Providing data science support for systems pharmacology and its implications to drug discovery.

PubMed

Hart, Thomas; Xie, Lei

2016-01-01

The conventional one-drug-one-target-one-disease drug discovery process has been less successful in tracking multi-genic, multi-faceted complex diseases. Systems pharmacology has emerged as a new discipline to tackle the current challenges in drug discovery. The goal of systems pharmacology is to transform huge, heterogeneous, and dynamic biological and clinical data into interpretable and actionable mechanistic models for decision making in drug discovery and patient treatment. Thus, big data technology and data science will play an essential role in systems pharmacology. This paper critically reviews the impact of three fundamental concepts of data science on systems pharmacology: similarity inference, overfitting avoidance, and disentangling causality from correlation. The authors then discuss recent advances and future directions in applying the three concepts of data science to drug discovery, with a focus on proteome-wide context-specific quantitative drug target deconvolution and personalized adverse drug reaction prediction. Data science will facilitate reducing the complexity of systems pharmacology modeling, detecting hidden correlations between complex data sets, and distinguishing causation from correlation. The power of data science can only be fully realized when integrated with mechanism-based multi-scale modeling that explicitly takes into account the hierarchical organization of biological systems from nucleic acid to proteins, to molecular interaction networks, to cells, to tissues, to patients, and to populations.

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

PubMed

Venkatakrishnan, K; Friberg, L E; Ouellet, D; Mettetal, J T; Stein, A; Trocóniz, I F; Bruno, R; Mehrotra, N; Gobburu, J; Mould, D R

2015-01-01

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety. © 2014 American Society for Clinical Pharmacology and Therapeutics.

A quantitative systems physiology model of renal function and blood pressure regulation: Model description.

PubMed

Hallow, K M; Gebremichael, Y

2017-06-01

Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses. Here we present a model of renal physiology and control mechanisms involved in maintaining sodium and water homeostasis. This model represents the core renal physiological processes involved in many research questions in drug development. The model runs in R and the code is made available. In a companion article, we present a case study using the model to explore mechanisms and pharmacology of salt-sensitive hypertension. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Quantitative Systems Pharmacology Model of NO Metabolome and Methemoglobin Following Long-Term Infusion of Sodium Nitrite in Humans

PubMed Central

Vega-Villa, K; Pluta, R; Lonser, R; Woo, S

2013-01-01

A long-term sodium nitrite infusion is intended for the treatment of vascular disorders. Phase I data demonstrated a significant nonlinear dose-exposure-toxicity relationship within the therapeutic dosage range. This study aims to develop a quantitative systems pharmacology model characterizing nitric oxide (NO) metabolome and methemoglobin after sodium nitrite infusion. Nitrite, nitrate, and methemoglobin concentration–time profiles in plasma and RBC were used for model development. Following intravenous sodium nitrite administration, nitrite undergoes conversion in RBC and tissue. Nitrite sequestered by RBC interacts more extensively with deoxyhemoglobin, which contributes greatly to methemoglobin formation. Methemoglobin is formed less-than-proportionally at higher nitrite doses as characterized with facilitated methemoglobin removal. Nitrate-to-nitrite reduction occurs in tissue and via entero-salivary recirculation. The less-than-proportional increase in nitrite and nitrate exposure at higher nitrite doses is modeled with a dose-dependent increase in clearance. The model provides direct insight into NO metabolome disposition and is valuable for nitrite dosing selection in clinical trials. PMID:23903463

Bedside to Bench: Integrating Quantitative Clinical Pharmacology and Reverse Translation to Optimize Drug Development.

PubMed

Gibbs, John P; Menon, Rajeev; Kasichayanula, Sreeneeranj

2018-02-01

With so much emphasis on reducing attrition and becoming more efficient in the delivery of healthcare, there are many opportunities to leverage existing clinical data in drug development and to foster the practice of reverse translation. The application of quantitative approaches to convert clinical trial and real-world data to knowledge will continue to drive innovation. Herein we discuss recent examples of reverse translation and consider future opportunities to capture critical clinical knowledge to inform decision-making in drug development. © 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.

PubMed

Stroh, M; Carlile, D J; Li, C-C; Wagg, J; Ribba, B; Ramanujan, S; Jin, J; Xu, J; Charoin, J-E; Xhu, Z-X; Morcos, P N; Davis, J D; Phipps, A

2015-09-01

Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT.

Graphical Modeling Meets Systems Pharmacology.

PubMed

Lombardo, Rosario; Priami, Corrado

2017-01-01

A main source of failures in systems projects (including systems pharmacology) is poor communication level and different expectations among the stakeholders. A common and not ambiguous language that is naturally comprehensible by all the involved players is a boost to success. We present bStyle, a modeling tool that adopts a graphical language close enough to cartoons to be a common media to exchange ideas and data and that it is at the same time formal enough to enable modeling, analysis, and dynamic simulations of a system. Data analysis and simulation integrated in the same application are fundamental to understand the mechanisms of actions of drugs: a core aspect of systems pharmacology.

Graphical Modeling Meets Systems Pharmacology

PubMed Central

Lombardo, Rosario; Priami, Corrado

2017-01-01

A main source of failures in systems projects (including systems pharmacology) is poor communication level and different expectations among the stakeholders. A common and not ambiguous language that is naturally comprehensible by all the involved players is a boost to success. We present bStyle, a modeling tool that adopts a graphical language close enough to cartoons to be a common media to exchange ideas and data and that it is at the same time formal enough to enable modeling, analysis, and dynamic simulations of a system. Data analysis and simulation integrated in the same application are fundamental to understand the mechanisms of actions of drugs: a core aspect of systems pharmacology. PMID:28469411

Use of quantitative pharmacology tools to improve malaria treatments.

PubMed

Davis, Timothy M E; Moore, Brioni R; Salman, Sam; Page-Sharp, Madhu; Batty, Kevin T; Manning, Laurens

2016-01-01

The use of pharmacokinetic (PK) and pharmacodynamic (PD) data to inform antimalarial treatment regimens has accelerated in the past few decades, due in no small part to the stimulus provided by progressive development of parasite resistance to most of the currently available drugs. An understanding of the disposition, interactions, efficacy and toxicity of the mainstay of contemporary antimalarial treatment, artemisinin combination therapy (ACT), has been facilitated by PK/PD studies which have been used to refine treatment regimens across the spectrum of disease, especially in special groups including young children and pregnant women. The present review highlights recent clinically-important examples of the ways in which these quantitative pharmacology tools have been applied to improve ACT, as well as 8-aminoquinoline use and the characterisation of novel antimalarial therapies such as the spiroindolones.

Microdialysis as an Important Technique in Systems Pharmacology-a Historical and Methodological Review.

PubMed

Hammarlund-Udenaes, Margareta

2017-09-01

Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

Clinical application of a light-pen computer system for quantitative angiography

NASA Technical Reports Server (NTRS)

Alderman, E. L.

1975-01-01

The paper describes an angiographic analysis system which uses a video disk for recording and playback, a light-pen for data input, minicomputer processing, and an electrostatic printer/plotter for hardcopy output. The method is applied to quantitative analysis of ventricular volumes, sequential ventriculography for assessment of physiologic and pharmacologic interventions, analysis of instantaneous time sequence of ventricular systolic and diastolic events, and quantitation of segmental abnormalities. The system is shown to provide the capability for computation of ventricular volumes and other measurements from operator-defined margins by greatly reducing the tedium and errors associated with manual planimetry.

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use.

PubMed

Nayak, Satyaprakash; Sander, Oliver; Al-Huniti, Nidal; de Alwis, Dinesh; Chain, Anne; Chenel, Marylore; Sunkaraneni, Soujanya; Agrawal, Shruti; Gupta, Neeraj; Visser, Sandra A G

2018-03-01

Quantitative pharmacology (QP) applications in translational medicine, drug-development, and therapeutic use were crowd-sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial-burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model-informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy. © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Systems pharmacology - Towards the modeling of network interactions.

PubMed

Danhof, Meindert

2016-10-30

Mechanism-based pharmacokinetic and pharmacodynamics (PKPD) and disease system (DS) models have been introduced in drug discovery and development research, to predict in a quantitative manner the effect of drug treatment in vivo in health and disease. This requires consideration of several fundamental properties of biological systems behavior including: hysteresis, non-linearity, variability, interdependency, convergence, resilience, and multi-stationarity. Classical physiology-based PKPD models consider linear transduction pathways, connecting processes on the causal path between drug administration and effect, as the basis of drug action. Depending on the drug and its biological target, such models may contain expressions to characterize i) the disposition and the target site distribution kinetics of the drug under investigation, ii) the kinetics of target binding and activation and iii) the kinetics of transduction. When connected to physiology-based DS models, PKPD models can characterize the effect on disease progression in a mechanistic manner. These models have been found useful to characterize hysteresis and non-linearity, yet they fail to explain the effects of the other fundamental properties of biological systems behavior. Recently systems pharmacology has been introduced as novel approach to predict in vivo drug effects, in which biological networks rather than single transduction pathways are considered as the basis of drug action and disease progression. These models contain expressions to characterize the functional interactions within a biological network. Such interactions are relevant when drugs act at multiple targets in the network or when homeostatic feedback mechanisms are operative. As a result systems pharmacology models are particularly useful to describe complex patterns of drug action (i.e. synergy, oscillatory behavior) and disease progression (i.e. episodic disorders). In this contribution it is shown how physiology-based PKPD and

A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine

PubMed Central

Stern, Andrew M.; Schurdak, Mark E.; Bahar, Ivet; Berg, Jeremy M.; Taylor, D. Lansing

2016-01-01

Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)–driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. PMID:26962875

Quantitative systems toxicology

PubMed Central

Bloomingdale, Peter; Housand, Conrad; Apgar, Joshua F.; Millard, Bjorn L.; Mager, Donald E.; Burke, John M.; Shah, Dhaval K.

2017-01-01

The overarching goal of modern drug development is to optimize therapeutic benefits while minimizing adverse effects. However, inadequate efficacy and safety concerns remain to be the major causes of drug attrition in clinical development. For the past 80 years, toxicity testing has consisted of evaluating the adverse effects of drugs in animals to predict human health risks. The U.S. Environmental Protection Agency recognized the need to develop innovative toxicity testing strategies and asked the National Research Council to develop a long-range vision and strategy for toxicity testing in the 21st century. The vision aims to reduce the use of animals and drug development costs through the integration of computational modeling and in vitro experimental methods that evaluates the perturbation of toxicity-related pathways. Towards this vision, collaborative quantitative systems pharmacology and toxicology modeling endeavors (QSP/QST) have been initiated amongst numerous organizations worldwide. In this article, we discuss how quantitative structure-activity relationship (QSAR), network-based, and pharmacokinetic/pharmacodynamic modeling approaches can be integrated into the framework of QST models. Additionally, we review the application of QST models to predict cardiotoxicity and hepatotoxicity of drugs throughout their development. Cell and organ specific QST models are likely to become an essential component of modern toxicity testing, and provides a solid foundation towards determining individualized therapeutic windows to improve patient safety. PMID:29308440

A Quantitative Ethnopharmacological Documentation of Natural Pharmacological Agents Used by Pediatric Patients in Mauritius

PubMed Central

Mahomoodally, M. Fawzi; Sreekeesoon, D. Priyamka

2014-01-01

The pediatric population constitutes the most vulnerable patients due to a dearth of approved drugs. Consequently, there is a pressing need to probe novel natural pharmacological agents in an endeavour to develop new drugs to address pediatric illnesses. To date, no studies have explored the use of natural therapies for pediatric health care in Mauritius. Parents (n = 325) from different regions of the island were interviewed. Quantitative indexes such as fidelity level (FL), informant consensus factor (F IC), and use-value (UV) were calculated. Thirty-two plants were reported to be used by pediatric patients. Gastrointestinal disorders (F IC = 0.97) encompassing regurgitation, infantile colic, and stomach aches were the most common ailments managed with herbs. Matricaria chamomilla used for infantile colic and its pharmacological properties has previously been documented for pediatric patients. Product from A. mellifera (UV = 0.75) was the most utilized zootherapy for managing cough. Most plants and animal products reported in this study have bioactive constituents supported by existing scientific literature but their use for the pediatric population is scant. The present ethnopharmacological study has opened new perspectives for further research into their pharmacology, which can subsequently support and facilitate timely pediatric medicinal product development. PMID:24949418

Drug-disease modeling in the pharmaceutical industry - where mechanistic systems pharmacology and statistical pharmacometrics meet.

PubMed

Helmlinger, Gabriel; Al-Huniti, Nidal; Aksenov, Sergey; Peskov, Kirill; Hallow, Karen M; Chu, Lulu; Boulton, David; Eriksson, Ulf; Hamrén, Bengt; Lambert, Craig; Masson, Eric; Tomkinson, Helen; Stanski, Donald

2017-11-15

Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP). We next describe the convergence - or rather selected integration - of PMX and QSP approaches into 'middle-out' drug-disease models, which retain selected mechanistic aspects, while remaining parsimonious, fit-for-purpose, and able to address variability and the testing of covariates. We further propose development opportunities for drug-disease systems models, to increase their utility and applicability throughout the preclinical and clinical spectrum of pharmaceutical R&D. Copyright © 2017 Elsevier B.V. All rights reserved.

A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine.

PubMed

Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet; Berg, Jeremy M; Taylor, D Lansing

2016-07-01

Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)-driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. © 2016 Society for Laboratory Automation and Screening.

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use

PubMed Central

Nayak, Satyaprakash; Sander, Oliver; Al‐Huniti, Nidal; de Alwis, Dinesh; Chain, Anne; Chenel, Marylore; Sunkaraneni, Soujanya; Agrawal, Shruti; Gupta, Neeraj

2018-01-01

Quantitative pharmacology (QP) applications in translational medicine, drug‐development, and therapeutic use were crowd‐sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial‐burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model‐informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy. PMID:29330855

Ginsenoside Re: pharmacological effects on cardiovascular system.

PubMed

Peng, Lu; Sun, Shi; Xie, Lai-Hua; Wicks, Sheila M; Xie, Jing-Tian

2012-08-01

Ginsenosides are the bioactive constituents of ginseng, a key herb in traditional Chinese medicine. As a single component of ginseng, ginsenoside Re (G-Re) belongs to the panaxatriol group. Many reports demonstrated that G-Re possesses the multifaceted beneficial pharmacological effects on cardiovascular system. G-Re has negative effect on cardiac contractility and autorhythmicity. It causes alternations in cardiac electrophysiological properties, which may account for its antiarrhythmic effect. In addition, G-Re also exerts antiischemic effect and induces angiogenic regeneration. In this review, we first outline the chemistry and the pharmacological effects of G-Re on the cardiovascular system. © 2011 Blackwell Publishing Ltd.

Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine.

PubMed

Antman, Elliott; Weiss, Scott; Loscalzo, Joseph

2012-01-01

The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of clinical medicine and pharmacology. Principles of systems pharmacology can be applied to drug design and, ultimately, testing in human clinical trials. Rather than focusing exclusively on single drug targets, systems pharmacology examines the holistic response of a phenotype-dependent pathway or pathways to drug perturbation. Knowledge of individual pharmacogenetic profiles further modulates the responses to these drug perturbations, moving the field toward more individualized ('personalized') drug development. The speed with which the information required to assess these system responses and their genomic underpinnings is changing and the importance of identifying the optimal drug or drug combinations for maximal benefit and minimal risk require that clinical trial design strategies be adaptable. In this paper, we review the tenets of adaptive clinical trial design as they may apply to an era of expanding knowledge of systems pharmacology and pharmacogenomics, and clinical trail design in network medicine. Copyright © 2012 Wiley Periodicals, Inc.

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

PubMed Central

2014-01-01

Background Copper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. Results We found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu’s positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson’s disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin. Conclusions A functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations. PMID:24708151

Systems Biology, Systems Medicine, Systems Pharmacology: The What and The Why.

PubMed

Stéphanou, Angélique; Fanchon, Eric; Innominato, Pasquale F; Ballesta, Annabelle

2018-05-09

Systems biology is today such a widespread discipline that it becomes difficult to propose a clear definition of what it really is. For some, it remains restricted to the genomic field. For many, it designates the integrated approach or the corpus of computational methods employed to handle the vast amount of biological or medical data and investigate the complexity of the living. Although defining systems biology might be difficult, on the other hand its purpose is clear: systems biology, with its emerging subfields systems medicine and systems pharmacology, clearly aims at making sense of complex observations/experimental and clinical datasets to improve our understanding of diseases and their treatments without putting aside the context in which they appear and develop. In this short review, we aim to specifically focus on these new subfields with the new theoretical tools and approaches that were developed in the context of cancer. Systems pharmacology and medicine now give hope for major improvements in cancer therapy, making personalized medicine closer to reality. As we will see, the current challenge is to be able to improve the clinical practice according to the paradigm shift of systems sciences.

Pharmacology-based toxicity assessment: towards quantitative risk prediction in humans.

PubMed

Sahota, Tarjinder; Danhof, Meindert; Della Pasqua, Oscar

2016-05-01

Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits

Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo

PubMed Central

Ramsey, Simeon J; Attkins, Neil J; Fish, Rebecca; van der Graaf, Piet H

2011-01-01

BACKGROUND AND PURPOSE A series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF1) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan. EXPERIMENTAL APPROACH A non-equilibrium binding kinetic assay was developed to determine the receptor binding kinetics of non-peptide CRF1 antagonists. Nonlinear, mixed-effects modelling was used to obtain estimates of the compounds association and dissociation rates. We present an integrated pharmacokinetic–pharmacodynamic (PKPD) approach, whereby the time course of in vivo CRF1 receptor binding of novel compounds can be predicted on the basis of in vitro assays. KEY RESULTS The non-competitive antagonist behaviour appeared to be correlated to the CRF1 receptor off-rate kinetics. The integrated PKPD model suggested that, at least in a qualitative manner, the in vitro assay can be used to triage and select compounds for further in vivo investigations. CONCLUSIONS AND IMPLICATIONS This study provides evidence for a link between ligand offset kinetics and insurmountable/non-competitive antagonism at the CRF1 receptor. The exact molecular pharmacological nature of this association remains to be determined. In addition, we have developed a quantitative framework to study and integrate in vitro and in vivo receptor binding kinetic behaviour of CRF1 receptor antagonists in an efficient manner in a drug discovery setting. PMID:21449919

Outside-In Systems Pharmacology Combines Innovative Computational Methods With High-Throughput Whole Vertebrate Studies.

PubMed

Schulthess, Pascal; van Wijk, Rob C; Krekels, Elke H J; Yates, James W T; Spaink, Herman P; van der Graaf, Piet H

2018-04-25

To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside-in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high-throughput, low-resource dose-exposure-effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Effectiveness of Psychological and Pharmacological Treatments for Nocturnal Enuresis.

ERIC Educational Resources Information Center

Houts, Arthur C.; And Others

1994-01-01

Assesses overall effectiveness of psychological and pharmacological treatments, relative effectiveness of specific treatments, and moderators of treatment effectiveness for nocturnal enuretic children via quantitative integration of research. Findings confirm that more children benefit from psychological than from pharmacological interventions and…

Harnessing Big Data for Systems Pharmacology.

PubMed

Xie, Lei; Draizen, Eli J; Bourne, Philip E

2017-01-06

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

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders.

PubMed

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), c aenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

PubMed Central

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), caenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders. PMID:29093681

A Quantitative Analysis of Undisclosed Conflicts of Interest in Pharmacology Textbooks.

PubMed

Piper, Brian J; Telku, Hassenet M; Lambert, Drew A

2015-01-01

Disclosure of potential conflicts of interest (CoI) is a standard practice for many biomedical journals but not for educational materials. The goal of this investigation was to determine whether the authors of pharmacology textbooks have undisclosed financial CoIs and to identify author characteristics associated with CoIs. The presence of potential CoIs was evaluated by submitting author names (N = 403; 36.3% female) to a patent database (Google Scholar) as well as a database that reports on the compensation ($USD) received from 15 pharmaceutical companies (ProPublica's Dollars for Docs). All publications (N = 410) of the ten highest compensated authors from 2009 to 2013 and indexed in Pubmed were also examined for disclosure of additional companies that the authors received research support, consulted, or served on speaker's bureaus. A total of 134 patents had been awarded (Maximum = 18/author) to textbook authors. Relative to DiPiro's Pharmacotherapy: A Pathophysiologic Approach, contributors to Goodman and Gilman's Pharmacological Basis of Therapeutics and Katzung's Basic and Clinical Pharmacology were more frequently patent holders (OR = 6.45, P < .0005). Female authors were less likely than males to have > 1 patent (OR = 0.15, P < .0005). A total of $2,411,080 USD (28.3% for speaking, 27.0% for consulting, and 23.9% for research), was received by 53 authors (Range = $299 to $310,000/author). Highly compensated authors were from multiple fields including oncology, psychiatry, neurology, and urology. The maximum number of additional companies, not currently indexed in the Dollars for Docs database, for which an author had potential CoIs was 73. Financial CoIs are common among the authors of pharmacology and pharmacotherapy textbooks. Full transparency of potential CoIs, particularly patents, should become standard procedure for future editions of educational materials in pharmacology.

Harnessing Big Data for Systems Pharmacology

PubMed Central

Xie, Lei; Draizen, Eli J.; Bourne, Philip E.

2017-01-01

Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable. PMID:27814027

Quantitative and Systems Pharmacology. 1. In Silico Prediction of Drug-Target Interactions of Natural Products Enables New Targeted Cancer Therapy.

PubMed

Fang, Jiansong; Wu, Zengrui; Cai, Chuipu; Wang, Qi; Tang, Yun; Cheng, Feixiong

2017-11-27

Natural products with diverse chemical scaffolds have been recognized as an invaluable source of compounds in drug discovery and development. However, systematic identification of drug targets for natural products at the human proteome level via various experimental assays is highly expensive and time-consuming. In this study, we proposed a systems pharmacology infrastructure to predict new drug targets and anticancer indications of natural products. Specifically, we reconstructed a global drug-target network with 7,314 interactions connecting 751 targets and 2,388 natural products and built predictive network models via a balanced substructure-drug-target network-based inference approach. A high area under receiver operating characteristic curve of 0.96 was yielded for predicting new targets of natural products during cross-validation. The newly predicted targets of natural products (e.g., resveratrol, genistein, and kaempferol) with high scores were validated by various literature studies. We further built the statistical network models for identification of new anticancer indications of natural products through integration of both experimentally validated and computationally predicted drug-target interactions of natural products with known cancer proteins. We showed that the significantly predicted anticancer indications of multiple natural products (e.g., naringenin, disulfiram, and metformin) with new mechanism-of-action were validated by various published experimental evidence. In summary, this study offers powerful computational systems pharmacology approaches and tools for the development of novel targeted cancer therapies by exploiting the polypharmacology of natural products.

Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes.

PubMed

Fang, J; Cai, C; Wang, Q; Lin, P; Zhao, Z; Cheng, F

2017-03-01

Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology. Natural products with polypharmacological profiles have been demonstrated as promising agents for the development of novel cancer therapies. In this study, we developed an integrated systems pharmacology framework that facilitated identifying potential natural products that target mutated genes across 15 cancer types or subtypes in the realm of precision medicine. High performance was achieved for our systems pharmacology framework. In case studies, we computationally identified novel anticancer indications for several US Food and Drug Administration-approved or clinically investigational natural products (e.g., resveratrol, quercetin, genistein, and fisetin) through targeting significantly mutated genes in multiple cancer types. In summary, this study provides a powerful tool for the development of molecularly targeted cancer therapies through targeting the clinically actionable alterations by exploiting the systems pharmacology of natural products. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The Japanese Postmarketing Adverse Event Relief System: A Confluence of Regulatory Science, the Legal System, and Clinical Pharmacology.

