junior doctor level in all CanMEDS competencies. The stimulating characteristics of the LC-SRC, the high levels of intrinsic motivation and the qualitative comments of the students in this study makes the LC-SRC an attractive place for learning.

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

In Germany and throughout Europe, medicinal products for adults have been developed and evaluated systematically for decades. Medicinal products for children and adolescents, however, have only been researched for the past ten years. As a result, many medicinal products have been administered to children without systematic clinical trials, for example regarding dosage or pharmaceutical form.EU Regulation 1901/2006 aimes to close the gaps in the medical treatment of children and adolescents. In order to do so, the regulation provides for paediatric use marketing authorisations (PUMA) for previously authorised products no longer covered by intellectual property rights and also grants holders of such PUMA licenses further property rights. However, only two PUMA licenses have been applied for. Thus, the PUMA license instrument is hardly being used despite the fact that many medicinal products have a great potential for closing medical gaps for children and adolescents.In order to improve the situation regarding medicinal products for children and adolescents, this scientific symposium "More Medicines for Minors" intended to promote dialogue among the parties involved and to provide an opportunity to discuss reasons for the reluctance to apply for PUMA licenses. Speakers specialised in paediatric and adolescent medicine as well as those from licensing authorities, the Federal Joint Committee (Gemeinsamer Bundesausschuss, G‑BA), the pharmaceutical industry and the federal ministries presented problems and possible solutions from their point of view with the aim of making the PUMA license instrument more attractive.

In the search of new robust and environmental-friendly analytical methods able to answer quantitative issues in pharmacology, we explore liquid chromatography (LC) associated with elemental mass spectrometry (ICP-MS) to monitor peptides in such complex biological matrices. The novelty is to use mass spectrometry to replace radiolabelling and radioactivity measurements, which represent up-to now the gold standard to measure organic compound concentrations in life science. As a proof of concept, we choose the vasopressin (AVP)/V1A receptor system for model pharmacological assays. The capacity of ICP-MS to provide highly sensitive quantitation of metallic and hetero elements, whatever the sample medium, prompted us to investigate this technique in combination with appropriate labelling of the peptide of interest. Selenium, that is scarcely present in biological media, was selected as a good compromise between ICP-MS response, covalent tagging ability using conventional sulfur chemistry and peptide detection specificity. Applying selenium monitoring by elemental mass spectrometry in pharmacology is challenging due to the very high salt content and organic material complexity of the samples that produces polyatomic aggregates and thus potentially mass interferences with selenium detection. Hyphenation with a chromatographic separation was found compulsory. Noteworthy, we aimed to develop a straightforward quantitative protocol that can be performed in any laboratory equipped with a standard macrobore LC-ICP-MS system, in order to avoid time-consuming sample treatment or special implementation of instrumental set-up, while allowing efficient suppression of all mass interferences to reach the targeted sensitivity. Significantly, a quantification limit of 57 ng Se L-1 (72 femtomoles of injected Se) was achieved, the samples issued from the pharmacological assays being directly introduced into the LC-ICP-MS system. The established method was successfully validated and applied to the measurement of the vasopressin ligand affinity for its V1A receptor through the determination of the dissociation constant (Kd) which was compared to the one recorded with conventional radioactivity assays.

Introduction: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated., Objective: The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data., Methods: Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects)., Results: In the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 ± 1.98 and 6.38 ± 1.50 ms in women and men, respectively., Conclusion: The QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points.

Biomarkers have the potential to expedite drug development, increase patient safety, and optimize clinical response. Yet few have achieved regulatory qualification. A survey was conducted to clarify industry's perspective on biomarker qualification and identify the most promising biomarkers for drug development. The results across toxicities/clinical areas highlight challenges in regulatory qualification, although early prioritization and alignment on an evidentiary standard framework are key factors in facilitating biomarker development and qualification., (© 2015 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

David Triggle's career as an educator, researcher, essayist and ethicist in many ways has paralleled the post WWII emergence of the "biomedical research ecosystem" that originated in the concept of the "Endless Frontier". In the ensuing 70 years biomedical research has irreparably changed the nature of society with vaccines, the birth control pill and new generations of drugs and biologics to treat infections, sexually transmitted diseases, psychiatric disorders and cardiovascular diseases. These have led to a shift in the population demographic to the elderly and the chronically sick leading to major issues in the provision of effective and affordable healthcare for much of the world's population. In the present article, in addition to providing a brief biography and an appreciation of David Triggle's contributions to science, the authors expand on three topics in which he has had a major interest: improving the quality, reproducibility and relevance of basic biomedical research; declining career opportunities for graduates in an era of decreased funding-the end of the "Endless Frontier"; and the dynamic between the provision for universal healthcare and the dysfunctional, wasteful and politicized systems of the current medical-industrial complex in delivering healthcare., (Copyright © 2015 Elsevier Inc. All rights reserved.)

