Management of Muscle Spasms in Adult Patients with Cerebral Palsy.

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.

Youth Suicide: A Population Crying for Help? A System Overloaded? Who Can Help?

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.

Lower scores in pharmacokinetics than in pharmacodynamics assessment among students in a health and life sciences curriculum.

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.

New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology.

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.

New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology.

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 explanation 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.

Evaluating the Pharmacological Management of Terminal Delirium in Imminently Dying Patients With and Without the Comfort Measure Order Set.

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.

Toward a Consensus on Applying Quantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics in Translational Pharmacology Research: A White Paper.

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.

Nordic symposium on "toxicology and pharmacology without animal experiments-Will it be possible in the next 10 years?"

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.

Rethinking Pharmacological Nomenclature.

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.

An overview of the safety pharmacology society strategic plan.

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.

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications.

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.

Redefining the pharmacology and pharmacy subject category in the journal citation reports using medical subject headings (MeSH).

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.

Safety pharmacology methods and models in an evolving regulatory environment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2016 Safety Pharmacology Society (SPS), Canadian Society of Pharmacology and Therapeutics (CSPT), and Japanese Safety Pharmacology Society (JSPS) joint meeting held in Vancouver, B.C., Canada. This issue of JPTM continues the tradition of providing a publication summary of articles primarily presented at the joint meeting with direct bearing on the discipline of SP. As the regulatory landscape is expected to evolve with revision announced for the existing guidance document on non-clinical proarrhythmia risk assessment (ICHS7B) there is also imminent inception of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. Thus, the field of SP is dynamically progressing with characterization and implementation of numerous alternative non-clinical safety models. Novel method development and refinement in all areas of the discipline are reflected in the content.

Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative.

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 (INa), L-type Ca2+ current (Ica-L), and K+ currents (Ito, IK1, IKs, and IKr), 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 (IKr), 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.

Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex.

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.

Motivation and competence of participants in a learner-centered student-run clinic: an exploratory pilot study.

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.

Standardization and validation of objective structured practical examination in pharmacology: Our experience and lessons learned.

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.