PubMed

Tominaga, T; Miyazaki, S; Oniyama, Y; Weber, A D; Kondo, T

2017-08-01

The Japanese Postmarketing Relief System provides for compensation to patients with adverse reactions, based on the acknowledgment that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries' healthcare systems. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Concepts and challenges in quantitative pharmacology and model-based drug development.

PubMed

Zhang, Liping; Pfister, Marc; Meibohm, Bernd

2008-12-01

Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today's drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK-PD modeling, exposure-response modeling, pharmacometrics, quantitative pharmacology, and MBDD. MBDD is viewed as a paradigm and a mindset in which models constitute the instruments and aims of drug development efforts. MBDD covers the whole spectrum of the drug development process instead of being limited to a certain type of modeling technique or application area. The implementation of MBDD requires pharmaceutical companies to foster innovation and make changes at three levels: (1) to establish mindsets that are willing to get acquainted with MBDD, (2) to align processes that are adaptive to the requirements of MBDD, and (3) to create a closely collaborating organization in which all members play a role in MBDD. Pharmaceutical companies that are able to embrace the changes MBDD poses will likely be able to improve their success rate in drug development, and the beneficiaries will ultimately be the patients in need.

Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach[S

PubMed Central

Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A.; Ramanujan, Saroja

2016-01-01

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. PMID:26522778

Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach.

PubMed

Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A; Ramanujan, Saroja

2016-01-01

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Structural systems pharmacology: a new frontier in discovering novel drug targets.

PubMed

Tan, Hepan; Ge, Xiaoxia; Xie, Lei

2013-08-01

The modern target-based drug discovery process, characterized by the one-drug-one-gene paradigm, has been of limited success. In contrast, phenotype-based screening produces thousands of active compounds but gives no hint as to what their molecular targets are or which ones merit further research. This presents a question: What is a suitable target for an efficient and safe drug? In this paper, we argue that target selection should take into account the proteome-wide energetic and kinetic landscape of drug-target interactions, as well as their cellular and organismal consequences. We propose a new paradigm of structural systems pharmacology to deconvolute the molecular targets of successful drugs as well as to identify druggable targets and their drug-like binders. Here we face two major challenges in structural systems pharmacology: How do we characterize and analyze the structural and energetic origins of drug-target interactions on a proteome scale? How do we correlate the dynamic molecular interactions to their in vivo activity? We will review recent advances in developing new computational tools for biophysics, bioinformatics, chemoinformatics, and systems biology related to the identification of genome-wide target profiles. We believe that the integration of these tools will realize structural systems pharmacology, enabling us to both efficiently develop effective therapeutics for complex diseases and combat drug resistance.

Systems pharmacology augments drug safety surveillance

PubMed Central

Lorberbaum, Tal; Nasir, Mavra; Keiser, Michael J.; Vilar, Santiago; Hripcsak, George; Tatonetti, Nicholas P.

2014-01-01

Small molecule drugs are the foundation of modern medical practice yet their use is limited by the onset of unexpected and severe adverse events (AEs). Regulatory agencies rely on post-marketing surveillance to monitor safety once drugs are approved for clinical use. Despite advances in pharmacovigilance methods that address issues of confounding bias, clinical data of AEs are inherently noisy. Systems pharmacology– the integration of systems biology and chemical genomics – can illuminate drug mechanisms of action. We hypothesize that these data can improve drug safety surveillance by highlighting drugs with a mechanistic connection to the target phenotype (enriching true positives) and filtering those that do not (depleting false positives). We present an algorithm, the modular assembly of drug safety subnetworks (MADSS), to combine systems pharmacology and pharmacovigilance data and significantly improve drug safety monitoring for four clinically relevant adverse drug reactions. PMID:25670520

A quantitative systems pharmacology model of blood coagulation network describes in vivo biomarker changes in non-bleeding subjects.

PubMed

Lee, D; Nayak, S; Martin, S W; Heatherington, A C; Vicini, P; Hua, F

2016-12-01

Essentials Baseline coagulation activity can be detected in non-bleeding state by in vivo biomarker levels. A detailed mathematical model of coagulation was developed to describe the non-bleeding state. Optimized model described in vivo biomarkers with recombinant activated factor VII treatment. Sensitivity analysis predicted prothrombin fragment 1 + 2 and D-dimer are regulated differently. Background Prothrombin fragment 1 + 2 (F 1 + 2 ), thrombin-antithrombin III complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatically normal subjects or hemophilic patients. They are often used as safety or pharmacodynamic biomarkers for hemostatis-modulating therapies in the clinic, and provide insights into in vivo coagulation activity. Objectives To develop a quantitative systems pharmacology (QSP) model of the blood coagulation network to describe in vivo biomarkers, including F 1 + 2 , TAT, and D-dimer, under non-bleeding conditions. Methods The QSP model included intrinsic and extrinsic coagulation pathways, platelet activation state-dependent kinetics, and a two-compartment pharmacokinetics model for recombinant activated factor VII (rFVIIa). Literature data on F 1 + 2 and D-dimer at baseline and changes with rFVIIa treatment were used for parameter optimization. Multiparametric sensitivity analysis (MPSA) was used to understand key proteins that regulate F 1 + 2 , TAT and D-dimer levels. Results The model was able to describe tissue factor (TF)-dependent baseline levels of F 1 + 2 , TAT and D-dimer in a non-bleeding state, and their increases in hemostatically normal subjects and hemophilic patients treated with different doses of rFVIIa. The amount of TF required is predicted to be very low in a non-bleeding state. The model also predicts that these biomarker levels will be similar in hemostatically normal subjects and hemophilic patients. MPSA revealed that F 1 + 2 and TAT levels are highly correlated, and that D-dimer is

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

PubMed

Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin C; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Lee, Joo Yeon; Liu, Jiang; Mulugeta, Yeruk; Yu, Jingyu; Zhao, Ping; Sinha, Vikram

2016-07-01

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy. Copyright © 2016 U.S. Government work not protected by U.S. copyright.

Pharmacological MRI (phMRI) of the Human Central Nervous System.

PubMed

Lanfermann, H; Schindler, C; Jordan, J; Krug, N; Raab, P

2015-10-01

Pharmacological magnetic resonance imaging (phMRI) of the central nervous system (CNS) addresses the increasing demands in the biopharma industry for new methods that can accurately predict, as early as possible, whether novel CNS agents will be effective and safe. Imaging of physiological and molecular-level function can provide a more direct measure of a drug mechanism of action, enabling more predictive measures of drug activity. The availability of phMRI of the nervous system within the professional infrastructure of the Clinical Research Center (CRC) Hannover as proof of concept center ensures that advances in basic science progress swiftly into benefits for patients. Advanced standardized MRI techniques including quantitative MRI, kurtosis determination, functional MRI, and spectroscopic imaging of the entire brain are necessary for phMRI. As a result, MR scanners will evolve into high-precision measuring instruments for assessment of desirable and undesirable effects of drugs as the basic precondition for individually tailored therapy. The CRC's Imaging Unit with high-end large-scale equipment will allow the following unique opportunities: for example, identification of MR-based biomarkers to assess the effect of drugs (surrogate parameters), establishment of normal levels and reference ranges for MRI-based biomarkers, evaluation of the most relevant MRI sequences for drug monitoring in outpatient care. Another very important prerequisite for phMRI is the MHH Core Facility as the scientific and operational study unit of the CRC partner Hannover Medical School. This unit is responsible for the study coordination, conduction, complete study logistics, administration, and application of the quality assurance system based on required industry standards.

Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services.

PubMed

Karlsen Bjånes, Tormod; Mjåset Hjertø, Espen; Lønne, Lars; Aronsen, Lena; Andsnes Berg, Jon; Bergan, Stein; Otto Berg-Hansen, Grim; Bernard, Jean-Paul; Larsen Burns, Margrete; Toralf Fosen, Jan; Frost, Joachim; Hilberg, Thor; Krabseth, Hege-Merete; Kvan, Elena; Narum, Sigrid; Austgulen Westin, Andreas

2016-01-01

More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

PubMed Central

Chen, Yu; Palczewska, Grazyna; Mustafi, Debarshi; Golczak, Marcin; Dong, Zhiqian; Sawada, Osamu; Maeda, Tadao; Maeda, Akiko; Palczewski, Krzysztof

2013-01-01

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases. PMID:24231350

Pharmacological effects of Chinese herb aconite (fuzi) on cardiovascular system.

PubMed

Zhao, Dandan; Wang, Jie; Cui, Yanjing; Wu, Xinfang

2012-09-01

Fuzi (aconite, Radix Aconiti praeparata), a widely used Chinese herb, plays a significant role in the cardiovascular system. This is mainly reflected by Fuzi's cardiotonic effect, its protective effect on myocardial cells, and its effect on heart rate and rhythm, blood pressure, and hemodynamics. In this article, the pharmacological effects and the corresponding mechanisms of Fuzi (aconite) and its active components on cardiovascular system are reviewed.

Fuzzy pharmacology: theory and applications.

PubMed

Sproule, Beth A; Naranjo, Claudio A; Türksen, I Burhan

2002-09-01

Fuzzy pharmacology is a term coined to represent the application of fuzzy logic and fuzzy set theory to pharmacological problems. Fuzzy logic is the science of reasoning, thinking and inference that recognizes and uses the real world phenomenon that everything is a matter of degree. It is an extension of binary logic that is able to deal with complex systems because it does not require crisp definitions and distinctions for the system components. In pharmacology, fuzzy modeling has been used for the mechanical control of drug delivery in surgical settings, and work has begun evaluating its use in other pharmacokinetic and pharmacodynamic applications. Fuzzy pharmacology is an emerging field that, based on these initial explorations, warrants further investigation.

PHARMACOLOGY PART 1: INTRODUCTION TO PHARMAOCLOGY AND PHARMACODYNAMICS.

PubMed

Currie, Geoffrey M

2018-03-29

There is an emerging need for greater understanding of pharmacology principles amongst technical staff. Indeed, the responsibility of dose preparation and administration, under any level of supervision, demands foundation understanding of pharmacology. This is true for radiopharmaceuticals, contrast media and pharmaceutical interventions / adjunctive medications. Regulation around the same might suggest a need to embed pharmacology theory in undergraduate education programs and there is a need to disseminate that same foundation understanding to practicing clinicians. Moreover, pharmacology foundations can provide key understanding of the principles that underpin quantitative techniques (e.g. pharmacokinetics). This article is the first in a series of articles that aims to enhance the understanding of pharmacological principles relevant to nuclear medicine. This article will deal with the introductory concepts, terminology and principles that underpin the concepts to be discussed in the remainder of the series. The second article will build on the pharmacodynamic principles examined in this article with a treatment of pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in general nuclear medicine, the fourth pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in nuclear cardiology, and the fifth the pharmacology related to contrast media associated with computed tomography (CT) and magnetic resonance imaging (MRI). Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

CancerHSP: anticancer herbs database of systems pharmacology

NASA Astrophysics Data System (ADS)

Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

2015-06-01

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

PubMed Central

Benson, Helen E; Sharman, Joanna L; Mpamhanga, Chido P; Parton, Andrew; Southan, Christopher; Harmar, Anthony J; Ghazal, Peter

2017-01-01

Background and Purpose An ever‐growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single‐drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. Experimental Approach Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. Key Results We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi‐drug treatments with high efficacy and minimal off‐target effects. Conclusion and Implications We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses. PMID:28910500

Quercetin, kaempferol and isorhamnetin in Elaeagnus pungens Thunb. leaf: pharmacological activities and quantitative determination studies.

PubMed

Zhu, Ji-Xiao; Wen, Le; Zhong, Wei-Jin; Xiong, Li; Liang, Jian; Wang, Hong-Ling

2018-05-26

Elaeagnus pungens (E. pungens) leaf was documented to be very effective to treat asthma and chronic bronchitis both as traditional Chinese medicine and minority traditional medicine; yet the actual effective components still remain unknown. This work is to investigate the anti-inflammatory, antalgic and antitussive activities of E. pungens leaf, quercetin and kaempferol, and their contents in E. pungens leaf. Pharmacological experiments showed they could considerably reduce ear-swelling of mouse and relieve writhing reaction of mouse; they could also prevent mouse from coughing, significantly. These findings suggested quercetin and kaempferol are major effective components treating asthma and chronic bronchitis. Quantitative analysis results indicated the levels of quercetin, kaempferol and isorhamnetin varied greatly in different species of Elaeagnus and in different plant parts: E. pungens leaf is more similar to Elaeagnus umbellate leaf chemically; quercetin level is exceptionally high in Elaeagnus oldhami leaf; E. pungens leaf is a better medical part for treating asthma and chronic bronchitis in comparison with other parts. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Quantitative analysis of iris changes after physiologic and pharmacologic mydriasis in a rural Chinese population.

PubMed

Zhang, Ye; Li, Si Zhen; Li, Lei; He, Ming Guang; Thomas, Ravi; Wang, Ning Li

2014-04-24

To estimate and compare the change in iris cross-sectional area (IA) and iris volume (IV) following physiologic and pharmacologic pupil dilation in primary angle closure suspects (PACS) and normal subjects. Anterior segment-optical coherence tomography (AS-OCT) measurements in light, dark, and following pharmacologic dilation were obtained on 186 PACS and 224 normal subjects examined during the 5-year follow-up of the Handan Eye Study. Iris cross-sectional area, IV, and other biometric parameters calculated using the Zhongshan angle assessment program in the right eyes of all subjects were analyzed. The mean IA and IV decreased in dark compared with light and after pharmacologic dilation in both PACS and normal eyes. This change was statistically significant in normal eyes: light versus pharmacologic dilation for IA (P = 0.038) and for IV, both light versus dark (P = 0.031) and light versus pharmacologic dilation (P = 0.012). A longer axial length (P = 0.028) and a greater change in pupil diameter (PD) (P < 0.001) were associated with a larger decrease of IA for the light to dark comparison. A diagnosis of normal eyes (P = 0.011), larger PD in dark (P = 0.001), and a larger change in PD (P = 0.001) were associated with a larger decrease of IV from light to dark. The differences in iris behavior between PACS and normal rural Chinese subjects following physiologic or pharmacologic pupillary dilation may help provide insights into the pathogenesis of angle closure. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

PDTCM: a systems pharmacology platform of traditional Chinese medicine for psoriasis.

PubMed

Wang, Dongmei; Gu, Jiangyong; Zhu, Wei; Luo, Fang; Chen, Lirong; Xu, Xiaojie; Lu, Chuanjian

2017-12-01

Psoriasis is a refractory skin disorder, and usually requires a lifetime control. Traditional Chinese medicine (TCM) is effective and safe for this disease. However, the cellular and molecular mechanisms of TCM remedies for psoriasis are still not fully understood. TCM contains numerous natural products. Natural products have historically been invaluable as a resource of therapeutic agents. Yet, there is no integrated information about active compounds of TCM for psoriasis. We use systems pharmacology methods to develop the Psoriasis Database of Traditional Chinese Medicine (PDTCM). The database covered a number of psoriasis-related information (formulas, TCM, compounds, target proteins, diseases and biomarkers). With these data information, an online platform was constructed Results: PDTCM comprises 38 empirical therapeutic formulas, 34373 compounds from 1424 medicinal plants, 44 psoriasis-related proteins and 76 biomarkers from 111 related diseases. On this platform, users can screen active compounds for a psoriasis-related target and explore molecular mechanisms of TCM. Accordingly, users can also download the retrieved structures and data information with a defined value set. In addition, it helps to get a better understanding of Chinese prescriptions in disease treatment. With the systems pharmacology-based data, PDTCM would become a valuable resource for TCM in psoriasis-related research. Key messages PDTCM platform comprises a great deal of data on TCM and psoriasis. On this platform, users can retrieve and get needed information with systems pharmacology methods, such as active compounds screening, target prediction and molecular mechanisms exploration. It is a tool for psoriasis-related research on natural drugs systematically.

Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases

PubMed Central

Zhou, Wei; Wang, Jinan; Wu, Ziyin; Huang, Chao; Lu, Aiping; Wang, Yonghua

2016-01-01

Multi-herb therapy has been widely used in Traditional Chinese medicine and tailored to meet the specific needs of each individual. However, the potential molecular or systems mechanisms of them to treat various diseases have not been fully elucidated. To address this question, a systems pharmacology approach, integrating pharmacokinetics, pharmacology and systems biology, is used to comprehensively identify the drug-target and drug-disease networks, exemplified by three representative Radix Salviae Miltiorrhizae herb pairs for treating various diseases (coronary heart disease, dysmenorrheal and nephrotic syndrome). First, the compounds evaluation and the multiple targeting technology screen the active ingredients and identify the specific targets for each herb of three pairs. Second, the herb feature mapping reveals the differences in chemistry and pharmacological synergy between pairs. Third, the constructed compound-target-disease network explains the mechanisms of treatment for various diseases from a systematic level. Finally, experimental verification is taken to confirm our strategy. Our work provides an integrated strategy for revealing the mechanism of synergistic herb pairs, and also a rational way for developing novel drug combinations for treatments of complex diseases. PMID:27841365

Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases.

PubMed

Zhou, Wei; Wang, Jinan; Wu, Ziyin; Huang, Chao; Lu, Aiping; Wang, Yonghua

2016-11-14

Multi-herb therapy has been widely used in Traditional Chinese medicine and tailored to meet the specific needs of each individual. However, the potential molecular or systems mechanisms of them to treat various diseases have not been fully elucidated. To address this question, a systems pharmacology approach, integrating pharmacokinetics, pharmacology and systems biology, is used to comprehensively identify the drug-target and drug-disease networks, exemplified by three representative Radix Salviae Miltiorrhizae herb pairs for treating various diseases (coronary heart disease, dysmenorrheal and nephrotic syndrome). First, the compounds evaluation and the multiple targeting technology screen the active ingredients and identify the specific targets for each herb of three pairs. Second, the herb feature mapping reveals the differences in chemistry and pharmacological synergy between pairs. Third, the constructed compound-target-disease network explains the mechanisms of treatment for various diseases from a systematic level. Finally, experimental verification is taken to confirm our strategy. Our work provides an integrated strategy for revealing the mechanism of synergistic herb pairs, and also a rational way for developing novel drug combinations for treatments of complex diseases.

Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases

NASA Astrophysics Data System (ADS)

Zhou, Wei; Wang, Jinan; Wu, Ziyin; Huang, Chao; Lu, Aiping; Wang, Yonghua

2016-11-01

Multi-herb therapy has been widely used in Traditional Chinese medicine and tailored to meet the specific needs of each individual. However, the potential molecular or systems mechanisms of them to treat various diseases have not been fully elucidated. To address this question, a systems pharmacology approach, integrating pharmacokinetics, pharmacology and systems biology, is used to comprehensively identify the drug-target and drug-disease networks, exemplified by three representative Radix Salviae Miltiorrhizae herb pairs for treating various diseases (coronary heart disease, dysmenorrheal and nephrotic syndrome). First, the compounds evaluation and the multiple targeting technology screen the active ingredients and identify the specific targets for each herb of three pairs. Second, the herb feature mapping reveals the differences in chemistry and pharmacological synergy between pairs. Third, the constructed compound-target-disease network explains the mechanisms of treatment for various diseases from a systematic level. Finally, experimental verification is taken to confirm our strategy. Our work provides an integrated strategy for revealing the mechanism of synergistic herb pairs, and also a rational way for developing novel drug combinations for treatments of complex diseases.

Post-mortem clinical pharmacology

PubMed Central

Ferner, R E

2008-01-01

Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of ‘lethal concentrations’ are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements. PMID:18637886

[Renin-angiotensin-aldosterone system (RAAS) and its pharmacologic modulation].

PubMed

Giestas, Anabela; Palma, Isabel; Ramos, Maria Helena

2010-01-01

The renin-angiotensin-aldosterone system (RAAS) is a neuroendocrine complex system that regulates the modulation of salt and water homeostasis, and regulation of blood pressure. Through its multiple interactions it protects the endothelium, heart, brain and kidney. In addition, the RAAS regulates the vascular response to injury and inflammation. Chronic activation/dysregulation of the RAAS leads to hypertension and perpetuates a cascade of proinflammatory, prothrombotic and atherogenic effects associated with endorgan damage (heart, brain, kidney, endothelium). Consequently, the RAAS is an important therapeutic target in these situations. This article presents an overview of physiology, pathophysiology and pharmacologic modulation of the RAAS.

Systems pharmacology-based drug discovery for marine resources: an example using sea cucumber (Holothurians).

PubMed

Guo, Yingying; Ding, Yan; Xu, Feifei; Liu, Baoyue; Kou, Zinong; Xiao, Wei; Zhu, Jingbo

2015-05-13

Sea cucumber, a kind of marine animal, have long been utilized as tonic and traditional remedies in the Middle East and Asia because of its effectiveness against hypertension, asthma, rheumatism, cuts and burns, impotence, and constipation. In this study, an overall study performed on sea cucumber was used as an example to show drug discovery from marine resource by using systems pharmacology model. The value of marine natural resources has been extensively considered because these resources can be potentially used to treat and prevent human diseases. However, the discovery of drugs from oceans is difficult, because of complex environments in terms of composition and active mechanisms. Thus, a comprehensive systems approach which could discover active constituents and their targets from marine resource, understand the biological basis for their pharmacological properties is necessary. In this study, a feasible pharmacological model based on systems pharmacology was established to investigate marine medicine by incorporating active compound screening, target identification, and network and pathway analysis. As a result, 106 candidate components of sea cucumber and 26 potential targets were identified. Furthermore, the functions of sea cucumber in health improvement and disease treatment were elucidated in a holistic way based on the established compound-target and target-disease networks, and incorporated pathways. This study established a novel strategy that could be used to explore specific active mechanisms and discover new drugs from marine sources. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Qualitative, semi-quantitative, and quantitative simulation of the osmoregulation system in yeast

PubMed Central

Pang, Wei; Coghill, George M.

2015-01-01

In this paper we demonstrate how Morven, a computational framework which can perform qualitative, semi-quantitative, and quantitative simulation of dynamical systems using the same model formalism, is applied to study the osmotic stress response pathway in yeast. First the Morven framework itself is briefly introduced in terms of the model formalism employed and output format. We then built a qualitative model for the biophysical process of the osmoregulation in yeast, and a global qualitative-level picture was obtained through qualitative simulation of this model. Furthermore, we constructed a Morven model based on existing quantitative model of the osmoregulation system. This model was then simulated qualitatively, semi-quantitatively, and quantitatively. The obtained simulation results are presented with an analysis. Finally the future development of the Morven framework for modelling the dynamic biological systems is discussed. PMID:25864377

Toward an integrated software platform for systems pharmacology

PubMed Central

Ghosh, Samik; Matsuoka, Yukiko; Asai, Yoshiyuki; Hsin, Kun-Yi; Kitano, Hiroaki

2013-01-01

Understanding complex biological systems requires the extensive support of computational tools. This is particularly true for systems pharmacology, which aims to understand the action of drugs and their interactions in a systems context. Computational models play an important role as they can be viewed as an explicit representation of biological hypotheses to be tested. A series of software and data resources are used for model development, verification and exploration of the possible behaviors of biological systems using the model that may not be possible or not cost effective by experiments. Software platforms play a dominant role in creativity and productivity support and have transformed many industries, techniques that can be applied to biology as well. Establishing an integrated software platform will be the next important step in the field. © 2013 The Authors. Biopharmaceutics & Drug Disposition published by John Wiley & Sons, Ltd. PMID:24150748

Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy.