As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities. It also encourages participation in SPS activities by other professionals (toxicologists, clinicians, academics) who wish to broaden their professional expertise. It provides an opportunity for candidates to strengthen their fundamental scientific knowledge, and stimulates the sharing of data, methods and model development in the form of publications and presentations on relevant topics in SP. Accreditation in SP occurs after candidates successfully complete a written certification examination conducted at the annual SPS meeting. The DSP exam consists primarily of material pertinent to the conduct of SP vital function core battery studies (i.e., cardiovascular, respiratory and central nervous systems), supplemental SP studies (i.e., renal/urinary, gastrointestinal, immunology, and hematology), Regulatory Guidelines (ICH Guidelines) as well as relevant cross-functional knowledge (e.g., physiology, pharmacology, toxicology, biochemistry, pathology, pharmacokinetics, dosing formulation, analytical methods, and statistics). Maintenance of the DSP certification results from the accrual of credits which are gained from a range of educational and scientific contributions. Eligibility requirements include a combination of at least a bachelor degree in science and two years of relevant professional SP experience and one poster presentation on a SP topic as first author at a recognized major scientific meeting., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Clinical practice guidelines (CPGs) and structured product labels (SPLs) are both intended to promote evidence-based medical practices and guide clinicians' prescribing decisions. However, it is unclear how well CPG recommendations about pharmacologic therapies for certain diseases match SPL indications for recommended drugs. In this study, we use publicly available data and text mining methods to examine drug-disease associations in CPG recommendations and SPL treatment indications for 15 common chronic conditions. Preliminary results suggest that there is a mismatch between guideline-recommended pharmacologic therapies and SPL indications. Conflicting or inconsistent recommendations and indications may complicate clinical decision making and implementation or measurement of best practices.

The theme of this month's issue of Clinical Pharmacology & Therapeutics is pharmacometrics. When looking back at the early days of pharmacometrics, current contributions to the drug development process look impressive. The questions are whether the original promise is being kept and how the impact can become even greater.

The mission of the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee is to provide best practices and recommendations for standard pharmacometric analyses-e.g., population pharmacokinetics/pharmacodynamics (PK/PD), exposure-response, disease models-with the goal of increasing consistency, productivity, quality, communication, and impact of pharmacometrics on decision making. We present the progress and plans of the committee and call for volunteers to start new initiatives.

Descriptive, exploratory, and inferential statistics are necessary components of hypothesis-driven biomedical research. Despite the ubiquitous need for these tools, the emphasis on statistical methods in pharmacology has become dominated by inferential methods often chosen more by the availability of user-friendly software than by any understanding of the data set or the critical assumptions of the statistical tests. Such frank misuse of statistical methodology and the quest to reach the mystical α<0.05 criteria has hampered research via the publication of incorrect analysis driven by rudimentary statistical training. Perhaps more critically, a poor understanding of statistical tools limits the conclusions that may be drawn from a study by divorcing the investigator from their own data. The net result is a decrease in quality and confidence in research findings, fueling recent controversies over the reproducibility of high profile findings and effects that appear to diminish over time. The recent development of "omics" approaches leading to the production of massive higher dimensional data sets has amplified these issues making it clear that new approaches are needed to appropriately and effectively mine this type of data. Unfortunately, statistical education in the field has not kept pace. This commentary provides a foundation for an intuitive understanding of statistics that fosters an exploratory approach and an appreciation for the assumptions of various statistical tests that hopefully will increase the correct use of statistics, the application of exploratory data analysis, and the use of statistical study design, with the goal of increasing reproducibility and confidence in the literature., (Copyright © 2013. Published by Elsevier Inc.)

Continuing development of safe and effective new medicines is critically important for global health, social prosperity and the economy. The drug discovery-development pipeline depends critically on close partnerships between scientists and clinicians and on educational programmes that ensure that the pharmacological workforce, in its broadest sense, is fit for purpose. Here I consider factors that have influenced the development of basic and clinical pharmacology in UK universities over the past 40 years and discuss ways in which basic pharmacologists, clinical pharmacologists and scientists from different disciplines can work together effectively, while retaining their professional identities and fostering developments in their disciplines. Specifically, I propose the establishment of Institutes of Drug Discovery and Development, whose activities could include development and implementation of a translational pharmacology research strategy, drawing on the collective expertise of the membership and the university as whole; provision of a forum for regular seminars and symposia to promote the discipline, encourage collaboration and develop a cohesive community; provision of a research advisory service, covering, for example, data management, applications for ethics permission, clinical trials design, statistics and regulatory affairs; liaison with potential funders and leadership of major funding bids, including funding for doctoral training; provision of advice on intellectual property protection and the commercialization of research; liaison with corporate partners to facilitate collaboration, knowledge transfer and effective translation; and leadership of undergraduate and postgraduate education in basic and clinical pharmacology and related sciences for medical and science students, including continuing professional development and transferable skills., (© 2012 The Author. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) under varying conditions (100% air versus 5% CO2-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations., (2010 Elsevier Inc. All rights reserved.)