PubMed

Lötsch, Jörn; Ultsch, Alfred

2016-04-01

A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The pharmacological effects of Salvia species on the central nervous system.

PubMed

Imanshahidi, Mohsen; Hosseinzadeh, Hossein

2006-06-01

Salvia is an important genus consisting of about 900 species in the family Lamiaceae. Some species of Salvia have been cultivated world wide for use in folk medicine and for culinary purposes. The dried root of Salvia miltiorrhiza, for example, has been used extensively for the treatment of coronary and cerebrovascular disease, sleep disorders, hepatitis, hepatocirrhosis, chronic renal failure, dysmenorrhea, amenorrhea, carbuncles and ulcers. S. officinalis, S. leriifolia, S. haematodes, S. triloba and S. divinorum are other species with important pharmacological effects. In this review, the pharmacological effects of Salvia species on the central nervous system will be reviewed. These include sedative and hypnotic, hallucinogenic, skeletal muscle relaxant, analgesic, memory enhancing, anticonvulsant, neuroprotective and antiparkinsonian activity, as well as the inhibition of ethanol and morphine withdrawal syndrome.

Qualitative, semi-quantitative, and quantitative simulation of the osmoregulation system in yeast.

PubMed

Pang, Wei; Coghill, George M

2015-05-01

In this paper we demonstrate how Morven, a computational framework which can perform qualitative, semi-quantitative, and quantitative simulation of dynamical systems using the same model formalism, is applied to study the osmotic stress response pathway in yeast. First the Morven framework itself is briefly introduced in terms of the model formalism employed and output format. We then built a qualitative model for the biophysical process of the osmoregulation in yeast, and a global qualitative-level picture was obtained through qualitative simulation of this model. Furthermore, we constructed a Morven model based on existing quantitative model of the osmoregulation system. This model was then simulated qualitatively, semi-quantitatively, and quantitatively. The obtained simulation results are presented with an analysis. Finally the future development of the Morven framework for modelling the dynamic biological systems is discussed. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Real-time quantitative fluorescence measurement of microscale cell culture analog systems

NASA Astrophysics Data System (ADS)

Oh, Taek-il; Kim, Donghyun; Tatosian, Daniel; Sung, Jong Hwan; Shuler, Michael

2007-02-01

A microscale cell culture analog (μCCA) is a cell-based lab-on-a-chip assay that, as an animal surrogate, is applied to pharmacological studies for toxicology tests. A μCCA typically comprises multiple chambers and microfluidics that connect the chambers, which represent animal organs and blood flow to mimic animal metabolism more realistically. A μCCA is expected to provide a tool for high-throughput drug discovery. Previously, a portable fluorescence detection system was investigated for a single μCCA device in real-time. In this study, we present a fluorescence-based imaging system that provides quantitative real-time data of the metabolic interactions in μCCAs with an emphasis on measuring multiple μCCA samples simultaneously for high-throughput screening. The detection system is based on discrete optics components, with a high-power LED and a charge-coupled device (CCD) camera as a light source and a detector, for monitoring cellular status on the chambers of each μCCA sample. Multiple samples are characterized mechanically on a motorized linear stage, which is fully-automated. Each μCCA sample has four chambers, where cell lines MES-SA/DX- 5, and MES-SA (tumor cells of human uterus) have been cultured. All cell-lines have been transfected to express the fusion protein H2B-GFP, which is a human histone protein fused at the amino terminus to EGFP. As a model cytotoxic drug, 10 μM doxorubicin (DOX) was used. Real-time quantitative data of the intensity loss of enhanced green fluorescent protein (EGFP) during cell death of target cells have been collected over several minutes to 40 hours. Design issues and improvements are also discussed.

Impact of amyloid-beta changes on cognitive outcomes in Alzheimer's disease: analysis of clinical trials using a quantitative systems pharmacology model.

PubMed

Geerts, Hugo; Spiros, Athan; Roberts, Patrick

2018-02-02

Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission. Preclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging. When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Aβ levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid

Model reduction in mathematical pharmacology : Integration, reduction and linking of PBPK and systems biology models.

PubMed

Snowden, Thomas J; van der Graaf, Piet H; Tindall, Marcus J

2018-03-26

In this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model of bacterial chemotactic signalling in Escherichia coli and a model of extracellular regulatory kinase activation mediated via the extracellular growth factor and nerve growth factor receptor pathways. Each system is tested under the simulated administration of three hypothetical compounds; a strong base, a weak base, and an acid, mirroring the parameterisation of pindolol, midazolam, and thiopental, respectively. Our method can produce up to an 80% decrease in simulation time, allowing substantial speed-up for computationally intensive applications including parameter fitting or agent based modelling. The approach provides a straightforward means to construct simplified Quantitative Systems Pharmacology models that still provide significant insight into the mechanisms of drug action. Such a framework can potentially bridge pre-clinical and clinical modelling - providing an intermediate level of model granularity between classical, empirical approaches and mechanistic systems describing the molecular scale.

Systems Pharmacology Dissection of the Anti-Inflammatory Mechanism for the Medicinal Herb Folium Eriobotryae

PubMed Central

Zhang, Jingxiao; Li, Yan; Chen, Su-Shing; Zhang, Lilei; Wang, Jinghui; Yang, Yinfeng; Zhang, Shuwei; Pan, Yanqiu; Wang, Yonghua; Yang, Ling

2015-01-01

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations. PMID:25636035

Outpatient pharmacologic weaning for neonatal abstinence syndrome: a systematic review.

PubMed

Murphy-Oikonen, Jodie; McQueen, Karen

2018-05-09

AimThe purpose of this systematic review was to assess the literature regarding the effectiveness and safety of outpatient pharmacologic weaning for infants with neonatal abstinence syndrome (NAS). NAS is a multi-system disorder observed in infants experiencing withdrawal from opioid exposure in utero. Infants requiring pharmacologic treatment to manage withdrawal, traditionally receive treatment as a hospital inpatient resulting in lengthy hospitalization periods. However, there is evidence to suggest that some healthcare institutions are continuing outpatient pharmacologic weaning for select infants in a home environment. As there is no standard of care to guide outpatient weaning, assessment of the safety and effectiveness of this approach is warranted. A systematic review of outpatient weaning for infants with NAS was conducted using the electronic databases PubMed, Nursing and Allied Health, CINAHL, Evidence-Based Medicine, Web of Science, Medline, and PsychINFO. Studies were eligible for inclusion in the review if they fulfilled the following criteria: (1) reported original data on outcomes related to the effectiveness or safety of outpatient weaning for infants with NAS, (2) infants were discharged from hospital primarily receiving opioid pharmacologic treatment for NAS, (3) the method included quantitative designs that included an inpatient comparison group, and (4) articles were published in English in a peer-reviewed journal.FindingsThe search identified 154 studies, of which 18 provided information related to NAS and outpatient weaning. After reviewing the remaining full-text studies, six studies met all inclusion and exclusion criteria. All studies identified that outpatient weaning for select infants was associated with shorter hospitalization compared with infants weaned in-hospital only and may be potentially effective in reducing associated healthcare costs. However, duration of pharmacologic treatment was longer in the outpatient weaning groups in

PTSD: from neurobiology to pharmacological treatments

PubMed Central

Kelmendi, Benjamin; Adams, Thomas G.; Yarnell, Stephanie; Southwick, Steven; Abdallah, Chadi G.; Krystal, John H.

2016-01-01

Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention. Highlights of the article We reviewed the neurobiological abnormalities in PTSD as they relate to well-established, preliminary, and future targets for pharmacological interventions. Abnormalities across different neurotransmitter systems have been implicated in the pathophysiology of PTSD but none of these systems function uniformly among all patients with PTSD First-line pharmacotherapy for PTSD provides a suboptimal response rates. Future pharmacological targets for PTSD include the cannabinoid and oxytocin systems, as well glutamatergic modulating agents. Drug development for PTSD should specifically address various dimensions of PTSD symptomatology. PMID:27837583

TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.

PubMed

Ru, Jinlong; Li, Peng; Wang, Jinan; Zhou, Wei; Li, Bohui; Huang, Chao; Li, Pidong; Guo, Zihu; Tao, Weiyang; Yang, Yinfeng; Xu, Xue; Li, Yan; Wang, Yonghua; Yang, Ling

2014-01-01

Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski's rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.

Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.

PubMed

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-05-01

Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (σp ) and lipophilic (πp ) parameters of the para substituents. For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity. © 2014 The British Pharmacological Society.

Virtual Systems Pharmacology (ViSP) software for simulation from mechanistic systems-level models.

PubMed

Ermakov, Sergey; Forster, Peter; Pagidala, Jyotsna; Miladinov, Marko; Wang, Albert; Baillie, Rebecca; Bartlett, Derek; Reed, Mike; Leil, Tarek A

2014-01-01

Multiple software programs are available for designing and running large scale system-level pharmacology models used in the drug development process. Depending on the problem, scientists may be forced to use several modeling tools that could increase model development time, IT costs and so on. Therefore, it is desirable to have a single platform that allows setting up and running large-scale simulations for the models that have been developed with different modeling tools. We developed a workflow and a software platform in which a model file is compiled into a self-contained executable that is no longer dependent on the software that was used to create the model. At the same time the full model specifics is preserved by presenting all model parameters as input parameters for the executable. This platform was implemented as a model agnostic, therapeutic area agnostic and web-based application with a database back-end that can be used to configure, manage and execute large-scale simulations for multiple models by multiple users. The user interface is designed to be easily configurable to reflect the specifics of the model and the user's particular needs and the back-end database has been implemented to store and manage all aspects of the systems, such as Models, Virtual Patients, User Interface Settings, and Results. The platform can be adapted and deployed on an existing cluster or cloud computing environment. Its use was demonstrated with a metabolic disease systems pharmacology model that simulates the effects of two antidiabetic drugs, metformin and fasiglifam, in type 2 diabetes mellitus patients.

Virtual Systems Pharmacology (ViSP) software for simulation from mechanistic systems-level models

PubMed Central

Ermakov, Sergey; Forster, Peter; Pagidala, Jyotsna; Miladinov, Marko; Wang, Albert; Baillie, Rebecca; Bartlett, Derek; Reed, Mike; Leil, Tarek A.

2014-01-01

Multiple software programs are available for designing and running large scale system-level pharmacology models used in the drug development process. Depending on the problem, scientists may be forced to use several modeling tools that could increase model development time, IT costs and so on. Therefore, it is desirable to have a single platform that allows setting up and running large-scale simulations for the models that have been developed with different modeling tools. We developed a workflow and a software platform in which a model file is compiled into a self-contained executable that is no longer dependent on the software that was used to create the model. At the same time the full model specifics is preserved by presenting all model parameters as input parameters for the executable. This platform was implemented as a model agnostic, therapeutic area agnostic and web-based application with a database back-end that can be used to configure, manage and execute large-scale simulations for multiple models by multiple users. The user interface is designed to be easily configurable to reflect the specifics of the model and the user's particular needs and the back-end database has been implemented to store and manage all aspects of the systems, such as Models, Virtual Patients, User Interface Settings, and Results. The platform can be adapted and deployed on an existing cluster or cloud computing environment. Its use was demonstrated with a metabolic disease systems pharmacology model that simulates the effects of two antidiabetic drugs, metformin and fasiglifam, in type 2 diabetes mellitus patients. PMID:25374542

EEG Markers for Attention Deficit Disorder: Pharmacological and Neurofeedback Applications.

ERIC Educational Resources Information Center

Sterman, M. Barry

2000-01-01

Examined contribution of EEG findings in the classification and treatment of attention deficit and related behavioral problems in children. Found that quantitative EEG methods disclosed patterns of abnormality in children with ADD, suggested improved guidelines for pharmacological treatment, and introduced neurofeedback, a behavioral treatment for…

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

PubMed

Kiyosawa, Naoki; Manabe, Sunao

2016-01-01

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

A pharma perspective on the systems medicine and pharmacology of inflammation.

PubMed

Lahoz-Beneytez, Julio; Schnizler, Katrin; Eissing, Thomas

2015-02-01

Biological systems are complex and comprehend multiple scales of organisation. Hence, holistic approaches are necessary to capture the behaviour of these entities from the molecular and cellular to the whole organism level. This also applies to the understanding and treatment of different diseases. Traditional systems biology has been successful in describing different biological phenomena at the cellular level, but it still lacks of a holistic description of the multi-scale interactions within the body. The importance of the physiological context is of particular interest in inflammation. Regulatory agencies have urged the scientific community to increase the translational power of bio-medical research and it has been recognised that modelling and simulation could be a path to follow. Interestingly, in pharma R&D, modelling and simulation has been employed since a long time ago. Systems pharmacology, and particularly physiologically based pharmacokinetic/pharmacodynamic models, serve as a suitable framework to integrate the available and emerging knowledge at different levels of the drug development process. Systems medicine and pharmacology of inflammation will potentially benefit from this framework in order to better understand inflammatory diseases and to help to transfer the vast knowledge on the molecular and cellular level into a more physiological context. Ultimately, this may lead to reliable predictions of clinical outcomes such as disease progression or treatment efficacy, contributing thereby to a better care of patients. Copyright © 2014 Elsevier Inc. All rights reserved.

A Quantitative Approach to Assessing System Evolvability

NASA Technical Reports Server (NTRS)

Christian, John A., III

2004-01-01

When selecting a system from multiple candidates, the customer seeks the one that best meets his or her needs. Recently the desire for evolvable systems has become more important and engineers are striving to develop systems that accommodate this need. In response to this search for evolvability, we present a historical perspective on evolvability, propose a refined definition of evolvability, and develop a quantitative method for measuring this property. We address this quantitative methodology from both a theoretical and practical perspective. This quantitative model is then applied to the problem of evolving a lunar mission to a Mars mission as a case study.

[Pharmacological differences between inhibitor drugs of the renin-angiotensin aldosterone system].

PubMed

Méndez-Durán, Antonio

2011-01-01

The activation of the renin-angiotensin-aldosterone cascade is a mechanism that generates high blood pressure. The structure has been identified and can be blocked through specific enzymatic pathways or receptors. We have a diversity of medications that act on this system. It is useful to develop the skill in clinical practice for selecting a drug from a wide variety. Renin-angiotensin system inhibitors share many pharmacological and pharmacokinetic characteristics but not all them are equivalent. Knowledge based on scientific evidence allows the clinician to choose the ideal drug for each patient.

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma.

PubMed

Ande, Anusha; Chaar, Maher; Ait-Oudhia, Sihem

2018-05-03

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. A comprehensive and multiscale QSP/PK/PD model was developed, qualified, and translated to clinical settings. Model fittings and simulations were performed using Monolix software. The S6-kinase protein was identified as critical in the mTOR signaling pathway for describing everolimus lack of efficacy in HCC patients. The net growth rate constant (kg) of HCC cells was estimated at 0.02 h -1 (2.88%RSE). The partition coefficient of everolimus into the tumor (kp) was determined at 0.06 (12.98%RSE). The kg in patients was calculated from the doubling time of TV in naturally progressing HCC patients, and was determined at 0.004 day -1 . Model-predicted and observed PFS were in good agreement for placebo and everolimus-treated patients. In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors.

Quantitative risk assessment system (QRAS)

NASA Technical Reports Server (NTRS)

Tan, Zhibin (Inventor); Mosleh, Ali (Inventor); Weinstock, Robert M (Inventor); Smidts, Carol S (Inventor); Chang, Yung-Hsien (Inventor); Groen, Francisco J (Inventor); Swaminathan, Sankaran (Inventor)

2001-01-01

A quantitative risk assessment system (QRAS) builds a risk model of a system for which risk of failure is being assessed, then analyzes the risk of the system corresponding to the risk model. The QRAS performs sensitivity analysis of the risk model by altering fundamental components and quantifications built into the risk model, then re-analyzes the risk of the system using the modifications. More particularly, the risk model is built by building a hierarchy, creating a mission timeline, quantifying failure modes, and building/editing event sequence diagrams. Multiplicities, dependencies, and redundancies of the system are included in the risk model. For analysis runs, a fixed baseline is first constructed and stored. This baseline contains the lowest level scenarios, preserved in event tree structure. The analysis runs, at any level of the hierarchy and below, access this baseline for risk quantitative computation as well as ranking of particular risks. A standalone Tool Box capability exists, allowing the user to store application programs within QRAS.

Pharmacological AMP Kinase Activators Target the Nucleolar Organization and Control Cell Proliferation

PubMed Central

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Aims Phenformin, resveratrol and AICAR stimulate the energy sensor 5′-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Methods Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. Results AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. Conclusions AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents

Pharmacological AMP kinase activators target the nucleolar organization and control cell proliferation.

PubMed

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Phenformin, resveratrol and AICAR stimulate the energy sensor 5'-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential

An Educational Board Game to Assist PharmD Students in Learning Autonomic Nervous System Pharmacology.

PubMed

Jones, J Shawn; Tincher, Lindsay; Odeng-Otu, Emmanuel; Herdman, Michelle

2015-10-25

Objective. To examine whether playing a board game can assist PharmD students in learning autonomic nervous system (ANS) pharmacology. Design. Of 72 students enrolled in a required second-year pharmacology course, 22 students volunteered to play the board game, which was followed by an in-class examination consisting of 42 ANS questions (ANSQs) and 8 control questions (CTLQs). Participants were given a pretest and a posttest to assess immediate educational improvement. Participants' scores for pretest, posttest, in-class examination, and ANSQs were compared. Also, scores for examination, ANSQs, and CTLQs were compared between board game participants (PART) and nonparticipating classmates (NPART). Assessment. Board game participants scored progressively higher between the pretest, posttest, examination, and ANSQs. Additionally, PART scores were higher than NPART scores for examination and ANSQs. Difference between PART and NPART CTLQ scores was not significant. Conclusion. A board game can assist PharmD students in learning ANS pharmacology.

Rehmannia glutinosa: review of botany, chemistry and pharmacology.

PubMed

Zhang, Ru-Xue; Li, Mao-Xing; Jia, Zheng-Ping

2008-05-08

Rehmannia glutinosa, a widely used traditional Chinese herb, belongs to the family of Scrophulariaceae, and is taken to nourish Yin and invigorate the kidney in traditional Chinese medicine (TCM) and has a very high medicinal value. In recent decades, a great number of chemical and pharmacological studies have been done on Rehmannia glutinosa. More than 70 compounds including iridoids, saccharides, amino acid, inorganic ions, as well as other trace elements have been found in the herb. Studies show that Rehmannia glutinosa and its active principles possess wide pharmacological actions on the blood system, immune system, endocrine system, cardiovascular system and the nervous system. Currently, the effective monomeric compounds or active parts have been screened for the pharmacological activity of Rehmannia glutinosa and the highest quality scientific data is delivered to support the further application and exploitation for new drug development.

Quantitative method of medication system interface evaluation.

PubMed

Pingenot, Alleene Anne; Shanteau, James; Pingenot, James D F

2007-01-01

The objective of this study was to develop a quantitative method of evaluating the user interface for medication system software. A detailed task analysis provided a description of user goals and essential activity. A structural fault analysis was used to develop a detailed description of the system interface. Nurses experienced with use of the system under evaluation provided estimates of failure rates for each point in this simplified fault tree. Means of estimated failure rates provided quantitative data for fault analysis. Authors note that, although failures of steps in the program were frequent, participants reported numerous methods of working around these failures so that overall system failure was rare. However, frequent process failure can affect the time required for processing medications, making a system inefficient. This method of interface analysis, called Software Efficiency Evaluation and Fault Identification Method, provides quantitative information with which prototypes can be compared and problems within an interface identified.

Tissue-Specific Analysis of Pharmacological Pathways.

PubMed

Hao, Yun; Quinnies, Kayla; Realubit, Ronald; Karan, Charles; Tatonetti, Nicholas P

2018-06-19

Understanding the downstream consequences of pharmacologically targeted proteins is essential to drug design. Current approaches investigate molecular effects under tissue-naïve assumptions. Many target proteins, however, have tissue-specific expression. A systematic study connecting drugs to target pathways in in vivo human tissues is needed. We introduced a data-driven method that integrates drug-target relationships with gene expression, protein-protein interaction, and pathway annotation data. We applied our method to four independent genomewide expression datasets and built 467,396 connections between 1,034 drugs and 954 pathways in 259 human tissues or cell lines. We validated our results using data from L1000 and Pharmacogenomics Knowledgebase (PharmGKB), and observed high precision and recall. We predicted and tested anticoagulant effects of 22 compounds experimentally that were previously unknown, and used clinical data to validate these effects retrospectively. Our systematic study provides a better understanding of the cellular response to drugs and can be applied to many research topics in systems pharmacology. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine.

PubMed

Kim, Jihye; Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kang, Jaewoo; Tan, Aik Choon

2018-01-01

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis.

Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine

PubMed Central

Kim, Jihye; Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kang, Jaewoo

2018-01-01

Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis. PMID:29765977

[PROFESSOR VLADIMIR V. NIKOLAEV AND RUSSIAN PHARMACOLOGY.

PubMed

Bondarchuk, N G; Fisenko, V P

2016-01-01

Various stages of scientific research activity of Prof. Vladimir V. Nikolaev are analyzed. The importance of Prof. Nikolaev's discovery of the two-neuron parasympathetic nervous system and some new methods of pharmacological substances evaluation is shown. Prof. Nikolaev is known as the editor of the first USSR Pharmacopoeia. Peculiarities of pharmacology teaching at the First Moscow Medical institute under conditions of changing social demands are described. Successful research of Prof. Nikolaev with colleagues in studying new mechanisms of drug action and developing original pharmacological substances is summarized.

Effectiveness of an audience response system in teaching pharmacology to baccalaureate nursing students.

PubMed

Vana, Kimberly D; Silva, Graciela E; Muzyka, Diann; Hirani, Lorraine M

2011-06-01

It has been proposed that students' use of an audience response system, commonly called clickers, may promote comprehension and retention of didactic material. Whether this method actually improves students' grades, however, is still not determined. The purpose of this study was to evaluate whether a lecture format utilizing multiple-choice PowerPoint slides and an audience response system was more effective than a lecture format using only multiple-choice PowerPoint slides in the comprehension and retention of pharmacological knowledge in baccalaureate nursing students. The study also assessed whether the additional use of clickers positively affected students' satisfaction with their learning. Results from 78 students who attended lecture classes with multiple-choice PowerPoint slides plus clickers were compared with those of 55 students who utilized multiple-choice PowerPoint slides only. Test scores between these two groups were not significantly different. A satisfaction questionnaire showed that 72.2% of the control students did not desire the opportunity to use clickers. Of the group utilizing the clickers, 92.3% recommend the use of this system in future courses. The use of multiple-choice PowerPoint slides and an audience response system did not seem to improve the students' comprehension or retention of pharmacological knowledge as compared with those who used solely multiple-choice PowerPoint slides.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection.

PubMed

Sadekar, S; Figueroa, I; Tabrizi, M

2015-07-01

Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

Pharmacology of intracellular signalling pathways

PubMed Central

Nahorski, Stefan R

2006-01-01

This article provides a brief and somewhat personalized review of the dramatic developments that have occurred over the last 45 years in our understanding of intracellular signalling pathways associated with G-protein-coupled receptor activation. Signalling via cyclic AMP, the phosphoinositides and Ca2+ is emphasized and these systems have already been revealed as new pharmacological targets. The therapeutic benefits of most of such targets are, however, yet to be realized, but it is certain that the discipline of pharmacology needs to widen its boundaries to meet these challenges in the future. PMID:16402119

Pharmacological Properties of Melanin and its Function in Health.

PubMed

ElObeid, Adila Salih; Kamal-Eldin, Afaf; Abdelhalim, Mohamed Anwar K; Haseeb, Adil M

2017-06-01

The biological pigment melanin is present in most of the biological systems. It manifests a host of biological and pharmacological properties. Its role as a molecule with special properties and functions affecting general health, including photoprotective and immunological action, are well recognized. Its antioxidant, anti-inflammatory, immunomodulatory, radioprotective, hepatic, gastrointestinal and hypoglycaemic benefits have only recently been recognized and studied. It is also associated with certain disorders of the nervous system. In this MiniReview, we consider the steadily increasing literature on the bioavailability and functional activity of melanin. Published literature shows that melanin may play a number of possible pharmacological effects such as protective, stimulatory, diagnostic and curative roles in human health. In this MiniReview, possible health roles and pharmacological effects are considered. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Medical curriculum and pharmacology: An appraisal

PubMed Central

Haranath, P.S.R.K.

2016-01-01

Pharmacology was introduced with Western Medical Education in India in 1900s. RN Chopra was the first Professor of Pharmacology along with patient care in School of Tropical Medicine Calcutta. Now Pharmacologists do not have clinical care nor give laboratory services to hospitals. Medical Education advanced in the West in 1960s with more emphasis on Integrated Teaching and Student Self-study and less on didactic lectures. System Based Learning and Problem Based Learning reduced importance of individual subjects. Medical Council of India (MCI) has mandatory regulations with no major changes in the last 5 decades. Universities and Medical institutions have no freedom in teaching programs. In Pharmacology didactic lectures dominate teaching. Practicals started with Dispensing Pharmacy were later replaced with Experimental Pharmacology. At present after restrictions on animals for study practicals are converted to Theoretical Exercises on Prescription writing and Incompatibilities. Students study mostly before examinations with little influence of yearlong teaching. Suggestions in line with Western Countries: Reduce the course of Pharmacology to 6 months. Examinations should be completely Internal with frequent tests by Internal Examiners. MD (Therapeutics) course may be introduced to teach Pharmacology in first semester. MCI rules to be only advisory and not mandatory. Teaching Institutions should form an independent Association and have freedom in teaching programs. A Nonofficial National Board of Medical Examination has to be formed to conduct an Entrance Test for admissions to Medical College and a National test for each graduate before registration. PMID:28031600

Principles of Safety Pharmacology

PubMed Central

Pugsley, M K; Authier, S; Curtis, M J

2008-01-01

Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.). PMID:18604233

Deciphering the Mechanism of Action of Wrightia tinctoria for Psoriasis Based on Systems Pharmacology Approach.

PubMed

Sundarrajan, Sudharsana; Lulu, Sajitha; Arumugam, Mohanapriya

2017-11-01

Psoriasis is a chronic immune-mediated disorder of the skin. The disease manifests itself with red or silvery scaly plaques distributing over the lower back, scalp, and extensor aspects of limbs. Several medications are available for the treatment of psoriasis; however, high rates of remission and side-effects still persist as a major concern. Siddha, one of the traditional systems of Indian medicine offers cure to many dermatological conditions, including psoriasis. The oil prepared from the leaves of Wrightia tinctoria is prescribed by many healers for the treatment of psoriasis. This work aims to decipher the mechanism of action of the W. tinctoria in curing psoriasis and its associated comorbidities. The work integrates various pharmacology approaches such as drug-likeness evaluation, oral bioavailability predictions, and network pharmacology approaches to understand the roles of various bioactive components of the herb. This work identified 67 compounds of W. tinctoria interacting with 238 protein targets. The compounds were found to act through synergistic mechanism in reviving the disrupted process in the diseased state. The results of this work not only shed light on the pharmacological action of the herb but also validate the usage of safe herbal drugs.

Ginseng leaf-stem: bioactive constituents and pharmacological functions

PubMed Central

Wang, Hongwei; Peng, Dacheng; Xie, Jingtian

2009-01-01

Ginseng root is used more often than other parts such as leaf stem although extracts from ginseng leaf-stem also contain similar active ingredients with pharmacological functions. Ginseng's leaf-stems are more readily available at a lower cost than its root. This article reviews the pharmacological effects of ginseng leaf-stem on some diseases and adverse effects due to excessive consumption. Ginseng leaf-stem extract contains numerous active ingredients, such as ginsenosides, polysaccharides, triterpenoids, flavonoids, volatile oils, polyacetylenic alcohols, peptides, amino acids and fatty acids. The extract contains larger amounts of the same active ingredients than the root. These active ingredients produce multifaceted pharmacological effects on the central nervous system, as well as on the cardiovascular, reproductive and metabolic systems. Ginseng leaf-stem extract also has anti-fatigue, anti-hyperglycemic, anti-obesity, anti-cancer, anti-oxidant and anti-aging properties. In normal use, ginseng leaf-stem extract is quite safe; adverse effects occur only when it is over dosed or is of poor quality. Extracts from ginseng root and leaf-stem have similar multifaceted pharmacological activities (for example central nervous and cardiovascular systems). In terms of costs and source availability, however, ginseng leaf-stem has advantages over its root. Further research will facilitate a wider use of ginseng leaf-stem. PMID:19849852

In silico pharmacology for drug discovery: applications to targets and beyond

PubMed Central

Ekins, S; Mestres, J; Testa, B

2007-01-01

Computational (in silico) methods have been developed and widely applied to pharmacology hypothesis development and testing. These in silico methods include databases, quantitative structure-activity relationships, similarity searching, pharmacophores, homology models and other molecular modeling, machine learning, data mining, network analysis tools and data analysis tools that use a computer. Such methods have seen frequent use in the discovery and optimization of novel molecules with affinity to a target, the clarification of absorption, distribution, metabolism, excretion and toxicity properties as well as physicochemical characterization. The first part of this review discussed the methods that have been used for virtual ligand and target-based screening and profiling to predict biological activity. The aim of this second part of the review is to illustrate some of the varied applications of in silico methods for pharmacology in terms of the targets addressed. We will also discuss some of the advantages and disadvantages of in silico methods with respect to in vitro and in vivo methods for pharmacology research. Our conclusion is that the in silico pharmacology paradigm is ongoing and presents a rich array of opportunities that will assist in expediating the discovery of new targets, and ultimately lead to compounds with predicted biological activity for these novel targets. PMID:17549046

Hemisphere Asymmetry of Response to Pharmacologic Treatment in an Alzheimer's Disease Mouse Model.

PubMed

Manousopoulou, Antigoni; Saito, Satoshi; Yamamoto, Yumi; Al-Daghri, Nasser M; Ihara, Masafumi; Carare, Roxana O; Garbis, Spiros D

2016-01-01

The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer's disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel hemisphere-specific therapeutic targets.

Systems Pharmacology Dissection of Traditional Chinese Medicine Wen-Dan Decoction for Treatment of Cardiovascular Diseases.

PubMed

Lan, Tao-Hua; Zhang, Lu-Lu; Wang, Yong-Hua; Wu, Huan-Lin; Xu, Dan-Ping

2018-01-01

Cardiovascular diseases (CVDs) have been recognized as first killer of human health. The underlying mechanisms of CVDs are extremely complicated and not fully revealed, leading to a challenge for CVDs treatment in modern medicine. Traditional Chinese medicine (TCM) characterized by multiple compounds and targets has shown its marked effects on CVDs therapy. However, system-level understanding of the molecular mechanisms is still ambiguous. In this study, a system pharmacology approach was developed to reveal the underlying molecular mechanisms of a clinically effective herb formula (Wen-Dan Decoction) in treating CVDs. 127 potential active compounds and their corresponding 283 direct targets were identified in Wen-Dan Decoction. The networks among active compounds, targets, and diseases were built to reveal the pharmacological mechanisms of Wen-Dan Decoction. A "CVDs pathway" consisted of several regulatory modules participating in therapeutic effects of Wen-Dan Decoction in CVDs. All the data demonstrates that Wen-Dan Decoction has multiscale beneficial activity in CVDs treatment, which provides a new way for uncovering the molecular mechanisms and new evidence for clinical application of Wen-Dan Decoction in cardiovascular disease.

Carbon nanotubes exhibit fibrillar pharmacology in primates

DOE PAGES

Alidori, Simone; Thorek, Daniel L. J.; Beattie, Bradley J.; ...

2017-08-28

Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation.more » Kidney and liver are the two major organ systems that accumulate and excrete [ 86Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t 1/2 = 11.9 hours). Thus, these favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man.« less

Carbon nanotubes exhibit fibrillar pharmacology in primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alidori, Simone; Thorek, Daniel L. J.; Beattie, Bradley J.

Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation.more » Kidney and liver are the two major organ systems that accumulate and excrete [ 86Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t 1/2 = 11.9 hours). Thus, these favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man.« less

Quantitative Predictive Models for Systemic Toxicity (SOT)

EPA Science Inventory

Models to identify systemic and specific target organ toxicity were developed to help transition the field of toxicology towards computational models. By leveraging multiple data sources to incorporate read-across and machine learning approaches, a quantitative model of systemic ...

Pharmacological management of sepsis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fletcher, J.R.

Systemic sepsis continues to be the most-difficult management problem in caring for the combat casualty. The complications of sepsis pervade all areas of injury to soldiers in the field, whether it is mechanical (missiles), thermal (burns), chemical, biological, or radiation injury. With the advent of tactical nuclear weapons, the problem of sepsis will be much higher in future wars than has previously been experienced through the world. The purpose of this chapter is a) to review the data suggesting pharmacological agents that may benefit the septic patient, and b) to emphasize the adjunctive therapies that should be explored in clinicalmore » trials. The pharmacological management of sepsis remains controversial. Most of the drugs utilized clinically treat the symptoms of the disease and are not necessarily directed at fundamental mechanisms that are known to be present in sepsis. A broad data base is emerging, indicating that NSAID should be used in human clinical trials. Prostaglandins are sensitive indicators of cellular injury and may be mediators for a number of vasoactive chemicals. Opiate antagonists and calcium channel blockers require more in-depth data; however, recent studies generate excitement for their potential use in the critically ill patient. Pharmacological effects of antibiotics, in concert with other drugs, suggest an entirely new approach to pharmacological treatment in sepsis. There is no doubt that new treatment modalities or adjunctive therapies must be utilized to alter the poor prognosis of severe sepsis that we have observed in the past 4 decades.« less

Exhaust-System Leak Test : Quantitative Procedure

DOT National Transportation Integrated Search

1974-01-01

A quantitative, periodic motor vehicle safety-inspection test for determining the leakage rate of engine exhaust from an automotive exhaust system was investigated. Two technical approaches were evaluated, and the better one was selected for developm...

Combining systems pharmacology, transcriptomics, proteomics, and metabolomics to dissect the therapeutic mechanism of Chinese herbal Bufei Jianpi formula for application to COPD

PubMed Central

Zhao, Peng; Yang, Liping; Li, Jiansheng; Li, Ya; Tian, Yange; Li, Suyun

2016-01-01

Bufei Jianpi formula (BJF) has long been used as a therapeutic agent in the treatment of COPD. Systems pharmacology identified 145 active compounds and 175 potential targets of BJF in a previous study. Additionally, BJF was previously shown to effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production, in vivo. However, the system-level mechanism of BJF for the treatment of COPD is still unclear. The aim of this study was to gain insight into its system-level mechanisms by integrating transcriptomics, proteomics, and metabolomics together with systems pharmacology datasets. Using molecular function, pathway, and network analyses, the genes and proteins regulated in COPD rats and BJF-treated rats could be mainly attributed to oxidoreductase activity, antioxidant activity, focal adhesion, tight junction, or adherens junction. Furthermore, a comprehensive analysis of systems pharmacology, transcript, protein, and metabolite datasets is performed. The results showed that a number of genes, proteins, metabolites regulated in BJF-treated rats and potential target proteins of BJF were involved in lipid metabolism, cell junction, oxidative stress, and inflammatory response, which might be the system-level therapeutic mechanism of BJF treatment. PMID:27042044

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

PubMed Central

Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

2013-01-01

Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases. PMID:24179466

Dextroamphetamine: a pharmacologic countermeasure for space motion sickness and orthostatic dysfunction

NASA Technical Reports Server (NTRS)

Snow, L. Dale

1996-01-01

Dextroamphetamine has potential as a pharmacologic agent for the alleviation of two common health effects associated with microgravity. As an adjuvant to Space Motion Sickness (SMS) medication, dextroamphetamine can enhance treatment efficacy by reducing undesirable Central Nervous System (CNS) side effects of SMS medications. Secondly, dextroamphetamine may be useful for the prevention of symptoms of post-mission orthostatic intolerance caused by cardiovascular deconditioning during spaceflight. There is interest in developing an intranasal delivery form of dextroamphetanmine for use as a countermeasure in microgravity conditions. Development of this dosage form will require an analytical detection method with sensitivity in the low ng range (1 to 100 ng/mL). During the 1995 Summer Faculty Fellowship Program, two analytical methods were developed and evaluated for their suitability as quantitative procedures for dextroamphetamine in studies of product stability, bioavailability assessment, and pharmacokinetic evaluation. In developing some of the analytical methods, beta-phenylethylamine, a primary amine structurally similar to dextroamphetamine, was used. The first analytical procedure to be evaluated involved hexane extraction and subsequent fluorescamine labeling of beta-phenylethylamine. The second analytical procedure to be evaluated involved quantitation of dextroamphetamine by an Enzyme-Linked ImmunoSorbent Assay (ELISA).

Studies in neuroendocrine pharmacology

NASA Technical Reports Server (NTRS)

Maickel, R. P.

1976-01-01

The expertise and facilities available within the Medical Sciences Program section on Pharmacology were used along with informational input from various NASA sources to study areas relevant to the manned space effort. Topics discussed include effects of drugs on deprivation-induced fluid consumption, brain biogenic amines, biochemical responses to stressful stimuli, biochemical and behavioral pharmacology of amphetamines, biochemical and pharmacological studies of analogues to biologically active indole compounds, chemical pharmacology: drug metabolism and disposition, toxicology, and chemical methodology. Appendices include a bibliography, and papers submitted for publication or already published.

Quantitative Diagnosis of Continuous-Valued, Stead-State Systems

NASA Technical Reports Server (NTRS)

Rouquette, N.

1995-01-01

Quantitative diagnosis involves numerically estimating the values of unobservable parameters that best explain the observed parameter values. We consider quantitative diagnosis for continuous, lumped- parameter, steady-state physical systems because such models are easy to construct and the diagnosis problem is considerably simpler than that for corresponding dynamic models. To further tackle the difficulties of numerically inverting a simulation model to compute a diagnosis, we propose to decompose a physical system model in terms of feedback loops. This decomposition reduces the dimension of the problem and consequently decreases the diagnosis search space. We illustrate this approach on a model of thermal control system studied in earlier research.

Pharmacology of Marihuana (Cannabis sativa)

ERIC Educational Resources Information Center

Maickel, Roger P.

1973-01-01

A detailed discussion of marihuana (Cannabis sativa) providing the modes of use, history, chemistry, and physiologic properties of the drug. Cites research results relating to the pharmacologic effects of marihuana. These effects are categorized into five areas: behavioral, cardiovascular-respiratory, central nervous system, toxicity-toxicology,…

Chaos synchronization and Nelder-Mead search for parameter estimation in nonlinear pharmacological systems: Estimating tumor antigenicity in a model of immunotherapy.

PubMed

Pillai, Nikhil; Craig, Morgan; Dokoumetzidis, Aristeidis; Schwartz, Sorell L; Bies, Robert; Freedman, Immanuel

2018-06-19

In mathematical pharmacology, models are constructed to confer a robust method for optimizing treatment. The predictive capability of pharmacological models depends heavily on the ability to track the system and to accurately determine parameters with reference to the sensitivity in projected outcomes. To closely track chaotic systems, one may choose to apply chaos synchronization. An advantageous byproduct of this methodology is the ability to quantify model parameters. In this paper, we illustrate the use of chaos synchronization combined with Nelder-Mead search to estimate parameters of the well-known Kirschner-Panetta model of IL-2 immunotherapy from noisy data. Chaos synchronization with Nelder-Mead search is shown to provide more accurate and reliable estimates than Nelder-Mead search based on an extended least squares (ELS) objective function. Our results underline the strength of this approach to parameter estimation and provide a broader framework of parameter identification for nonlinear models in pharmacology. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effects of exercise training on the cardiovascular system: pharmacological approaches.

PubMed

Zanesco, Angelina; Antunes, Edson

2007-06-01

Physical exercise promotes beneficial health effects by preventing or reducing the deleterious effects of pathological conditions, such as arterial hypertension, coronary artery disease, atherosclerosis, diabetes mellitus, osteoporosis, Parkinson's disease, and Alzheimer disease. Human movement studies are becoming an emerging science in the epidemiological area and public health. A great number of studies have shown that exercise training, in general, reduces sympathetic activity and/or increases parasympathetic tonus either in human or laboratory animals. Alterations in autonomic nervous system have been correlated with reduction in heart rate (resting bradycardia) and blood pressure, either in normotensive or hypertensive subjects. However, the underlying mechanisms by which physical exercise produce bradycardia and reduces blood pressure has not been fully understood. Pharmacological studies have particularly contributed to the comprehension of the role of receptor and transduction signaling pathways on the heart and blood vessels in response to exercise training. This review summarizes and examines the data from studies using animal models and human to determine the effect of exercise training on the cardiovascular system.

Crataegus pinnatifida: chemical constituents, pharmacology, and potential applications.

PubMed

Wu, Jiaqi; Peng, Wei; Qin, Rongxin; Zhou, Hong

2014-01-30

Crataegus pinnatifida (Hawthorn) is widely distributed in China and has a long history of use as a traditional medicine. The fruit of C. pinnatifida has been used for the treatment of cardiodynia, hernia, dyspepsia, postpartum blood stasis, and hemafecia and thus increasing interest in this plant has emerged in recent years. Between 1966 and 2013, numerous articles have been published on the chemical constituents, pharmacology or pharmacologic effects and toxicology of C. pinnatifida. To review the pharmacologic advances and to discuss the potential perspective for future investigation, we have summarized the main literature findings of these publications. So far, over 150 compounds including flavonoids, triterpenoids, steroids, monoterpenoids, sesquiterpenoids, lignans, hydroxycinnamic acids, organic acids and nitrogen-containing compounds have been isolated and identified from C. pinnatifida. It has been found that these constituents and extracts of C. pinnatifida have broad pharmacological effects with low toxicity on, for example, the cardiovascular, digestive, and endocrine systems, and pathogenic microorganisms, supporting the view that C. pinnatifida has favorable therapeutic effects. Thus, although C. pinnatifida has already been widely used as pharmacological therapy, due to its various active compounds, further research is warranted to develop new drugs.

Applications of stable isotopes in clinical pharmacology

PubMed Central

Schellekens, Reinout C A; Stellaard, Frans; Woerdenbag, Herman J; Frijlink, Henderik W; Kosterink, Jos G W

2011-01-01

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans. PMID:21801197

Tobacco Harms, Nicotine Pharmacology, and Pharmacologic Tobacco Cessation Interventions for Women.

PubMed

Baraona, L Kim; Lovelace, Dawn; Daniels, Julie L; McDaniel, Linda

2017-05-01

Firsthand and secondhand tobacco use is linked to a multitude of harmful illnesses, adverse perinatal outcomes, and death. Cessation attempts among women may be hampered by their unique biologic response to nicotine. Current research has revealed epigenetic changes from intrauterine nicotine exposure that have intergenerational consequences. Multiple studies have demonstrated the efficacy of various pharmacologic tobacco cessation interventions in conjunction with behavioral counseling. Based on this evidence, the US Preventative Services Task Force (USPSTF) 2015 guideline recommends pharmacologic therapy for all nonpregnant persons who smoke in addition to behavioral counseling. The effectiveness of pharmacologic treatments among pregnant women is less clear, with far fewer studies evaluating potential benefits and harms. While exposure to pharmacologic therapies raises concerns for fetal safety, these potential risks must be weighed against those of continued tobacco use, which guarantees fetal exposure to nicotine. First-line tobacco cessation medications include nicotine replacement therapy (NRT), bupropion, and varenicline. Second-line medications include nortriptyline and clonidine. Pharmacokinetics, effectiveness, regimens, and safety profiles for nonpregnant, pregnant, and lactating women are reviewed. Alternative tobacco cessation options and potential new pharmacologic tobacco cessation agents are discussed. Initiating brief interventions, using the 5A's and 5R's model is described. © 2017 by the American College of Nurse-Midwives.

Pharmacological treatment of sexual offenders in German outpatient treatment centers.

PubMed

Turner, Daniel; Gregório Hertz, Priscilla; Sauter, Julia; Briken, Peer; Rettenberger, Martin

2018-05-04

In Germany, depending on a sexual offender's culpability and the severity of the offence, he/she can be placed either in the forensic-psychiatric or the correctional system. Numbers related to the pharmacological treatment of sexual offenders for the correctional system are missing so far. In sexual offenders, the pharmacological treatment of paraphilic disorders is of special importance. The present study aimed at assessing the prevalence of pharmacological sexual offender treatment in German outpatient treatment centers supervising mainly clients from the correctional sector. An online questionnaire was sent to 112 outpatient treatment centers and 21 provided data relevant for the present study. The included institutions reported about a total of 813 sexual offenders, of whom 200 (24.6%) were treated with pharmacological agents, most frequently antipsychotics (14.8%) and selective-serotonin-reuptake-inhibitors (7.1%). Of the total sample, 26.7% of sexual offenders were diagnosed with a paraphilic - mainly with a pedophilic - disorder. Only 2% were treated with androgen-deprivation therapy. Compared with forensic-psychiatric institutions, only a minority of sexual offenders are treated with medication specifically addressing paraphilic symptomatology. However, the prevalence of paraphilic disorders found in the present study suggests that pharmacological treatment of paraphilic fantasies and behaviors could be of great importance in the correctional sector as well.

A Second-Generation Device for Automated Training and Quantitative Behavior Analyses of Molecularly-Tractable Model Organisms

PubMed Central

Blackiston, Douglas; Shomrat, Tal; Nicolas, Cindy L.; Granata, Christopher; Levin, Michael

2010-01-01

A deep understanding of cognitive processes requires functional, quantitative analyses of the steps leading from genetics and the development of nervous system structure to behavior. Molecularly-tractable model systems such as Xenopus laevis and planaria offer an unprecedented opportunity to dissect the mechanisms determining the complex structure of the brain and CNS. A standardized platform that facilitated quantitative analysis of behavior would make a significant impact on evolutionary ethology, neuropharmacology, and cognitive science. While some animal tracking systems exist, the available systems do not allow automated training (feedback to individual subjects in real time, which is necessary for operant conditioning assays). The lack of standardization in the field, and the numerous technical challenges that face the development of a versatile system with the necessary capabilities, comprise a significant barrier keeping molecular developmental biology labs from integrating behavior analysis endpoints into their pharmacological and genetic perturbations. Here we report the development of a second-generation system that is a highly flexible, powerful machine vision and environmental control platform. In order to enable multidisciplinary studies aimed at understanding the roles of genes in brain function and behavior, and aid other laboratories that do not have the facilities to undergo complex engineering development, we describe the device and the problems that it overcomes. We also present sample data using frog tadpoles and flatworms to illustrate its use. Having solved significant engineering challenges in its construction, the resulting design is a relatively inexpensive instrument of wide relevance for several fields, and will accelerate interdisciplinary discovery in pharmacology, neurobiology, regenerative medicine, and cognitive science. PMID:21179424

Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine

NASA Astrophysics Data System (ADS)

Zhang, Wenjuan; Tao, Qin; Guo, Zihu; Fu, Yingxue; Chen, Xuetong; Shar, Piar Ali; Shahen, Mohamed; Zhu, Jinglin; Xue, Jun; Bai, Yaofei; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Wang, Yonghua

2016-09-01

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.

Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine

PubMed Central

Zhang, Wenjuan; Tao, Qin; Guo, Zihu; Fu, Yingxue; Chen, Xuetong; Shar, Piar Ali; Shahen, Mohamed; Zhu, Jinglin; Xue, Jun; Bai, Yaofei; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Wang, Yonghua

2016-01-01

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases. PMID:27597117

Pharmacological Treatment Effects on Eye Movement Control

ERIC Educational Resources Information Center

Reilly, James L.; Lencer, Rebekka; Bishop, Jeffrey R.; Keedy, Sarah; Sweeney, John A.

2008-01-01

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to…

Electric Field Quantitative Measurement System and Method

NASA Technical Reports Server (NTRS)

Generazio, Edward R. (Inventor)

2016-01-01

A method and system are provided for making a quantitative measurement of an electric field. A plurality of antennas separated from one another by known distances are arrayed in a region that extends in at least one dimension. A voltage difference between at least one selected pair of antennas is measured. Each voltage difference is divided by the known distance associated with the selected pair of antennas corresponding thereto to generate a resulting quantity. The plurality of resulting quantities defined over the region quantitatively describe an electric field therein.

[Pharmacological Basis for Therapeutics. Pharmacological Analysis of Summary of Product Characteristics (SPC) for Physicians].

PubMed

Lechat, Philippe

2015-01-01

The summary of product characteristics, the SPC, is the major annex document of Marketing Authorisation (MA) dossier for a medicine. This document is the reference document for health care professionnals since it contains all necessary and opposable information for its therapeutic use. The SPC is initially submitted by the MA applicant and deeply revised in details by regulatory authorities, the national agencies for national MA, and the European Medicine Agency (EMA) for the european centralized procedures. The SPC presents with 12 sections each one being divided into several paragraphs. Sections 1-3 present the name, dosage, qualitative and quantitative composition, the pharmaceutical form of the medicine. Section 4 contains all the clinical particulars: Therapeutic indications, posology and methods of administration, contra-indications, special warnings and precautions for use, interactions, impact on fertility, contraception, pregnancy, lactation, effects on ability to drive and use machines, undesirable effects and risk associated with overdose. Section 5 describes pharmacological properties (pharmacodynamics and pharmacokinetics) and preclinical safety data. Section 6 describes the pharmaceutical particulars: excipients, incompatibilities, shelf live, nature and content of container, special precautions for disposal. Sections 7-10 are administrative ones (date of MA, MA holder), sections 11 and 12 are specific to radiopharmaceuticals (dosimetry and modalities of preparation). SPC is available free of charge on national regulatory agency websites and on EMA website. Sections of SPC finally have to be considered as the pharmacological basis of therapeutic use for each medicine. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Pharmacologic therapy for erectile dysfunction and its interaction with the cardiovascular system.

PubMed

Ioakeimidis, Nikolaos; Kostis, John B

2014-01-01

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The PDE type 5 (PDE5) inhibitors are widely used to treat erectile dysfunction (ED). Recent, intense preclinical and clinical research with PDE5 inhibitors has shed light on new mechanisms and has revealed a number of pleiotropic effects on the cardiovascular (CV) system. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension, and both sildenafil and tadalafil are approved for this indication. However, current or future PDE5 inhibitors have the potential of becoming clinically useful in a variety of CV conditions such as heart failure, coronary artery disease, and hypertension. The present review discusses recent findings regarding pharmacologic treatment of ED and its interaction with the CV system and highlights current and future clinical applications beyond ED.

Publication trends in Naunyn-Schmiedeberg's Archives of Pharmacology: focus on pharmacology in Egypt.

PubMed

El-Mas, Mahmoud M; El-Gowelli, Hanan M; Michel, Martin C

2013-11-01

In a previous analysis of the country of origin of papers published in Naunyn-Schmiedeberg's Archives of Pharmacology, a major shift toward contributions from emerging market countries, was noticed in comparison of 2010 to 2001 publications. Repeating such analysis for 2012 publications in the journal confirmed this trend. An interesting new trend was the emerging presence of papers from a variety of Islamic countries including Egypt. Based on this trend, we shortly review the history and current structure of pharmacology in Egypt. It appears that the presence of Egyptian pharmacology in international journals including pharmacology journals has sharply been increasing over the last two decades. Challenges for a continuation of this encouraging trend are being discussed.

Pharmacometabolomics Informs Quantitative Radiomics for Glioblastoma Diagnostic Innovation.

PubMed

Katsila, Theodora; Matsoukas, Minos-Timotheos; Patrinos, George P; Kardamakis, Dimitrios

2017-08-01

Applications of omics systems biology technologies have enormous promise for radiology and diagnostics in surgical fields. In this context, the emerging fields of radiomics (a systems scale approach to radiology using a host of technologies, including omics) and pharmacometabolomics (use of metabolomics for patient and disease stratification and guiding precision medicine) offer much synergy for diagnostic innovation in surgery, particularly in neurosurgery. This synthesis of omics fields and applications is timely because diagnostic accuracy in central nervous system tumors still challenges decision-making. Considering the vast heterogeneity in brain tumors, disease phenotypes, and interindividual variability in surgical and chemotherapy outcomes, we believe that diagnostic accuracy can be markedly improved by quantitative radiomics coupled to pharmacometabolomics and related health information technologies while optimizing economic costs of traditional diagnostics. In this expert review, we present an innovation analysis on a systems-level multi-omics approach toward diagnostic accuracy in central nervous system tumors. For this, we suggest that glioblastomas serve as a useful application paradigm. We performed a literature search on PubMed for articles published in English between 2006 and 2016. We used the search terms "radiomics," "glioblastoma," "biomarkers," "pharmacogenomics," "pharmacometabolomics," "pharmacometabonomics/pharmacometabolomics," "collaborative informatics," and "precision medicine." A list of the top 4 insights we derived from this literature analysis is presented in this study. For example, we found that (i) tumor grading needs to be better refined, (ii) diagnostic precision should be improved, (iii) standardization in radiomics is lacking, and (iv) quantitative radiomics needs to prove clinical implementation. We conclude with an interdisciplinary call to the metabolomics, pharmacy/pharmacology, radiology, and surgery communities that

Sobol Sensitivity Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology Models

PubMed Central

Trame, MN; Lesko, LJ

2015-01-01

A systems pharmacology model typically integrates pharmacokinetic, biochemical network, and systems biology concepts into a unifying approach. It typically consists of a large number of parameters and reaction species that are interlinked based upon the underlying (patho)physiology and the mechanism of drug action. The more complex these models are, the greater the challenge of reliably identifying and estimating respective model parameters. Global sensitivity analysis provides an innovative tool that can meet this challenge. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 69–79; doi:10.1002/psp4.6; published online 25 February 2015 PMID:27548289

Herb pair Danggui-Honghua: mechanisms underlying blood stasis syndrome by system pharmacology approach

NASA Astrophysics Data System (ADS)

Yue, Shi-Jun; Xin, Lan-Ting; Fan, Ya-Chu; Li, Shu-Jiao; Tang, Yu-Ping; Duan, Jin-Ao; Guan, Hua-Shi; Wang, Chang-Yun

2017-01-01

Herb pair Danggui-Honghua has been frequently used for treatment of blood stasis syndrome (BSS) in China, one of the most common clinical pathological syndromes in traditional Chinese medicine (TCM). However, its therapeutic mechanism has not been clearly elucidated. In the present study, a feasible system pharmacology model based on chemical, pharmacokinetic and pharmacological data was developed via network construction approach to clarify the mechanisms of this herb pair. Thirty-one active ingredients of Danggui-Honghua possessing favorable pharmacokinetic profiles and biological activities were selected, interacting with 42 BSS-related targets to provide potential synergistic therapeutic actions. Systematic analysis of the constructed networks revealed that these targets such as HMOX1, NOS2, NOS3, HIF1A and PTGS2 were mainly involved in TNF signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway and neurotrophin signaling pathway. The contribution index of every active ingredient also indicated six compounds, including hydroxysafflor yellow A, safflor yellow A, safflor yellow B, Z-ligustilide, ferulic acid, and Z-butylidenephthalide, as the principal components of this herb pair. These results successfully explained the polypharmcological mechanisms underlying the efficiency of Danggui-Honghua for BSS treatment, and also probed into the potential novel therapeutic strategies for BSS in TCM.

The Chemical Basis of Pharmacology

PubMed Central

2010-01-01

Molecular biology now dominates pharmacology so thoroughly that it is difficult to recall that only a generation ago the field was very different. To understand drug action today, we characterize the targets through which they act and new drug leads are discovered on the basis of target structure and function. Until the mid-1980s the information often flowed in reverse: investigators began with organic molecules and sought targets, relating receptors not by sequence or structure but by their ligands. Recently, investigators have returned to this chemical view of biology, bringing to it systematic and quantitative methods of relating targets by their ligands. This has allowed the discovery of new targets for established drugs, suggested the bases for their side effects, and predicted the molecular targets underlying phenotypic screens. The bases for these new methods, some of their successes and liabilities, and new opportunities for their use are described. PMID:21058655

Pharmacological effects of biotin.

PubMed

Fernandez-Mejia, Cristina

2005-07-01

In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.

Only connect: the merger of BMC Pharmacology and BMC Clinical Pharmacology.

PubMed

Moylan, Elizabeth C; Morrey, Christopher; Appleford-Cook, Joanne M

2012-08-13

This editorial celebrates the launch of BMC Pharmacology and Toxicology within the BMC series of journals published by BioMed Central. The scope of the journal is interdisciplinary encompassing toxicology, experimental and clinical pharmacology including clinical trials. In this editorial we discuss the origins of this new journal and the ethos and policies under which it will operate.

Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans.

PubMed

Lee, Paul; Greenfield, Jerry R

2015-12-15

Humans maintain core temperature through a complex neuroendocrine circuitry, coupling environmental thermal and nutritional cues to heat-producing and dissipating mechanisms. Up to 40% of resting energy expenditure contributes to thermal homeostasis maintenance. Recent re-discovery of thermogenic brown adipose tissue (BAT) has brought the relation between ambient temperature, thermogenesis and systemic energy and substrate metabolism to the forefront. In addition to well-known pituitary-thyroid-adrenal axis, new endocrine signals, such as FGF21 and irisin, orchestrate crosstalk between white adipose tissue (WAT), BAT and muscle, tuning non-shivering and shivering thermogenesis responses. Cold exposure modulates the endocrine milieu, and cold-induced hormones cause bioenergetics transformation sufficient to impact whole body metabolism. This review will appraise the nature of human BAT and the basis of BAT-centred therapeutics, highlighting how the interaction between hormones and adipose tissue impacts metabolic responses. Non-pharmacological and pharmacological strategies of BAT recruitment and/or fat browning for metabolic benefits will be discussed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Quantitative Approach to the Formal Verification of Real-Time Systems.

DTIC Science & Technology

1996-09-01

Computer Science A Quantitative Approach to the Formal Verification of Real - Time Systems Sergio Vale Aguiar Campos September 1996 CMU-CS-96-199...ptisiic raieaiSI v Diambimos Lboiamtad _^ A Quantitative Approach to the Formal Verification of Real - Time Systems Sergio Vale Aguiar Campos...implied, of NSF, the Semiconduc- tor Research Corporation, ARPA or the U.S. government. Keywords: real - time systems , formal verification, symbolic

Computational Approaches to Drug Repurposing and Pharmacology

PubMed Central

Hodos, Rachel A; Kidd, Brian A; Khader, Shameer; Readhead, Ben P; Dudley, Joel T

2016-01-01

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing- finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we rationalize that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. PMID:27080087

Pharmacology of the Phosphate Binder, Lanthanum Carbonate

PubMed Central

Damment, Stephen JP

2011-01-01

Studies were conducted to compare the phosphate-binding efficacy of lanthanum carbonate directly with other clinically used phosphate binders and to evaluate any potential adverse pharmacology. To examine the phosphate-binding efficacy, rats with normal renal function and chronic renal failure received lanthanum carbonate, aluminum hydroxide, calcium carbonate, or sevelamer hydrochloride in several experimental models. Lanthanum carbonate and aluminum hydroxide markedly increased excretion of [32P]-phosphate in feces and reduced excretion in urine in rats with normal renal function (p < 0.05), indicating good dietary phosphate-binding efficacy. In rats with chronic renal failure, lanthanum carbonate and aluminum hydroxide reduced urinary phosphate excretion to a greater degree and more rapidly than calcium carbonate, which in turn was more effective than sevelamer hydrochloride. The potential to induce adverse pharmacological effects was assessed systematically in mice, rats, and dogs with normal renal function using standard in vivo models. There was no evidence of any adverse secondary pharmacological effects of lanthanum carbonate on the central nervous, cardiovascular, respiratory, or gastrointestinal systems. These studies indicate that lanthanum carbonate is the more potent of the currently available dietary phosphate binders. No adverse secondary pharmacological actions were observed in vivo in a systematic evaluation at high doses. PMID:21332344

Pharmacology and function of melatonin receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dubocovich, M.L.

The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that ismore » pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-(125I)iodomelatonin are identical. It is proposed that 2-(125I)iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-(125I)iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references.« less

Marine Pharmacology in 2012-2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

PubMed

Mayer, Alejandro M S; Rodríguez, Abimael D; Taglialatela-Scafati, Orazio; Fusetani, Nobuhiro

2017-08-29

The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998-2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012-2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories.

New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

PubMed

Greig, Nigel H; Reale, Marcella; Tata, Ada M

2013-08-01

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

The development of a computer assisted instruction and assessment system in pharmacology.

PubMed

Madsen, B W; Bell, R C

1977-01-01

We describe the construction of a computer based system for instruction and assessment in pharmacology, utilizing a large bank of multiple choice questions. Items were collected from many sources, edited and coded for student suitability, topic, taxonomy and difficulty and text references. Students reserve a time during the day, specify the type of test desired and questions are presented randomly from the subset satisfying their criteria. Answers are scored after each question and a summary given at the end of every test; details on item performance are recorded automatically. The biggest hurdle in implementation was the assembly, review, classification and editing of items, while the programming was relatively straight-forward. A number of modifications had to be made to the initial plans and changes will undoubtedly continue with further experience. When fully operational the system will possess a number of advantages including: elimination of test preparation, editing and marking; facilitated item review opportunities; increased objectivity, feedback, flexibility and descreased anxiety in students.

Assessing the effects of pharmacological agents on respiratory dynamics using time-series modeling.

PubMed

Wong, Kin Foon Kevin; Gong, Jen J; Cotten, Joseph F; Solt, Ken; Brown, Emery N

2013-04-01

Developing quantitative descriptions of how stimulant and depressant drugs affect the respiratory system is an important focus in medical research. Respiratory variables-respiratory rate, tidal volume, and end tidal carbon dioxide-have prominent temporal dynamics that make it inappropriate to use standard hypothesis-testing methods that assume independent observations to assess the effects of these pharmacological agents. We present a polynomial signal plus autoregressive noise model for analysis of continuously recorded respiratory variables. We use a cyclic descent algorithm to maximize the conditional log likelihood of the parameters and the corrected Akaike's information criterion to choose simultaneously the orders of the polynomial and the autoregressive models. In an analysis of respiratory rates recorded from anesthetized rats before and after administration of the respiratory stimulant methylphenidate, we use the model to construct within-animal z-tests of the drug effect that take account of the time-varying nature of the mean respiratory rate and the serial dependence in rate measurements. We correct for the effect of model lack-of-fit on our inferences by also computing bootstrap confidence intervals for the average difference in respiratory rate pre- and postmethylphenidate treatment. Our time-series modeling quantifies within each animal the substantial increase in mean respiratory rate and respiratory dynamics following methylphenidate administration. This paradigm can be readily adapted to analyze the dynamics of other respiratory variables before and after pharmacologic treatments.

Post-stroke Movement Disorders: Clinical Manifestations and Pharmacological Management

PubMed Central

Siniscalchi, Antonio; Gallelli, Luca; Labate, Angelo; Malferrari, Giovanni; Palleria, Caterina; Sarro, Giovambattista De

2012-01-01

Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in post-stroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach. PMID:23449883

Post-stroke Movement Disorders: Clinical Manifestations and Pharmacological Management.

PubMed

Siniscalchi, Antonio; Gallelli, Luca; Labate, Angelo; Malferrari, Giovanni; Palleria, Caterina; Sarro, Giovambattista De

2012-09-01

Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in post-stroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach.

Safety in Acute Pain Medicine-Pharmacologic Considerations and the Impact of Systems-Based Gaps.

PubMed

Weingarten, Toby N; Taenzer, Andreas H; Elkassabany, Nabil M; Le Wendling, Linda; Nin, Olga; Kent, Michael L

2018-05-02

In the setting of an expanding prevalence of acute pain medicine services and the aggressive use of multimodal analgesia, an overview of systems-based safety gaps and safety concerns in the setting of aggressive multimodal analgesia is provided below. Expert commentary. Recent evidence focused on systems-based gaps in acute pain medicine is discussed. A focused literature review was conducted to assess safety concerns related to commonly used multimodal pharmacologic agents (opioids, nonsteroidal anti-inflammatory drugs, gabapentanoids, ketamine, acetaminophen) in the setting of inpatient acute pain management. Optimization of systems-based gaps will increase the probability of accurate pain assessment, improve the application of uniform evidence-based multimodal analgesia, and ensure a continuum of pain care. While acute pain medicine strategies should be aggressively applied, multimodal regimens must be strategically utilized to minimize risk to patients and in a comorbidity-specific fashion.

NASA 2010 Pharmacology Evidence Review

NASA Technical Reports Server (NTRS)

Steinberg, Susan

2011-01-01

In 2008, the Institute of Medicine reviewed NASA's Human Research Program Evidence in assessing the Pharmacology risk identified in NASA's Human Research Program Requirements Document (PRD). Since this review there was a major reorganization of the Pharmacology discipline within the HRP, as well as a re-evaluation of the Pharmacology evidence. This panel is being asked to review the latest version of the Pharmacology Evidence Report. Specifically, this panel will: (1) Appraise the descriptions of the human health-related risk in the HRP PRD. (2) Assess the relevance and comprehensiveness of the evidence in identifying potential threats to long-term space missions. (3) Assess the associated gaps in knowledge and identify additional areas for research as necessary.

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

PubMed

Derendorf, H; Meltzer, E O

2008-10-01

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review

PubMed Central

Merlin, Jessica S.; Bulls, Hailey W.; Vucovich, Lee A.; Edelman, E. Jennifer; Starrels, Joanna L.

2016-01-01

Chronic pain occurs in as many as 85% of individuals with HIV and is associated with substantial functional impairment. Little guidance is available for HIV providers seeking to address their patients’ chronic pain. We conducted a systematic review to identify clinical trials and observational studies that examined the impact of pharmacologic or non-pharmacologic interventions on pain and/or functional outcomes among HIV-infected individuals with chronic pain in high-development countries. Eleven studies met inclusion criteria and were mostly low or very low quality. Seven examined pharmacologic interventions (gabapentin, pregabalin, capsaicin, analgesics including opioids) and four examined non-pharmacologic interventions (cognitive behavioral therapy, self-hypnosis, smoked cannabis). The only controlled studies with positive results were of capsaicin and cannabis, and had short-term follow-up (≤12 weeks). Among the seven studies of pharmacologic interventions, five had substantial pharmaceutical industry sponsorship. These findings highlight several important gaps in the HIV/chronic pain literature that require further research. PMID:27267445

Pharmacological modulation of mitochondrial calcium homeostasis.

PubMed

Arduino, Daniela M; Perocchi, Fabiana

2018-01-10

Mitochondria are pivotal organelles in calcium (Ca 2+ ) handling and signalling, constituting intracellular checkpoints for numerous processes that are vital for cell life. Alterations in mitochondrial Ca 2+ homeostasis have been linked to a variety of pathological conditions and are critical in the aetiology of several human diseases. Efforts have been taken to harness mitochondrial Ca 2+ transport mechanisms for therapeutic intervention, but pharmacological compounds that direct and selectively modulate mitochondrial Ca 2+ homeostasis are currently lacking. New avenues have, however, emerged with the breakthrough discoveries on the genetic identification of the main players involved in mitochondrial Ca 2+ influx and efflux pathways and with recent hints towards a deep understanding of the function of these molecular systems. Here, we review the current advances in the understanding of the mechanisms and regulation of mitochondrial Ca 2+ homeostasis and its contribution to physiology and human disease. We also introduce and comment on the recent progress towards a systems-level pharmacological targeting of mitochondrial Ca 2+ homeostasis. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System.

PubMed

Wehrwein, Erica A; Orer, Hakan S; Barman, Susan M

2016-06-13

Comprised of the sympathetic nervous system, parasympathetic nervous system, and enteric nervous system, the autonomic nervous system (ANS) provides the neural control of all parts of the body except for skeletal muscles. The ANS has the major responsibility to ensure that the physiological integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) in the face of perturbations exerted by both the external and internal environments. Many commonly prescribed drugs, over-the-counter drugs, toxins, and toxicants function by altering transmission within the ANS. Autonomic dysfunction is a signature of many neurological diseases or disorders. Despite the physiological relevance of the ANS, most neuroscience textbooks offer very limited coverage of this portion of the nervous system. This review article provides both historical and current information about the anatomy, physiology, and pharmacology of the sympathetic and parasympathetic divisions of the ANS. The ultimate aim is for this article to be a valuable resource for those interested in learning the basics of these two components of the ANS and to appreciate its importance in both health and disease. Other resources should be consulted for a thorough understanding of the third division of the ANS, the enteric nervous system. © 2016 American Physiological Society. Compr Physiol 6:1239-1278, 2016. Copyright © 2016 John Wiley & Sons, Inc.

Nurse Practitioner Pharmacology Education.

ERIC Educational Resources Information Center

Waigandt, Alex; Chang, Jane

A study compared the pharmacology training of nurse practitioner programs with medical and dental programs. Seventy-three schools in 14 states (40 nurse practitioner programs, 19 schools of medicine, and 14 schools of dentistry) were surveyed by mailed questionnaire about the number of hours devoted to the study of pharmacology. The major findings…

[The development of experimental pharmacology 1790-1850].

PubMed

Bickel, M H

2000-01-01

1. The use of drugs goes back to the origins of mankind. In historical times oral drug-lore became codified empiric drug theory (materia medica) and ultimately, in the 19th century, experimental pharmacology. The initiator of experimental pharmacology as an independent medical discipline is Rudolf Buchheim (1820-1879). This study traces the pathways leading to Buchheim and identifies his predecessors between 1790 and 1850. The history of empirical pharmacology and its major theories in Antiquity, the Middle Ages, and early modern times is summarized. For the 18th century an overview is given on early attempts at experimental testing of drug effects and on the new therapeutic systems and medical sects. 2. Many authors have dealt with the grievances of pharmacology and therapy between 1790 and 1850, among them chief representatives of contemporary medicine like the French Fourcroy, Bichat, Pinel, Alibert, Magendie, and the Germans Schönlein, Mitscherlich, Wunderlich, Henle, and Oesterlen. Their criticisms are a means for a better understanding of the situation. They cover the following aspects. Pharmacology is distorted by speculations on the causes of drug action and confusion with regard to terminology and indications. Drug actions are being tested with inadequate methods. An increase in the number of drugs is mistaken for an increase in knowledge. The statement is made that pharmacology is the least developed of all medical subjects. The critics point out that only a more developed chemistry, physiology, and etiology will allow a scientific pharmacology. The drug theories of the medical sects are likewise rejected. Polypharmacy, composite drugs, and absurd formulas are regarded with contempt. Aggressive drug therapy is repudiated, but this easily results in avoidance of drugs and in therapeutic nihilism. 3. In 1799 Johann Christian Reil elaborated his principles for a future pharmacology. Reil establishes the rules for clinical experiments on which a scientific

An overview of the safety pharmacology society strategic plan.