Previous studies have pointed out the question of effective training and information to health professionals on pharmacovigilance. The lack of training is known to induce inadequate use of drugs and noncompliance of patients. Pharmacology teaching is performed in the third year of medical studies at the Toulouse Faculty of Medicine. The aim of the study was to investigate the perception of risk of adverse drug reactions (ADRs) by medical students at the end of the one year pharmacology course and two years later, after clinical training period. Sixty-seven students were interviewed in May 2005 and in October 2007. Visual analogue scales were used to define a score of perceived risk of ADRs associated with each drug class (ranking from 0 to 10) before and after pharmacology training. The drug classes evaluated were antibiotics, anticoagulants, antidepressants, aspirin, contraceptive pill, corticosteroids, drugs for arterial hypertension, drugs for diabetes (other than insulin), hypnotics, hypocholesterolaemic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), postmenopausal hormone replacement therapy and tranquilisers. After pharmacology courses (May 2005), antidepressants were ranked as the most dangerous drugs by medical students [median score (25th-75th centiles): 7.7 (6.3-8.6)], followed by anticoagulants [7.6 (6.6-8.4)] and hypnotics [7.4 (6.1-8.1)]. Contraceptive pills was listed in the last position [median score [4.7 (2.2-6.7)]. Two years later (October 2007), anticoagulants moved into the first position [8.3 (7.3-9.2)], followed by NSAIDs [6.9 (5.0-8.4)] and aspirin [6.8 (5.8-8.4)]. Contraceptive pills remained in the last position. No change was observed for NSAIDs and aspirin, still ranked as dangerous drugs by medical students after clinical training. Values of perceived risk were significantly increased for anticoagulant (+9.2%, P < 0.01) and hypoglycemiant drugs (+27.7%, P < 0.0001). The perceived risk significantly decreased for hypocholesterolaemic (-14.3%, P < 0.0001) and antidepressant drugs (-19.5%, P < 0.0001), but not for hypnotics. The study shows that the perception of risk of ADRs by medical students was modified after clinical training. They were still aware of potentially serious ADRs associated with anticoagulants, aspirin or NSAIDs, but they remained less cautious for drugs such as antidepressants. Additional pharmacology training at the end of medical studies will be useful.

The technique of observing cellular interactions in real time using intravital microscopy is now a recognised technique in many laboratories. This review highlights the potential uses and pitfalls of this form of microscopy in drug research. This review covers topics such as applications of this highly versatile technique, the choice of vascular bed available (with particular emphasis on the cremaster muscle, the mesentery and the brain), and the types of measurements that can be collected. Where possible, we have provided examples and technical advice to aid the use of this technique in research. This article is not intended to be a complete overview of the use of intravital microscopy in drug research, and readers are encouraged to refer to the references engaged within., (Copyright 2010 Elsevier Inc. All rights reserved.)

Using the strictly same parameters (identical two publication years (2004-2005) and identical one-year citation window (2006)), impact factor (IF) 2006 was compared with h-index 2006 for one sample of "pharmacology and pharmacy" journals computed from the ISI Web of Science. For this sample, the IF and the h-index rankings of the journals are very different. The correlation coefficient between the IF and the h-index is low for "pharmacology and pharmacy" journals. The IF and h-index can be completely complementary when evaluating journals of the same scientific discipline., (2010 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: It has become apparent in recent years that there is a need for a substantial improvement in the processes used to clarify the inter-relationships between a compound's pharmacokinetic (PK) characteristics, its target actions and its safety profile. This is particularly challenging because most of the techniques currently used to obtain meaningful data involve low efficiency animal studies. To maximize the value of such in vivo studies, time and resources need to be better utilized. One way of making major advances is to adopt an integrative approach to designing and analysing in vivo pharmacodynamic (PD) studies. In this paper we address experimental design issues related to maximizing the information content about target engagement. Refined integration of PK and PD (known as 'quantitative pharmacology' or a PKPD approach) is advocated, enabling clarification of the interdependence of a drug's pharmacological properties on its target physiological system(s) and its systemic exposure characteristics., Methods: Several in vivo pharmacological Case Studies are presented which are used to illustrate the discussion of issues of experimental design. The impact of rate, extent and mode of administration is discussed from a pharmacological viewpoint, and we examine the consequences of temporal differences between concentration and response from the perspective of experimental design. We also consider the importance of differences in plasma protein binding (PPB) on our ability to assess a pharmacodynamic property or safety margin, and examine the usefulness of measuring ex vivo PPB. Finally, we outline the value of implementing a clearly pre-determined, integrated work flow to generate, validate and maximize in vivo PKPD or preclinical disease model data, and summarize the key issues of experimental design., Results and Discussion: Quantitative pharmacological reasoning focuses on concentration-response and response-time relationships with special emphasis on the impact of drugs on disease (Levy, 1993) and this perspective was written to raise awareness among in vivo scientists as to why PKPD integration is essential in their studies., (Copyright 2010 Elsevier Inc. All rights reserved.)

It has become increasingly difficult to perform animal experiments, because of issues related to the procurement of animals, and strict regulations and ethical issues related to their use. As a result, it is felt that the teaching of pharmacology should be more clinically oriented and that unnecessary animal experimentation should be avoided. Although a number of computer simulation models (CSMs) are available, they are not being widely used. Interactive demonstrations were conducted to encourage the departmental faculty to use CSMs. Four different animal experiments were selected, that dealt with actions of autonomic drugs. The students observed demonstrations of animal experiments involving conventional methods and the use of CSMs. This was followed by hands-on experience of the same experiment, but using CSMs in small groups, instead of hands-on experience with the animal procedures. Test scores and feedback showed that there was better understanding of the mechanisms of action of the drugs, gained in a shorter time. The majority of the students found the teaching programme used to be good to excellent. CSMs can be used repeatedly and independently by students, and this avoids unnecessary experimentation and also causing pain and trauma to animals. The CSM programme can be implemented in existing teaching schedules for pharmacology undergraduate teaching with basic infrastructure support, and is readily adaptable for use by other institutes., (2009 FRAME.)

There is increasing recognition of the need to identify specific sublethal effects of chemicals, such as reproductive toxicity, and specific modes of actions of the chemicals, such as interference with the endocrine system. To achieve these aims requires criteria which provide a basis to interpret study findings so as to separate these specific toxicities and modes of action from not only acute lethality per se but also from severe inanition and malaise that non-specifically compromise reproductive capacity and the response of endocrine endpoints. Mammalian toxicologists have recognized that very high dose levels are sometimes required to elicit both specific adverse effects and present the potential of non-specific "systemic toxicity". Mammalian toxicologists have developed the concept of a maximum tolerated dose (MTD) beyond which a specific toxicity or action cannot be attributed to a test substance due to the compromised state of the organism. Ecotoxicologists are now confronted by a similar challenge and must develop an analogous concept of a MTD and the respective criteria. As examples of this conundrum, we note recent developments in efforts to validate protocols for fish reproductive toxicity and endocrine screens (e.g. some chemicals originally selected as 'negatives' elicited decreases in fecundity or changes in endpoints intended to be biomarkers for endocrine modes of action). Unless analogous criteria can be developed, the potentially confounding effects of systemic toxicity may then undermine the reliable assessment of specific reproductive effects or biomarkers such as vitellogenin or spiggin. The same issue confronts other areas of aquatic toxicology (e.g., genotoxicity) and the use of aquatic animals for preclinical assessments of drugs (e.g., use of zebrafish for drug safety assessment). We propose that there are benefits to adopting the concept of an MTD for toxicology and pharmacology studies using fish and other aquatic organisms and the development of sound criteria for data interpretation when the exposure of organisms has exceeded the MTD. While the MTD approach is well established for oral, topical, inhalational or injection exposure routes in mammalian toxicology, we propose that for exposure of aquatic organisms via immersion, the term Maximum Tolerated Concentration (MTC) is more appropriate.

Aim: Clinical pharmacology at the Leiden University Medical Centre is primarily taught by the Teaching Resource Centre's (TRC) Pharmacology database. The TRC program contains schematic graphics using a unique icon language, explanation texts and feedback questions to explain pharmacology as it pertains to pathophysiology. Nearly each course of the curriculum has a chapter in the TRC database offered for self-study. Since using the TRC program is not compulsory, the question remains whether students benefit from using it., Methods: We compared the parameters of log-in attempts and time spent at each topic with students' final exam grades. Instead of looking at the regression of time spent on TRC on grade for one course, we looked at the individual student regression of time spent on TRC for different courses on grades. Spending more time using the TRC being associated with higher grades within an individual is a more powerful result than between students within a course, as better students are likely to spend more time using the TRC., Results: Students increasingly used the program throughout the curriculum. More importantly, the time spent using the program showed that increased TRC use by an individual student is associated with a (small) increase in grade. As expected for a noncompulsory activity, better students (those with higher than average exam scores) logged in to the TRC more frequently, but poorer students appeared to have a larger benefit., Conclusions: An increase in TRC use by an individual student correlates with an increase in course grades.