PubMed

Pugsley, M K; Authier, S; Koerner, J E; Redfern, W S; Markgraf, C G; Brabham, T; Correll, K; Soloviev, M V; Botchway, A; Engwall, M; Traebert, M; Valentin, J-P; Mow, T J; Greiter-Wilke, A; Leishman, D J; Vargas, H M

2018-01-09

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.

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

PubMed Central

Wong, Peiyan; Sze, Ying; Gray, Laura Jane; Chang, Cecilia Chin Roei; Cai, Shiwei; Zhang, Xiaodong

2015-01-01

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7–11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7–11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7–11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive

Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin.

PubMed

Tuli, Hardeep S; Sandhu, Sardul S; Sharma, A K

2014-02-01

An entomopathogenic fungus, Cordyceps sp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable candidate for ethno-pharmacological use. Main constituent of the extract derived from this fungus comprises a novel bio-metabolite called as Cordycepin (3'deoxyadenosine) which has a very potent anti-cancer, anti-oxidant and anti-inflammatory activities. The current review discusses about the broad spectrum potential of Cordycepin including biological and pharmacological actions in immunological, hepatic, renal, cardiovascular systems as well as an anti-cancer agent. The article also reviews the current efforts to delineate the mechanism of action of Cordycepin in various bio-molecular processes. The study will certainly draw the attention of scientific community to improve the bioactivity and production of Cordycepin for its commercial use in pharmacological and medical fields.

Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM.

PubMed

Wang, Yonghua; Zheng, Chunli; Huang, Chao; Li, Yan; Chen, Xuetong; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Zhang, Boli

2015-01-01

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future.

Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM

PubMed Central

Wang, Yonghua; Zheng, Chunli; Huang, Chao; Li, Yan; Chen, Xuetong; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Zhang, Boli

2015-01-01

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future. PMID:26101539

A review on phytochemistry, pharmacology and toxicology studies of Aconitum.

PubMed

Nyirimigabo, Eric; Xu, Yanyan; Li, Yubo; Wang, Yuming; Agyemang, Kojo; Zhang, Yanjun

2015-01-01

A number of species belonging to herbal genus Aconitum are well-known and popular for their medicinal benefits in Indian, Vietnamese, Korean, Japanese, Tibetan and Chinese systems of medicine. It is a valuable drug as well as an unpredictable toxic material. It is therefore imperative to understand and control the toxic potential of herbs from this genus. In this review, the ethnomedicinal, phytochemistry, pharmacology, structure activity relationship and toxicology studies of Aconitum were presented to add to knowledge for their safe application. A total of about 76 of all aconite species growing in China and surrounding far-east and Asian countries are used for various medical purposes. The main ingredients of aconite species are alkaloids, flavonoids, free fatty acids and polysaccharides. The tuberous roots of genus Aconitum are commonly applied for various diseases such as rheumatic fever, painful joints and some endocrinal disorders. It stimulates the tip of sensory nerve fibres. These tubers of Aconitum are used in the herbal medicines only after processing. There remain high toxicological risks of the improper medicinal applications of Aconitum. The cardio and neurotoxicities of this herb are potentially lethal. Many analytical methods have been reported for quantitatively and qualitatively characterization of Aconitum. Aconitum is a plant of great importance both in traditional medicine in general and in TCM in particular. Much attention should be put on Aconitum because of its narrow therapeutic range. However, Aconitum's toxicity can be reduced using different techniques and then benefit from its pharmacological activities. New methods, approaches and techniques should be developed for chemical and toxicological analysis to improve its quality and safety. © 2014 Royal Pharmaceutical Society.

Pharmacology for the Psychotherapist.

ERIC Educational Resources Information Center

Goldenberg, Myron Michael

This book covers those areas of pharmacology that are of importance and interest to the psychotherapist. The 1st chapter introduces the various types of drugs. The 2nd chapter presents an overview of pharmacology and its principles. The 3rd chapter reviews aspects of the human body of importance to understanding the workings of psychotropic drugs.…

Finnish nurses' and nursing students' pharmacological skills.

PubMed

Grandell-Niemi, Heidi; Hupli, Maija; Leino-Kilpi, Helena; Puukka, Pauli

2005-07-01

PURPOSES AND OBJECTIVES: The purposes of this study were to investigate the pharmacological skills of Finnish nurses and graduating nursing students, to determine how pharmacological skills are related to background factors and to identify differences between nurses and students and, finally, to examine how the instrument used, the Medication Calculation Skills Test, works. Pharmacology is a relevant and topical subject. In several studies, however, pharmacological skills of nurses and nursing students have been found insufficient. In addition, pharmacology as a subject is found to be difficult for both nursing students and nurses. The study was evaluative in nature; the data were collected using the Medication Calculation Skills Test, developed for the purposes of this study. The instrument was used to gather information on background factors and self-rated pharmacological and mathematical skills and to test actual skills in these areas. Results concerning pharmacological skills are reported in this paper. The maximum Medication Calculation Skills Test score was 24 points. The mean score for nurses was 18.6 and that for students 16.3. Half of (50%) the students attained a score of 67% and 57% of nurses attained a score of 79%. Nurses and students had some deficiencies in their pharmacological skills. Nurses had better pharmacological skills than students according to both self-ratings and actual performance on the test. It is vitally important that nurses have adequate pharmacological skills to administer medicines correctly. This study showed that the Medication Calculation Skills Test seems to work well in measuring pharmacological skills, even though it needs further evaluation. Findings from this study can be used when planning the nursing curriculum and further education for Registered Nurses.

Pharmacological treatment of tobacco dependence.

PubMed

Jarvik, M E; Henningfield, J E

1988-05-01

Pharmacologically based approaches for the treatment of tobacco dependence are reviewed. The rational basis for pharmacologic treatment approaches is that tobacco dependence is partially, and critically, mediated by the actions of tobacco-delivered nicotine to the central nervous system. These actions include direct reinforcing properties of nicotine itself, tolerance and physiologic dependence, possible beneficial effects of nicotine in the alleviation of anxiety and control of weight, and neurohormonal regulation which can become important to the maintenance of emotional well-being and performance at work. Insofar as tobacco abstinence leads to negative consequences, via these biobehavioral mechanisms, pharmacologic intervention should be able to assist in initial tobacco detoxification and help tobacco abstinent persons to avoid subsequent relapse. The purpose of this review is to survey some of the efforts to develop such interventions, as well as to elucidate some of the issues relevant to such development. Four distinct approaches are discussed: (1) Nicotine replacement, in which physiologic dependence is transferred to a safer and more therapeutically manageable nicotine delivering formulation; this category includes nicotine polacrilex gum; (2) Blockade therapy, in which a drug is taken that blocks the reinforcing properties of nicotine should relapse occur; (3) Nonspecific pharmacotherapy, in which the biobehaviorally mediated correlates of tobacco abstinence are treated on a symptomatic basis; (4) Deterrent therapy, in which a drug is taken prior to smoking such that any tobacco use would produce reliable aversive effects.

Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews

PubMed Central

Gartlehner, Gerald; Wagner, Gernot; Matyas, Nina; Titscher, Viktoria; Greimel, Judith; Lux, Linda; Gaynes, Bradley N; Viswanathan, Meera; Patel, Sheila; Lohr, Kathleen N

2017-01-01

Objectives This study aims to summarise the evidence on more than 140 pharmacological and non-pharmacological treatment options for major depressive disorder (MDD) and to evaluate the confidence that patients and clinicians can have in the underlying science about their effects. Design This is a review of systematic reviews. Data sources This study used MEDLINE, Embase, Cochrane Library, PsycINFO and Epistemonikos from 2011 up to February 2017 for systematic reviews of randomised controlled trials in adult patients with acute-phase MDD. Methods We dually reviewed abstracts and full-text articles, rated the risk of bias of eligible systematic reviews and graded the strength of evidence. Results Nineteen systematic reviews provided data on 28 comparisons of interest. For general efficacy, only second-generation antidepressants were supported with high strength evidence, presenting small beneficial treatment effects (standardised mean difference: −0.35; 95% CI −0.31 to −0.38), and a statistically significantly higher rate of discontinuation because of adverse events than patients on placebo (relative risk (RR) 1.88; 95% CI 1.0 to 3.28). Only cognitive behavioural therapy is supported by reliable evidence (moderate strength of evidence) to produce responses to treatment similar to those of second-generation antidepressants (45.5% vs 44.2%; RR 1.10; 95% CI 0.93 to 1.30). All remaining comparisons of non-pharmacological treatments with second-generation antidepressants either led to inconclusive results or had substantial methodological shortcomings (low or insufficient strength of evidence). Conclusions In contrast to pharmacological treatments, the majority of non-pharmacological interventions for treating patients with MDD are not evidence based. For patients with strong preferences against pharmacological treatments, clinicians should focus on therapies that have been compared directly with antidepressants. Trial registration number International

Dependence of quantitative accuracy of CT perfusion imaging on system parameters

NASA Astrophysics Data System (ADS)

Li, Ke; Chen, Guang-Hong

2017-03-01

Deconvolution is a popular method to calculate parametric perfusion parameters from four dimensional CT perfusion (CTP) source images. During the deconvolution process, the four dimensional space is squeezed into three-dimensional space by removing the temporal dimension, and a prior knowledge is often used to suppress noise associated with the process. These additional complexities confound the understanding about deconvolution-based CTP imaging system and how its quantitative accuracy depends on parameters and sub-operations involved in the image formation process. Meanwhile, there has been a strong clinical need in answering this question, as physicians often rely heavily on the quantitative values of perfusion parameters to make diagnostic decisions, particularly during an emergent clinical situation (e.g. diagnosis of acute ischemic stroke). The purpose of this work was to develop a theoretical framework that quantitatively relates the quantification accuracy of parametric perfusion parameters with CTP acquisition and post-processing parameters. This goal was achieved with the help of a cascaded systems analysis for deconvolution-based CTP imaging systems. Based on the cascaded systems analysis, the quantitative relationship between regularization strength, source image noise, arterial input function, and the quantification accuracy of perfusion parameters was established. The theory could potentially be used to guide developments of CTP imaging technology for better quantification accuracy and lower radiation dose.

Rapid Analysis of Pharmacology for Infectious Diseases

PubMed Central

Hopkins, Andrew L; Bickerton, G. Richard; Carruthers, Ian M; Boyer, Stephen K; Rubin, Harvey; Overington, John P

2011-01-01

Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to develop high productivity discovery systems that can be applied to a large number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori potential drug targets and analyze the pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of test-able pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes. In particular our goal is to identify potential drug targets present in a pathogen genome and prioritize which pharmacological experiments are most likely to discover drug-like lead compounds rapidly against a pathogen (i.e. which specific compounds and drug targets should be screened, in which assays and where they can be sourced). An integral part of the challenge is the development and integration of methods to predict druggability, essentiality, synthetic lethality and polypharmocology in pathogen genomes, while simultaneously integrating the inevitable issues of chemical tractability and the potential for acquired drug resistance from the start. PMID:21401504

Computing Quantitative Characteristics of Finite-State Real-Time Systems

DTIC Science & Technology

1994-05-04

Current methods for verifying real - time systems are essentially decision procedures that establish whether the system model satisfies a given...specification. We present a general method for computing quantitative information about finite-state real - time systems . We have developed algorithms that...our technique can be extended to a more general representation of real - time systems , namely, timed transition graphs. The algorithms presented in this

Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

PubMed

Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

2014-10-03

The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Quantitative model validation of manipulative robot systems

NASA Astrophysics Data System (ADS)

Kartowisastro, Iman Herwidiana

This thesis is concerned with applying the distortion quantitative validation technique to a robot manipulative system with revolute joints. Using the distortion technique to validate a model quantitatively, the model parameter uncertainties are taken into account in assessing the faithfulness of the model and this approach is relatively more objective than the commonly visual comparison method. The industrial robot is represented by the TQ MA2000 robot arm. Details of the mathematical derivation of the distortion technique are given which explains the required distortion of the constant parameters within the model and the assessment of model adequacy. Due to the complexity of a robot model, only the first three degrees of freedom are considered where all links are assumed rigid. The modelling involves the Newton-Euler approach to obtain the dynamics model, and the Denavit-Hartenberg convention is used throughout the work. The conventional feedback control system is used in developing the model. The system behavior to parameter changes is investigated as some parameters are redundant. This work is important so that the most important parameters to be distorted can be selected and this leads to a new term called the fundamental parameters. The transfer function approach has been chosen to validate an industrial robot quantitatively against the measured data due to its practicality. Initially, the assessment of the model fidelity criterion indicated that the model was not capable of explaining the transient record in term of the model parameter uncertainties. Further investigations led to significant improvements of the model and better understanding of the model properties. After several improvements in the model, the fidelity criterion obtained was almost satisfied. Although the fidelity criterion is slightly less than unity, it has been shown that the distortion technique can be applied in a robot manipulative system. Using the validated model, the importance of

Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

NASA Astrophysics Data System (ADS)

Ferrie, Ann M.; Sun, Haiyan; Fang, Ye

2011-07-01

We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs.

On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).

PubMed

Costa, Barbara

2007-08-01

Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.

Pharmacologic Effects in vivo in Brain by Vector-Mediated Peptide Drug Delivery

NASA Astrophysics Data System (ADS)

Bickel, Ulrich; Yoshikawa, Takayoshi; Landaw, Elliot M.; Faull, Kym F.; Pardridge, William M.

1993-04-01

Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 μg/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes.

PubMed

Nyman, Elin; Rozendaal, Yvonne J W; Helmlinger, Gabriel; Hamrén, Bengt; Kjellsson, Maria C; Strålfors, Peter; van Riel, Natal A W; Gennemark, Peter; Cedersund, Gunnar

2016-04-06

We are currently in the middle of a major shift in biomedical research: unprecedented and rapidly growing amounts of data may be obtained today, from in vitro, in vivo and clinical studies, at molecular, physiological and clinical levels. To make use of these large-scale, multi-level datasets, corresponding multi-level mathematical models are needed, i.e. models that simultaneously capture multiple layers of the biological, physiological and disease-level organization (also referred to as quantitative systems pharmacology-QSP-models). However, today's multi-level models are not yet embedded in end-usage applications, neither in drug research and development nor in the clinic. Given the expectations and claims made historically, this seemingly slow adoption may seem surprising. Therefore, we herein consider a specific example-type 2 diabetes-and critically review the current status and identify key remaining steps for these models to become mainstream in the future. This overview reveals how, today, we may use models to ask scientific questions concerning, e.g., the cellular origin of insulin resistance, and how this translates to the whole-body level and short-term meal responses. However, before these multi-level models can become truly useful, they need to be linked with the capabilities of other important existing models, in order to make them 'personalized' (e.g. specific to certain patient phenotypes) and capable of describing long-term disease progression. To be useful in drug development, it is also critical that the developed models and their underlying data and assumptions are easily accessible. For clinical end-usage, in addition, model links to decision-support systems combined with the engagement of other disciplines are needed to create user-friendly and cost-efficient software packages.

Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

PubMed Central

Simoes-Pires, Claudia; Hostettmann, Kurt; Haouala, Amina; Cuendet, Muriel; Falquet, Jacques; Graz, Bertrand; Christen, Philippe

2014-01-01

Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodiumfalciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant. PMID:25516845

Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana.

PubMed

Simoes-Pires, Claudia; Hostettmann, Kurt; Haouala, Amina; Cuendet, Muriel; Falquet, Jacques; Graz, Bertrand; Christen, Philippe

2014-12-01

Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate-amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

Pharmacological properties of Datura stramonium L. as a potential medicinal tree: An overview

PubMed Central

Soni, Priyanka; Siddiqui, Anees Ahmad; Dwivedi, Jaya; Soni, Vishal

2012-01-01

India has a great wealth of various naturally occurring plant drugs which have great potential pharmacological activities. Datura stramonium (D. stramonium) is one of the widely well known folklore medicinal herbs. The troublesome weed, D. stramonium is a plant with both poisonous and medicinal properties and has been proven to have great pharmacological potential with a great utility and usage in folklore medicine. D. stromonium has been scientifically proven to contain alkaloids, tannins, carbohydrates and proteins. This plant has contributed various pharmacological actions in the scientific field of Indian systems of medicines like analgesic and antiasthmatic activities. The present paper presents an exclusive review work on the ethnomedical, phytochemical, pharmacological activities of this plant. PMID:23593583

Neuroprotection for the new millennium. Matchmaking pharmacology and technology

NASA Technical Reports Server (NTRS)

Andrews, R. J.

2001-01-01

A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention--hence the abandonment of the "magic bullet" single pharmacologic agent for neuroprotection in favor of pharmacologic "cocktails". A second theme of the 1990s has been the progress in technology for neuroprotection, minimally- or non-invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely "jamming" the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or "hardware" interventions to influence the programming or "software" of the nervous system's physiologic response in certain disease states.

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action †

PubMed Central

Mayer, Alejandro M. S.; Rodríguez, Abimael D.; Taglialatela-Scafati, Orazio; Fusetani, Nobuhiro

2017-01-01

The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998–2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012–2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories. PMID:28850074

PHARMACOLOGY PART 2: INTRODUCTION TO PHARMACOKINETICS.

PubMed

Currie, Geoffrey M

2018-05-03

Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a series of articles that aims to enhance the understanding of pharmacological principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology and principles of pharmacodynamics explored in the first article in the series. Specifically, this article will focus on the basic principles associated with pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in general nuclear medicine, the fourth pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in nuclear cardiology, the fifth the pharmacology related to contrast media associated with computed tomography (CT) and magnetic resonance imaging (MRI), and the final article will address drugs in the emergency trolley. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity

PubMed Central

Hoppe, George; Yoon, Suzy; Gopalan, Banu; Savage, Alexandria R.; Brown, Rebecca; Case, Kelsey; Vasanji, Amit; Chan, E. Ricky; Silver, Randi B.; Sears, Jonathan E.

2016-01-01

Retinopathy of prematurity (ROP) causes 100,000 new cases of childhood blindness each year. ROP is initiated by oxygen supplementation necessary to prevent neonatal death. We used organ systems pharmacology to define the transcriptomes of mice that were cured of oxygen-induced retinopathy (OIR, ROP model) by hypoxia-inducible factor (HIF) stabilization via HIF prolyl hydroxylase inhibition using the isoquinolone Roxadustat or the 2-oxoglutarate analog dimethyloxalylglycine (DMOG). Although both molecules conferred a protective phenotype, gene expression analysis by RNA sequencing found that Roxadustat can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect hepatic HIF-1 stabilization and increased serum angiokines. As predicted by pathway analysis, Roxadustat rescued the hepatic HIF-1 knockout mouse from retinal oxygen toxicity, whereas DMOG could not. The simplicity of systemic treatment that targets both the liver and the eye provides a rationale for protecting the severely premature infant from oxygen toxicity. PMID:27091985

Quantitative magnetic resonance imaging phantoms: A review and the need for a system phantom.

PubMed

Keenan, Kathryn E; Ainslie, Maureen; Barker, Alex J; Boss, Michael A; Cecil, Kim M; Charles, Cecil; Chenevert, Thomas L; Clarke, Larry; Evelhoch, Jeffrey L; Finn, Paul; Gembris, Daniel; Gunter, Jeffrey L; Hill, Derek L G; Jack, Clifford R; Jackson, Edward F; Liu, Guoying; Russek, Stephen E; Sharma, Samir D; Steckner, Michael; Stupic, Karl F; Trzasko, Joshua D; Yuan, Chun; Zheng, Jie

2018-01-01

The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi-institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application-specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48-61, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

PubMed Central

2010-01-01

Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise

Audience response technology: engaging and empowering non-medical prescribing students in pharmacology learning.

PubMed

Lymn, Joanne S; Mostyn, Alison

2010-10-27

Non-medical prescribing (NMP) is a six month course for nurses and certain allied health professionals. It is critical that these students develop a good understanding of pharmacology; however, many students are mature learners with little or no formal biological science knowledge and struggle with the pharmacology component. The implications for patient safety are profound, therefore we encourage students not just to memorise enough pharmacology to pass the exam but to be able to integrate it into clinical practice. Audience response technology (ART), such as the KeePad system (KS) has been shown to promote an active approach to learning and provide instant formative feedback. The aim of this project, therefore, was to incorporate and evaluate the use the KS in promoting pharmacology understanding in NMP students. Questions were incorporated into eight pharmacology lectures, comprising a mix of basic and clinical pharmacology, using TurningPoint software. Student (n = 33) responses to questions were recorded using the KS software and the percentage of students getting the question incorrect and correct was made immediately available in the lecture in graphical form. Survey data collected from these students investigated student perceptions on the use of the system generally and specifically as a learning tool. More in depth discussion of the usefulness of the KS was derived from a focus group comprising 5 students. 100% of students enjoyed using the KS and felt it promoted their understanding of key concepts; 92% stated that it helped identify their learning needs and 87% agreed that the technology was useful in promoting integration of concepts. The most prevalent theme within feedback was that of identifying their own learning needs. Analysis of data from the focus group generated similar themes, with the addition of improving teaching. Repeated questioning produced a significant increase (p < 0.05) in student knowledge of specific pharmacological concepts. The

Audience response technology: Engaging and empowering non-medical prescribing students in pharmacology learning

PubMed Central

2010-01-01

Background Non-medical prescribing (NMP) is a six month course for nurses and certain allied health professionals. It is critical that these students develop a good understanding of pharmacology; however, many students are mature learners with little or no formal biological science knowledge and struggle with the pharmacology component. The implications for patient safety are profound, therefore we encourage students not just to memorise enough pharmacology to pass the exam but to be able to integrate it into clinical practice. Audience response technology (ART), such as the KeePad system (KS) has been shown to promote an active approach to learning and provide instant formative feedback. The aim of this project, therefore, was to incorporate and evaluate the use the KS in promoting pharmacology understanding in NMP students. Methods Questions were incorporated into eight pharmacology lectures, comprising a mix of basic and clinical pharmacology, using TurningPoint software. Student (n = 33) responses to questions were recorded using the KS software and the percentage of students getting the question incorrect and correct was made immediately available in the lecture in graphical form. Survey data collected from these students investigated student perceptions on the use of the system generally and specifically as a learning tool. More in depth discussion of the usefulness of the KS was derived from a focus group comprising 5 students. Results 100% of students enjoyed using the KS and felt it promoted their understanding of key concepts; 92% stated that it helped identify their learning needs and 87% agreed that the technology was useful in promoting integration of concepts. The most prevalent theme within feedback was that of identifying their own learning needs. Analysis of data from the focus group generated similar themes, with the addition of improving teaching. Repeated questioning produced a significant increase (p < 0.05) in student knowledge of specific

Pharmacological Characterization of Chemically Synthesized Monomeric phi29 pRNA Nanoparticles for Systemic Delivery

PubMed Central

Abdelmawla, Sherine; Guo, Songchuan; Zhang, Limin; Pulukuri, Sai M; Patankar, Prithviraj; Conley, Patrick; Trebley, Joseph; Guo, Peixuan; Li, Qi-Xiang

2011-01-01

Previous studies have shown that the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor folds into a compact structure, constituting a RNA nanoparticle that can be modularized with functional groups as a nanodelivery system. pRNA nanoparticles can also be self-assembled by the bipartite approach without altering folding property. The present study demonstrated that 2′-F-modified pRNA nanoparticles were readily manufactured through this scalable bipartite strategy, featuring total chemical synthesis and permitting diverse functional modularizations. The RNA nanoparticles were chemically and metabolically stable and demonstrated a favorable pharmacokinetic (PK) profile in mice (half-life (T1/2): 5–10 hours, clearance (Cl): <0.13 l/kg/hour, volume of distribution (Vd): 1.2 l/kg). It did not induce an interferon (IFN) response nor did it induce cytokine production in mice. Repeat intravenous administrations in mice up to 30 mg/kg did not result in any toxicity. Fluorescent folate-pRNA nanoparticles efficiently and specifically bound and internalized to folate receptor (FR)-bearing cancer cells in vitro. It also specifically and dose-dependently targeted to FR+ xenograft tumor in mice with minimal accumulation in normal tissues. This first comprehensive pharmacological study suggests that the pRNA nanoparticle had all the preferred pharmacological features to serve as an efficient nanodelivery platform for broad medical applications. PMID:21468004

Pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline.

PubMed

Shi, Jing-Shan; Yu, Jun-Xian; Chen, Xiu-Ping; Xu, Rui-Xia

2003-02-01

The pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline extracted from Uncaria rhynchophylla Miq Jacks were reviewed. The alkaloids mainly act on cardiovascular system and central nervous system including the hypotension, brachycardia, antiarrhythmia, and protection of cerebral ischemia and sedation. The active mechanisms were related to blocking of calcium channel, opening of potassium channel, and regulating of nerve transmitters transport and metabolism, etc.

Pharmacologic overview of Withania somnifera, the Indian Ginseng.

PubMed

Dar, Nawab John; Hamid, Abid; Ahmad, Muzamil

2015-12-01

Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents.

Neuropathic pain in people with cancer (part 2): pharmacological and non-pharmacological management.

PubMed

Taverner, Tarnia

2015-08-01

The aim of this paper is to provide an overview of the management of neuropathic pain associated with cancer and to provide helpful clinical advice for nurses working with patients who may have neuropathic pain. While cancer pain is a mixed-mechanism pain, this article will focus only on neuropathic pain management. The impact of neuropathic pain on patients' quality of life is great and while many patients recover from their cancer, a significant number continue to suffer from a neuropathic pain syndrome. Management of neuropathic pain is significantly different from management of nociceptive pain with respect to pharmacological and non-pharmacological strategies. Neuropathic pain is complex, and as such requires complex management using pharmacological as well as non-pharmacological approaches. Specific drugs for neuropathic pain may be effective for some patients, but not all; therefore, ongoing and comprehensive assessment and management are required. Furthermore, these patients may require trials of several drugs before they find one that works for them. It is important for nurses to understand neuropathic pain, its manifestation, impact on quality of life and management when nursing patients with neuropathic pain associated with cancer.

The Pharmacology of Regenerative Medicine

PubMed Central

Saul, Justin M.; Furth, Mark E.; Andersson, Karl-Erik

2013-01-01

Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase “regenerative pharmacology” to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is “the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues.” As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all. PMID:23818131

Pinocembrin: A Novel Natural Compound with Versatile Pharmacological and Biological Activities

PubMed Central

Rasul, Azhar; Millimouno, Faya Martin; Ali Eltayb, Wafa; Ali, Muhammad; Li, Jiang; Li, Xiaomeng

2013-01-01

Pinocembrin (5,7-dihydroxyflavanone) is one of the primary flavonoids isolated from the variety of plants, mainly from Pinus heartwood, Eucalyptus, Populus, Euphorbia, and Sparattosperma leucanthum, in the diverse flora and purified by various chromatographic techniques. Pinocembrin is a major flavonoid molecule incorporated as multifunctional in the pharmaceutical industry. Its vast range of pharmacological activities has been well researched including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities. In addition, pinocembrin can be used as neuroprotective against cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antiexcitotoxic effects. Pinocembrin exhibits pharmacological effects on almost all systems, and our aim is to review the pharmacological and therapeutic applications of pinocembrin with specific emphasis on mechanisms of actions. The design of new drugs based on the pharmacological effects of pinocembrin could be beneficial. This review suggests that pinocembrin is a potentially promising pharmacological candidate, but additional studies and clinical trials are required to determine its specific intracellular sites of action and derivative targets in order to fully understand the mechanism of its anti-inflammatory, anticancer, and apoptotic effects to further validate its medical applications. PMID:23984355

Interprofessional education in pharmacology using high-fidelity simulation.

PubMed

Meyer, Brittney A; Seefeldt, Teresa M; Ngorsuraches, Surachat; Hendrickx, Lori D; Lubeck, Paula M; Farver, Debra K; Heins, Jodi R

2017-11-01

This study examined the feasibility of an interprofessional high-fidelity pharmacology simulation and its impact on pharmacy and nursing students' perceptions of interprofessionalism and pharmacology knowledge. Pharmacy and nursing students participated in a pharmacology simulation using a high-fidelity patient simulator. Faculty-facilitated debriefing included discussion of the case and collaboration. To determine the impact of the activity on students' perceptions of interprofessionalism and their ability to apply pharmacology knowledge, surveys were administered to students before and after the simulation. Attitudes Toward Health Care Teams scale (ATHCT) scores improved from 4.55 to 4.72 on a scale of 1-6 (p = 0.005). Almost all (over 90%) of the students stated their pharmacology knowledge and their ability to apply that knowledge improved following the simulation. A simulation in pharmacology is feasible and favorably affected students' interprofessionalism and pharmacology knowledge perceptions. Pharmacology is a core science course required by multiple health professions in early program curricula, making it favorable for incorporation of interprofessional learning experiences. However, reports of high-fidelity interprofessional simulation in pharmacology courses are limited. This manuscript contributes to the literature in the field of interprofessional education by demonstrating that an interprofessional simulation in pharmacology is feasible and can favorably affect students' perceptions of interprofessionalism. This manuscript provides an example of a pharmacology interprofessional simulation that faculty in other programs can use to build similar educational activities. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease

PubMed Central

Zhang, Liping; Rajan, Vik; Lin, Eugene; Hu, Zhaoyong; Han, H. Q.; Zhou, Xiaolan; Song, Yanping; Min, Hosung; Wang, Xiaonan; Du, Jie; Mitch, William E.

2011-01-01

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC50 ∼1.2 nM) reversed the loss of body weight (≈5–7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38±1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21±1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.—Zhang, L., Rajan, V., Lin, E., Hu, Z., Han, H.Q., Zhou, X., Song, Y., Min, H., Wang, X., Du, J., Mitch, W. E. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. PMID:21282204

Deciphering the underlying mechanisms of Diesun Miaofang in traumatic injury from a systems pharmacology perspective

PubMed Central

ZHENG, CHUN-SONG; FU, CHANG-LONG; PAN, CAI-BIN; BAO, HONG-JUAN; CHEN, XING-QIANG; YE, HONG-ZHI; YE, JIN-XIA; WU, GUANG-WEN; LI, XI-HAI; XU, HUI-FENG; XU, XIAO-JIE; LIU, XIAN-XIANG

2015-01-01

Diesun Miaofang (DSMF) is a traditional herbal formula, which has been reported to activate blood, remove stasis, promote qi circulation and relieve pain. DSMF holds a great promise for the treatment of traumatic injury in an integrative and holistic manner. However, its underlying mechanisms remain to be elucidated. In the present study, a systems pharmacology model, which integrated cluster ligands, human intestinal absorption and aqueous solution prediction, chemical space mapping, molecular docking and network pharmacology techniques were used. The compounds from DSMF were diverse in the clusters and chemical space. The majority of the compounds exhibited drug-like properties. A total of 59 compounds were identified to interact with 16 potential targets. In the herb-compound-target network, the majority of compounds acted on only one target; however, a small number of compounds acted on a large number of targets, up to a maximum of 12. The comparison of key topological properties in compound-target networks associated with the above efficacy intuitively demonstrated that potential active compounds possessed diverse functions. These results successfully explained the polypharmcological mechanism underlying the efficiency of DSMF for the treatment of traumatic injury as well as provided insight into potential novel therapeutic strategies for traumatic injury from herbal medicine. PMID:25891262

Did the introduction of a prospective payment system for nursing home stays reduce the likelihood of pharmacological management of secondary ischaemic stroke?

PubMed

Lapane, Kate L; Hughes, Carmel M

2006-01-01

Since 1998, a prospective payment system (PPS) for Medicare services provided by nursing homes in the US has been in operation. Concerns have been expressed that the PPS may affect the quality of care delivered to residents. This study evaluates the impact of the PPS on pharmacological secondary ischaemic stroke prevention in nursing homes. The nationally mandated Minimum Data Set and Online Survey Certification and Automated Record data system from 1997 and 2000 for four states were used. We conducted a quasi-experimental study comparing the pharmacological treatment rates for secondary stroke prevention in the pre-PPS period (1997) with those in the post-PPS period (2000) in residents who experienced an ischaemic stroke within 6 months (n1997 = 5008; n2000 = 5243) of living in nursing facilities (n1997 = 1226; n2000 = 1092) in Kansas, Maine, Mississippi or Ohio. The sample was stratified according to recommendations for use of warfarin. Logistic regression models adjusting for clustering effects of residents residing in homes using generalised estimating equations provided estimates of the PPS effect on use of antiplatelets and the use of warfarin. The unadjusted proportion of use of pharmacological agents for the secondary prevention of stroke was similar for warfarin in both time periods and increased for antiplatelets in 2000. Relative to the pre-PPS era, the likelihood of use of antiplatelets increased in the post-PPS era (adjusted odds ratio 1.26; 95% CI 1.15, 1.38); there was no effect on the use of warfarin. Although the lack of a PPS effect on pharmacological management of secondary ischaemic stroke is encouraging, there is still room for improvement in overall stroke management.

A review on ethno-medicinal uses and pharmacology of Vernonia cinerea Less.

PubMed

Dogra, Nittya K; Kumar, Suresh

2015-01-01

Vernonia cinerea Less. (ash-coloured fleabane; Asteraceae) is a widely distributed plant throughout India. The plant has reputation as folklore medicine in various traditional systems of medicine. The plant has been evaluated for varied pharmacological activities to validate its traditional claims, and has been scientifically reported to possess anti-inflammatory, antidiabetic, renoprotective, anticancer, antiviral, antimicrobial activities, etc. This review emphasises on ethnopharmacology and pharmacology of V. cinerea.

Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity.

PubMed

Meng, Fan-Cheng; Wu, Zheng-Feng; Yin, Zhi-Qi; Lin, Li-Gen; Wang, Ruibing; Zhang, Qing-Wen

2018-01-01

Coptidis rhizoma (CR) is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall. (Ranunculaceae) and is commonly used in Traditional Chinese Medicine for the treatment of various diseases including bacillary dysentery, typhoid, tuberculosis, epidemic cerebrospinal meningitis, empyrosis, pertussis, and other illnesses. A literature survey was conducted via SciFinder, ScieneDirect, PubMed, Springer, and Wiley databases. A total of 139 selected references were classified on the basis of their research scopes, including chemical investigation, quality evaluation and pharmacological studies. Many types of secondary metabolites including alkaloids, lignans, phenylpropanoids, flavonoids, phenolic compounds, saccharides, and steroids have been isolated from CR. Among them, protoberberine-type alkaloids, such as berberine, palmatine, coptisine, epiberberine, jatrorrhizine, columamine, are the main components of CR. Quantitative determination of these alkaloids is a very important aspect in the quality evaluation of CR. In recent years, with the advances in isolation and detection technologies, many new instruments and methods have been developed for the quantitative and qualitative analysis of the main alkaloids from CR. The quality control of CR has provided safety for pharmacological applications. These quality evaluation methods are also frequently employed to screen the active components from CR. Various investigations have shown that CR and its main alkaloids exhibited many powerful pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetic, neuroprotective, cardioprotective, hypoglycemic, anti-Alzheimer and hepatoprotective activities. This review summarizes the recent phytochemical investigations, quality evaluation methods, the biological studies focusing on CR as well as its main alkaloids.

New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors

PubMed Central

Greig, Nigel H.; Reale, Marcella; Tata, Ada Maria

2016-01-01

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

Trichosanthis Fructus: botany, traditional uses, phytochemistry and pharmacology.

PubMed

Yu, Xiankuo; Tang, Liying; Wu, Hongwei; Zhang, Xiao; Luo, Hanyan; Guo, Rixin; Xu, Mengying; Yang, Hongjun; Fan, Jianwei; Wang, Zhuju; Su, Ruiqiang

2018-05-26

Trichosanthis Fructus (ripe fruits of Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms) is an essential traditional Chinese medicine to treat thoracic obstruction, angina, cardiac failure, myocardial infarction, pulmonary heart disease, some cerebral ischaemic diseases, etc. The present report reviews the advancements in research on the botany, traditional uses, phytochemistry and pharmacology of Trichosanthis Fructus. Finally, perspectives on future research and its possible directions are discussed. This review provides up-to-date information about the botany, traditional uses, phytochemistry, pharmacology, toxicity and quality control of Trichosanthis Fructus and discusses the perspectives on future research and possible directions of this traditional Chinese Medicine and its origin plants. The information on Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms was collected from published scientific materials, including books; monographs on medicinal plants; pharmacopoeia and electronic databases such as SCI finder, PubMed, Web of Science, ACS, Science Direct, Wiley, Springer, Taylor, CNKI and Google Scholar. Approximately 162 compounds, including terpenoids, phytosterols, flavonoids, nitrogenous compounds and lignans, have been isolated and identified from Trichosanthes kirilowii Maxim. and Trichosanthes rosthornii Harms. Numerous studies have shown that the extracts and compounds isolated from these two plants exhibit pharmacological activities, including protection against myocardial ischaemia, calcium antagonist, endothelial cell protection, anti-hypoxic, anti-platelet aggregation, expectorant, anti-inflammatory, cytotoxic and antioxidant. Trichosanthis Fructus is an essential traditional Chinese medicine with pharmacological activities that mainly affect the cardiovascular system. This review summarises its botany, traditional uses, phytochemistry and pharmacology. Future research is needed to clarify the different uses of the

Pharmacology in space. Part 2. Controlling motion sickness

NASA Technical Reports Server (NTRS)

Lathers, C. M.; Charles, J. B.; Bungo, M. W.

1989-01-01

In this second article in the two-part series on pharmacology in space, Claire Lathers and colleagues discuss the pharmacology of drugs used to control motion sickness in space and note that the pharmacology of the 'ideal' agent has yet to be worked out. That motion sickness may impair the pharmacological action of a drug by interfering with its absorption and distribution because of alteration of physiology is a problem unique to pharmacology in space. The authors comment on the problem of designing suitable ground-based studies to evaluate the pharmacological effect of drugs to be used in space and discuss the use of salivary samples collected during space flight to allow pharmacokinetic evaluations necessary for non-invasive clinical drug monitoring.

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

PubMed

Hanna, Debra; Romero, Klaus; Schito, Marco

2017-03-01

The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.

Accelerating time to reperfusion in acute myocardial infarction: prehospital and emergency department strategies, systems of care, and pharmacologic interventions.

PubMed

Ornato, Joseph P

2006-01-01

Although primary percutaneous coronary intervention has emerged as the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), it is available only in a minority of US hospitals. The fundamental problem is that there is presently no organized, uniform, national STEMI triage and treatment system that is comparable to the well-developed, highly successful system in the United States that directs major trauma victims to verified trauma centers. This article reviews prehospital and emergency department triage strategies, systems, and pharmacologic interventions for patients with STEMI that can help shorten the time to reperfusion in these patients.

Toxicological and pharmacological effects of gadolinium and samarium chlorides

PubMed Central

Haley, T. J.; Raymond, K.; Komesu, N.; Upham, H. C.

1961-01-01

A study has been made of the toxicology and pharmacology of gadolinium and samarium chlorides. The symptoms of acute toxicity following intraperitoneal injection are described. The chronic oral ingestion of both chemicals for 12 weeks produced no effects on growth or the blood picture, and only the male rats receiving gadolinium chloride showed liver damage. The pharmacological responses to both chemicals were mainly depressant on all systems studied, and death was associated with cardiovascular collapse coupled with respiratory paralysis. The greatest damage seen was on abraded skin, where non-healing ulcers were produced by both chemicals, whereas irritation of intact skin and ocular tissues was only transient in nature. PMID:13903826

The pharmacology of lysergic acid diethylamide: a review.

PubMed

Passie, Torsten; Halpern, John H; Stichtenoth, Dirk O; Emrich, Hinderk M; Hintzen, Annelie

2008-01-01

Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called "experimental psychosis" by altering neurotransmitter system and in psychotherapeutic procedures ("psycholytic" and "psychedelic" therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

[Evaluation of autonomic nervous system function with heart rate variability analysis in patients with hyperthyroidism and during euthyroidism after pharmacologic and surgical treatment].

PubMed

Barczyński, M; Tabor, S; Thor, P

1997-01-01

The aim of the present study was both to estimate autonomic nervous system (ANS) function in patients with hyperthyroidism by the heart rate variability (HRV) analysis and to evaluate the impact of pharmacological and surgical treatment on the ANS function. Analysis of the HRV underwent 10 female patients in course of thyreotoxicosis and after reaching full clinical and biochemical euthyroidism, after pharmacological therapy and in month after surgical treatment. The 10 minutes records at rest, in horizontal position were evaluated. The HRV parameters like mean of the heart rate, mean of RR intervals, standard deviation of all normal RR intervals (SDNN), range of the heart rate variability, low frequency (LF), high frequency (HF) components of the heart rate power spectral density and LF/HF ratio were assessed. The results were compared to those obtained from 10 age-, sex-, and body mass index-matched control subjects. The statistical significance (p < 0.05) was found in reduction of range of RR intervals, in increase of LF/HF ratio and in decrease of SDNN in hyperthyroidism in comparison to the control group (151.6/346.8 ms; 2.4/0.74; 24.4/57.2 ms2). In course of pharmacological euthyroidism there were statistically significant (p < 0.05) increase of range of RR intervals, reduction of LF/HF ratio and increase of SDNN in comparison to hyperthyroidism (270/151.6 ms; 0.995/2.4; 39/24.4 ms2). In euthyroidism after surgical treatment all the above parameters kept the similar levels as in pharmacological euthyroidism (no statistical significance for p < 0.05). On the base of the outcomes it was considered that in hyperthyroid patients there is advantage of sympathetic part of ANS over parasympathetic one which is due to sharp reduction of parasympathetic system activity. Pharmacological therapy with thyreostatics normalises balance of ANS to the level of the control group and after surgical treatment the balance keeps the same. Moreover, in the estimation of ANS as

MOLECULAR BIOLOGY OF PHARMACOLOGIC VITREOLYSIS

PubMed Central

Sebag, J

2005-01-01

Purpose Pharmacologic vitreolysis is a promising new therapy to improve vitreoretinal surgery and, ultimately, prevent disease by mitigating the contribution of vitreous to retinopathy. The mechanism of action of the agents being developed for pharmacologic vitreolysis remains unclear. The experiments in this thesis test the hypothesis that pharmacologic vitreolysis agents break down vitreous macromolecules into smaller particles. Methods Microplasmin, hyaluronidase, and collagenase were tested in solutions of hyaluronan (n = 15) and collagen (n = 15), explants of bovine vitreous (n = 15), dissected porcine vitreous (n = 9), and intact porcine eyes (n = 18). There were also 21 controls, totaling 93 specimens. Vitreous macromolecule sizes were determined with dynamic light scattering (DLS), performed at intervals from 10 minutes to 24 hours following injections. Results Studies of DLS reproducibility showed a coefficient of variance of less than 3.3% in all but one specimen. Microplasmin decreased porcine vitreous macromolecule size in a dose-dependent manner (correlation coefficient r = 0.93), with an 85% reduction after a 30-minute exposure to the maximum dose. Hyaluronidase decreased vitreous macromolecule size in hyaluronan solutions by 50% at high (1,000 IU/mL, P < .001) doses and in bovine vitreous by 20%. Collagenase decreased macromolecule size in collagen solutions by 20% at both low (1 mg/mL, P < .001) and high (10 mg/mL, P < .001) doses, but not at all in bovine vitreous. Conclusions Pharmacologic vitreolysis can induce a significant decrease in vitreous macromolecule sizes, depending upon the pharmacologic agents and the experimental model. Broad-spectrum agents were more effective than substrate-specific enzymes. Defining the molecular biology of pharmacologic vitreolysis has implications for surgical developments and may impact upon the design of clinical trials to induce prophylactic posterior vitreous detachment. PMID:17057814

Caenorhabditis elegans as Model System in Pharmacology and Toxicology: Effects of Flavonoids on Redox-Sensitive Signalling Pathways and Ageing

PubMed Central

Koch, Karoline; Havermann, Susannah; Büchter, Christian

2014-01-01

Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research. PMID:24895670

A quantitative analysis of the F18 flight control system

NASA Technical Reports Server (NTRS)

Doyle, Stacy A.; Dugan, Joanne B.; Patterson-Hine, Ann

1993-01-01

This paper presents an informal quantitative analysis of the F18 flight control system (FCS). The analysis technique combines a coverage model with a fault tree model. To demonstrate the method's extensive capabilities, we replace the fault tree with a digraph model of the F18 FCS, the only model available to us. The substitution shows that while digraphs have primarily been used for qualitative analysis, they can also be used for quantitative analysis. Based on our assumptions and the particular failure rates assigned to the F18 FCS components, we show that coverage does have a significant effect on the system's reliability and thus it is important to include coverage in the reliability analysis.

CONFOCAL MICROSCOPY SYSTEM PERFORMANCE: QA TESTS, QUANTITATION AND SPECTROSCOPY

EPA Science Inventory

Confocal Microscopy System Performance: QA tests, Quantitation and Spectroscopy.

Robert M. Zucker 1 and Jeremy M. Lerner 2,
1Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research Development, U.S. Environmen...

Sender–receiver systems and applying information theory for quantitative synthetic biology

PubMed Central

Barcena Menendez, Diego; Senthivel, Vivek Raj; Isalan, Mark

2015-01-01

Sender–receiver (S–R) systems abound in biology, with communication systems sending information in various forms. Information theory provides a quantitative basis for analysing these processes and is being applied to study natural genetic, enzymatic and neural networks. Recent advances in synthetic biology are providing us with a wealth of artificial S–R systems, giving us quantitative control over networks with a finite number of well-characterised components. Combining the two approaches can help to predict how to maximise signalling robustness, and will allow us to make increasingly complex biological computers. Ultimately, pushing the boundaries of synthetic biology will require moving beyond engineering the flow of information and towards building more sophisticated circuits that interpret biological meaning. PMID:25282688

Systems-level mechanisms of action of Panax ginseng: a network pharmacological approach.

PubMed

Park, Sa-Yoon; Park, Ji-Hun; Kim, Hyo-Su; Lee, Choong-Yeol; Lee, Hae-Jeung; Kang, Ki Sung; Kim, Chang-Eop

2018-01-01

Panax ginseng has been used since ancient times based on the traditional Asian medicine theory and clinical experiences, and currently, is one of the most popular herbs in the world. To date, most of the studies concerning P. ginseng have focused on specific mechanisms of action of individual constituents. However, in spite of many studies on the molecular mechanisms of P. ginseng , it still remains unclear how multiple active ingredients of P. ginseng interact with multiple targets simultaneously, giving the multidimensional effects on various conditions and diseases. In order to decipher the systems-level mechanism of multiple ingredients of P. ginseng , a novel approach is needed beyond conventional reductive analysis. We aim to review the systems-level mechanism of P. ginseng by adopting novel analytical framework-network pharmacology. Here, we constructed a compound-target network of P. ginseng using experimentally validated and machine learning-based prediction results. The targets of the network were analyzed in terms of related biological process, pathways, and diseases. The majority of targets were found to be related with primary metabolic process, signal transduction, nitrogen compound metabolic process, blood circulation, immune system process, cell-cell signaling, biosynthetic process, and neurological system process. In pathway enrichment analysis of targets, mainly the terms related with neural activity showed significant enrichment and formed a cluster. Finally, relative degrees analysis for the target-disease association of P. ginseng revealed several categories of related diseases, including respiratory, psychiatric, and cardiovascular diseases.

Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review.

PubMed

Gao, Shi-Man; Liu, Jiu-Shi; Wang, Min; Cao, Ting-Ting; Qi, Yao-Dong; Zhang, Ben-Gang; Sun, Xiao-Bo; Liu, Hai-Tao; Xiao, Pei-Gen

2018-06-12

reviewed in this paper. Species of the genus have long been used as traditional medicines and food materials, they are reported with a large number of chemical constituents with different structures, extensive pharmacological activities in immune system, blood system, digestive system, etc. and almost no toxicity. More profound studies on less popular species, pharmacodynamic material basis and pharmacological mechanism, and quality assurance are suggested to be carried out to fulfil the research on the long-term clinical use and new drug research of Codonopsis. Copyright © 2018 Elsevier B.V. All rights reserved.

[Contribution of animal experimentation to pharmacology].

PubMed

Sassard, Jean; Hamon, Michel; Galibert, Francis

2009-11-01

Animal experimentation is of considerable importance in pharmacology and cannot yet be avoided when studying complex, highly integrated physiological functions. The use of animals has been drastically reduced in the classical phases of pharmacological research, for example when comparing several compounds belonging to the same pharmacological class. However, animal experiments remain crucial for generating and validating new therapeutic concepts. Three examples of such research, conducted in strict ethical conditions, will be used to illustrate the different ways in which animal experimentation has contributed to human therapeutics.

Forensic pharmacology: An important and evolving subspecialty needs recognition in India

PubMed Central

Malve, Harshad Onkarrao

2016-01-01

With training in pharmacology, a pharmacologist has an expert knowledge as well as working experience in the subjects of therapeutics, pharmacokinetics, and toxicology along with exposure to subjects such as forensic medicine during the medical education. All these knowledge domains can be applied and act as an interface to the forensic situations. The skills and expertise of a forensic pharmacologist can be useful in a large and diverse number of legal cases. With an ever increasing incidence of criminal and civil cases in India, the development and inclusion of forensic pharmacologist in the judicial system of India are the need of the hour. The research in pharmacology has witnessed great technological advancement that allows it to expand its scope beyond the domain of therapeutics, thus enabling Indian pharmacologists to explore the niche area of Forensic Pharmacology. Differing pharmacokinetics and pharmacodynamics of drugs in living and dead, drug interactions, abuse of drugs, personal injury or death due to drug exposure leading to medico-legal issues, environmental exposure to chemicals, and doping and forensic pharmacovigilance are the diverse aspects of Forensic Pharmacology. PMID:27134459

Methods of the pharmacological imaging of the cannabinoid system (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition.

PubMed

van Hell, Hendrika H; Bossong, Matthijs G; Jager, Gerry; Kahn, René S; Ramsey, Nick F

2011-03-01

Various lines of (pre)clinical research indicate that cannabinoid agents carry the potential for therapeutic application to reduce symptoms in several psychiatric disorders. However, direct testing of the involvement of cannabinoid brain systems in psychiatric syndromes is essential for further development. In the Pharmacological Imaging of the Cannabinoid System (PhICS) study, the involvement of the endocannabinoid system in cognitive brain function is assessed by comparing acute effects of the cannabinoid agonist Δ9-tetrahydrocannabinol (THC) on brain function between healthy controls and groups of psychiatric patients showing cognitive dysfunction. This article describes the objectives and methods of the PhICS study and presents preliminary results of the administration procedure on subjective and neurophysiological parameters. Core elements in the methodology of PhICS are the administration method (THC is administered by inhalation using a vaporizing device) and a comprehensive use of pharmacological magnetic resonance imaging (phMRI) combining several types of MRI scans including functional MRI (fMRI), Arterial Spin Labeling (ASL) to measure brain perfusion, and resting-state fMRI. Additional methods like neuropsychological testing further specify the exact role of the endocannabinoid system in regulating cognition. Preliminary results presented in this paper indicate robust behavioral and subjective effects of THC. In addition, fMRI paradigms demonstrate activation of expected networks of brain regions in the cognitive domains of interest. The presented administration and assessment protocol provides a basis for further research on the involvement of the endocannabionoid systems in behavior and in psychopathology, which in turn may lead to development of therapeutic opportunities of cannabinoid ligands. Copyright © 2011 John Wiley & Sons, Ltd.

A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability.

PubMed

Calabrese, Evan; Badea, Alexandra; Watson, Charles; Johnson, G Allan

2013-05-01

There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease. Published by Elsevier Inc.

Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology.

PubMed

Ferner, Robin E; Aronson, Jeffrey K

2016-01-01

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions. © 2015 The British Pharmacological Society.

Platycladus orientalis leaves: a systemic review on botany, phytochemistry and pharmacology.

PubMed

Shan, Ming-Qiu; Shang, Jing; Ding, An-Wei

2014-01-01

Platycladus orientalis leaves (Cebaiye) have been used for thousands of years as traditional Chinese medicine (TCM). According to the theory of TCM, they are categorized as a blood-cooling and hematostatic herb. In clinical practice, they were usually prescribed with heat-clearing herbs to reinforce the efficacy of hemostasis. The review provides the up-to-date information from 1980 to present that is available on the botany, processing research, phytochemistry, pharmacology and toxicology of the leaves. The information is collected from scientific journals, books, theses and reports via library and electronic search (Google Scholar, Pubmed and CNKI). Through literature reports, we can find that the leaves show a wide spectrum of pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, disinsection, anticancer, diuretic, hair growth-promoting, neuroprotective and antifibrotic activities. Diterpene and flavonoids would be active constituents in P. orientalis leaves. Many studies have provided evidence for various traditional uses. However, there is a great need for additional studies to elucidate the mechanism of blood-cooling and hematostatic activity of the leaves. Therefore, the present review on the botany, traditional uses, phytochemistry and toxicity has provided preliminary information for further studies of this herb.

Non Pharmacological Cognitive Enhancers - Current Perspectives.

PubMed

Sachdeva, Ankur; Kumar, Kuldip; Anand, Kuljeet Singh

2015-07-01

Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. Many of these Non Pharmacological Cognitive Enhancers seem to be more efficacious compared to currently available Pharmacological Cognitive Enhancers. This review describes and summarizes evidence on various Non Pharmacological Cognitive Enhancers such as physical exercise, sleep, meditation and yoga, spirituality, nutrients, computer training, brain stimulation, and music. We also discuss their role in ageing and different neuro-psychiatric disorders, and current status of Cochrane database recommendations. We searched the Pubmed database for the articles and reviews having the terms 'non pharmacological and cognitive' in the title, published from 2000 till 2014. A total of 11 results displayed, out of which 10 were relevant to the review. These were selected and reviewed. Appropriate cross-references within the articles along with Cochrane reviews were also considered and studied.

Development of Clinical Pharmacology in the Russian Federation.

PubMed

Petrov, V I; Kagramanyan, I N; Khokhlov, A L; Frolov, M U; Lileeva, E G

2016-05-01

The article aims to provide the history, organization, and approaches to clinical pharmacology in the Russian Federation. This article is based on major international and Russian documents, along with groundbreaking historical facts and scientific articles related to the development of modern clinical pharmacology the Russian Federation. Improving the quality of drug therapy is the main goal of clinical pharmacology in the Russian Federation. Decisions of the World Health Organization, scientific achievements, and the work of well-known scientists among the world community and in the Russian Federation have strongly influenced the development of clinical pharmacology the Russian Federation. Clinical pharmacology in the Russian Federation addresses a wide range of problems; it actively engages in modern scientific research, education; and clinical practice. Clinical pharmacologists participate in studies of new drugs and often have a specific area of expertise. The future development of clinical pharmacology in the Russian Federation will be related to improvements in training, refinement of the framework that regulates clinical pharmacologists, and the creation of clinical pharmacology laboratories with modern equipment. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Statistical reporting of clinical pharmacology research.

PubMed

Ring, Arne; Schall, Robert; Loke, Yoon K; Day, Simon

2017-06-01

Research in clinical pharmacology covers a wide range of experiments, trials and investigations: clinical trials, systematic reviews and meta-analyses of drug usage after market approval, the investigation of pharmacokinetic-pharmacodynamic relationships, the search for mechanisms of action or for potential signals for efficacy and safety using biomarkers. Often these investigations are exploratory in nature, which has implications for the way the data should be analysed and presented. Here we summarize some of the statistical issues that are of particular importance in clinical pharmacology research. © 2017 The British Pharmacological Society.

Nanobiology for the pharmacology of cellular ion channels.

PubMed

Kabanov, Alexander V; Kirpichnikov, Mikhail P; Khokhlov, Alexey R

2009-03-01

Writing this editorial is especially pleasing. First, it provides us an opportunity to introduce new directives to the field of Neuroimmune Pharmacology and to explain why the field of nanomedicine is likely an important part of its future growth and development. Second, it is an opportunity to showcase research in this area currently operative in Russia that may not be readily accessible to the readership. Third, it is a platform to better explain why the Journal Editorial leadership was enthusiastic about the science and its relationship to the Society on NeuroImmune Pharmacology strategic goals. All are brought to bear in this issue of the Journal of Neuroimmune Pharmacology. The issue includes articles presented at a recent joint US-Russian workshop entitled, "Health in the 21st Century: Nanomedicine and Self-Organization of Biological Systems" held at M.V. Lomonosov Moscow State University (MSU), Moscow, Russia, December 10-11, 2007. The conjoint meeting was organized through the Departments of Biology, Chemistry, and Physics, MSU and by the Center for Drug Delivery and Nanomedicine and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (Omaha, NE). The speakers included established internationally regarded scientists from these institutions as well as graduate students and faculties at MSU. In addition to selected papers by workshop contributors, we have included several papers closely aligned to the theme of nanomedicine and nanopharmacology of the central nervous system in order to provide a biological anchor for this research. We understand that such works are new to many but hope that its organization and interdisciplinary approaches will appeal to this audience. All together, it is our hope that, by gathering basic and clinical scientists with the common interest of using nanotechnology in the delivery of therapeutic agents with a focus on nanopharmacology and complex supramolecular biological assembly, the

Pharmacological chaperoning: a primer on mechanism and pharmacology.

PubMed

Leidenheimer, Nancy J; Ryder, Katelyn G

2014-05-01

Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs are considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast

Proteome analysis of snake venom toxins: pharmacological insights.

PubMed

Georgieva, Dessislava; Arni, Raghuvir K; Betzel, Christian

2008-12-01

Snake venoms are an extremely rich source of pharmacologically active proteins with a considerable clinical and medical potential. To date, this potential has not been fully explored, mainly because of our incomplete knowledge of the venom proteome and the pharmacological properties of its components, in particular those devoid of enzymatic activity. This review summarizes the latest achievements in the determination of snake venom proteome, based primarily on the development of new strategies and techniques. Detailed knowledge of the venom toxin composition and biological properties of the protein constituents should provide the scaffold for the design of new more effective drugs for the treatment of the hemostatic system and heart disorders, inflammation, cancer and consequences of snake bites, as well as new tools for clinical diagnostic and assays of hemostatic parameters.

A Checklist for Successful Quantitative Live Cell Imaging in Systems Biology

PubMed Central

Sung, Myong-Hee

2013-01-01

Mathematical modeling of signaling and gene regulatory networks has provided unique insights about systems behaviors for many cell biological problems of medical importance. Quantitative single cell monitoring has a crucial role in advancing systems modeling of molecular networks. However, due to the multidisciplinary techniques that are necessary for adaptation of such systems biology approaches, dissemination to a wide research community has been relatively slow. In this essay, I focus on some technical aspects that are often under-appreciated, yet critical in harnessing live cell imaging methods to achieve single-cell-level understanding and quantitative modeling of molecular networks. The importance of these technical considerations will be elaborated with examples of successes and shortcomings. Future efforts will benefit by avoiding some pitfalls and by utilizing the lessons collectively learned from recent applications of imaging in systems biology. PMID:24709701

Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action for Herbal Medicines in Stroke Treatment and Prevention

PubMed Central

Zhang, Jingxiao; Li, Yan; Chen, Xuetong; Pan, Yanqiu; Zhang, Shuwei; Wang, Yonghua

2014-01-01

Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes. PMID:25093322

Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses

PubMed Central

Baker, Jillian G.; Kemp, Philip; March, Julie; Fretwell, Laurice; Hill, Stephen J.; Gardiner, Sheila M.

2011-01-01

β-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (β1; HR) and hindquarters vascular conductance (β2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P<0.05, ANOVA) at 5 doses between 6.7 and 670 μg/kg (i.v.) and shifted the dose-response curve for isoprenaline to higher agonist concentrations without altering HVC responses. In contrast, at doses of 67 μg/kg (i.v.) and above, ICI 118551 substantially reduced the HVC response to isoprenaline without affecting HR responses. ZD 7114, xamoterol, and bucindolol significantly increased basal HR (ΔHR: +122±12, +129±11, and +59±11 beats/min, respectively; n=6), whereas other β-blockers caused significant reductions (all at 2 mg/kg i.v.). The agonist effects of xamoterol and ZD 7114 were equivalent to that of the highest dose of isoprenaline. Bucindolol, however, significantly antagonized the response to the highest doses isoprenaline. An excellent correlation was obtained between in vivo and in vitro measures of β1-adrenoceptor efficacy (R2=0.93; P<0.0001).—Baker, J. G., Kemp, P., March, J., Fretwell, L., Hill, S. J., Gardiner, S. M. Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses. PMID:21865315

Transdermal fentanyl: pharmacology and toxicology.

PubMed

Nelson, Lewis; Schwaner, Robert

2009-12-01

To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain. Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review. Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use. Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.

Content of non-pharmacological care for systemic sclerosis and educational needs of European health professionals: a EUSHNet survey.

PubMed

Willems, Linda M; Redmond, Anthony C; Stamm, Tanja A; Boström, Carina; Decuman, Saskia; Kennedy, Ann Tyrrell; Brozd, Jadranka; Roškar, Sanja; Smith, Vanessa; Vliet Vlieland, Theodora P M; van den Ende, Cornelia H M

2015-01-01

To describe the non-pharmacological care in systemic sclerosis (SSc) provided by European health professionals (HPs) including referrals, treatment targets, interventions, and educational needs. In this observational study, European HPs working in SSc care were invited to complete an online survey through announcements by EUSTAR (European League Against Rheumatism (EULAR) Scleroderma Trials and Research) and FESCA (Federation of European Scleroderma Associations), the EULAR HPs' newsletter, websites of national patient and HP associations, and by personal invitation. In total, 56 HPs, from 14 different European countries and 7 different disciplines, responded to the survey. A total of 133 specific indications for referral were reported, 72% of which could be linked to the International Classification of Functioning, Disability and Health domain "body functions and structures". Of the 681 reported treatment targets 45% was related to "body functions and structures". In total, 105 different interventions were reported as being used to address these treatment targets. Almost all (98%) respondents reported having educational needs, with the topics of management of stiffness (67%), pain (60%), and impaired hand function (56%) being mentioned most frequently. Non-pharmacological care in SSc varies in Europe with respect to the content of interventions, reasons for referral, and treatment targets. Reasons for referral to HPs are not well-aligned to HPs subsequent treatment targets in SSc care suggesting suboptimal communication between physicians and HPs. The wide variations reported indicate a need to consolidate geographically disparate expertise within countries and to develop and improve standards of non-pharmacological care in SSc.

Comparison of automated home-cage monitoring systems: emphasis on feeding behaviour, activity and spatial learning following pharmacological interventions.

PubMed

Robinson, Lianne; Riedel, Gernot

2014-08-30

Different automated systems have been developed to facilitate long-term and continuous assessment of behaviours including locomotor activity, feeding behaviour and circadian activity. This study assessed the effectiveness of three different observation systems as methods for determining strain and pharmacological induced differences in locomotor activity, feeding behaviour and spatial learning. The effect of the CB1 antagonist AM251 on feeding behaviour was determined in the PhenoMaster and PhenoTyper. Next, effects of cholinergic (scopolamine) and glutamatergic (Phenylcyclidine, PCP) receptor antagonism and dopaminergic agonism (apomorphine) on activity were assessed in the PhenoTyper and IntelliCage. Finally, the IntelliCage was utilised to determine differences in activity and spatial learning of C57BL/6 and DBA/2 mouse strains following pharmacological intervention. AM251 induced a suppression of food intake, feeding behaviour and a reduction in body weight in both the PhenoTyper and PhenoMaster. Apomorphine reduced activity in both the PhenoTyper and IntelliCage. Whereas, decreased activity was evident with PCP in the PhenoTyper, but not IntelliCage and Scopolamine induced a trend towards elevated levels of activity in the IntelliCage but not PhenoTyper. Strain differences in activity and spatial learning were also evident, with increased corner visits and drug induced impairments only observed with C57BL/6 mice. The automated home cage observation systems determined similar drug and strain effects on behaviour to those observed using traditional methods. All three observation systems reported drug-induced changes in behaviour however, they differ in their application of spatial learning tasks and utilisation of single versus group housed recordings. Copyright © 2014 Elsevier B.V. All rights reserved.

Current status and future directions of pharmacological therapy for acromegaly.

PubMed

Mercado, Moisés; Espinosa, Etual; Ramírez, Claudia

2016-09-01

Acromegaly is a chronic systemic disorder caused in the vast majority of cases by a GH-secreting pituitary adenoma and resulting in significant morbidity and mortality if left untreated. The treatment of choice is the trans-sphenoidal resection of the adenoma, and although 80% of patients with microadenomas or confined macroadenomas achieve biochemical remission, the surgical success rate for patients harboring tumors with extrasellar extension is below 50%. Thus, a considerable proportion of patients will require some form of adjuvant treatment. Acromegaly can be approached pharmacologically by inhibiting GH secretion by the tumor (somatostatin analogues, dopamine agonists) or by antagonizing GH actions at its target tissues (GH receptor antagonists). The primary pharmacological treatment of acromegaly is increasingly gaining acceptance by both physicians and patients. The decision to use primary pharmacological treatment has to take into account the clinical characteristics of the patient (presence of comorbidities that significantly increase the surgical risk) and the biological nature of the adenoma (tumor size and location), as well as other aspects such as the availability of a pituitary surgeon and the cost of medications. This review provides a critical summary and update of the pharmacological treatment of acromegaly focusing both, on well-established agents and strategies as well as on novel compounds that are currently being developed.

Evaluation of a filmed clinical scenario as a teaching resource for an introductory pharmacology unit for undergraduate health students: A pilot study.

PubMed

East, Leah; Hutchinson, Marie

2015-12-01

Simulation is frequently being used as a learning and teaching resource for both undergraduate and postgraduate students, however reporting of the effectiveness of simulation particularly within the pharmacology context is scant. The aim of this pilot study was to evaluate a filmed simulated pharmacological clinical scenario as a teaching resource in an undergraduate pharmacological unit. Pilot cross-sectional quantitative survey. An Australian university. 32 undergraduate students completing a healthcare degree including nursing, midwifery, clinical science, health science, naturopathy, and osteopathy. As a part of an undergraduate online pharmacology unit, students were required to watch a filmed simulated pharmacological clinical scenario. To evaluate student learning, a measurement instrument developed from Bloom's cognitive domains (knowledge, comprehension, application, analysis, synthesis and evaluation) was employed to assess pharmacological knowledge conceptualisation and knowledge application within the following fields: medication errors; medication adverse effects; medication interactions; and, general pharmacology. The majority of participants were enrolled in an undergraduate nursing or midwifery programme (72%). Results demonstrated that the majority of nursing and midwifery students (56.52%) found the teaching resource complementary or more useful compared to a lecture although less so compared to a tutorial. Students' self-assessment of learning according to Bloom's cognitive domains indicated that the filmed scenario was a valuable learning tool. Analysis of variance indicated that health science students reported higher levels of learning compared to midwifery and nursing. Students' self-report of the learning benefits of a filmed simulated clinical scenario as a teaching resource suggest enhanced critical thinking skills and knowledge conceptualisation regarding pharmacology, in addition to being useful and complementary to other teaching and

Constellation Pharmacology: A new paradigm for drug discovery

PubMed Central

Schmidt, Eric W.; Olivera, Baldomero M.

2015-01-01

Constellation Pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (“constellations”) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation Pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically-active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the on-going development of Constellation Pharmacology, there is a positive-feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As Constellation Pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform. PMID:25562646

Treatment of Pancreatic Cancer with Pharmacological Ascorbate

PubMed Central

Cieslak, John A.; Cullen, Joseph J.

2016-01-01

The prognosis for patients diagnosed with pancreatic cancer remains dismal, with less than 3% survival at 5 years. Recent studies have demonstrated that high-dose, intravenous pharmacological ascorbate (ascorbic acid, vitamin C) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells vs. normal cells, suggesting a promising new role of ascorbate as a therapeutic agent. At physiologic concentrations, ascorbate functions as a reducing agent and antioxidant. However, when pharmacological ascorbate is given intravenously, it is possible to achieve millimolar plasma concentration. At these pharmacological levels, and in the presence of catalytic metal ions, ascorbate can induce oxidative stress through the generation of hydrogen peroxide (H2O2). Recent in vitro and in vivo studies have demonstrated ascorbate oxidation occurs extracellularly, generating H2O2 flux into cells resulting in oxidative stress. Pharmacologic ascorbate also inhibits the growth of pancreatic tumor xenografts and displays synergistic cytotoxic effects when combined with gemcitabine in pancreatic cancer. Phase I trials of pharmacological ascorbate in pancreatic cancer patients have demonstrated safety and potential efficacy. In this chapter, we will review the mechanism of ascorbate-induced cytotoxicity, examine the use of pharmacological ascorbate in treatment and assess the current data supporting its potential as an adjuvant in pancreatic cancer. PMID:26201606

Towards quantitative mass spectrometry-based metabolomics in microbial and mammalian systems.

PubMed

Kapoore, Rahul Vijay; Vaidyanathan, Seetharaman

2016-10-28

Metabolome analyses are a suite of analytical approaches that enable us to capture changes in the metabolome (small molecular weight components, typically less than 1500 Da) in biological systems. Mass spectrometry (MS) has been widely used for this purpose. The key challenge here is to be able to capture changes in a reproducible and reliant manner that is representative of the events that take place in vivo Typically, the analysis is carried out in vitro, by isolating the system and extracting the metabolome. MS-based approaches enable us to capture metabolomic changes with high sensitivity and resolution. When developing the technique for different biological systems, there are similarities in challenges and differences that are specific to the system under investigation. Here, we review some of the challenges in capturing quantitative changes in the metabolome with MS based approaches, primarily in microbial and mammalian systems.This article is part of the themed issue 'Quantitative mass spectrometry'. © 2016 The Author(s).

Extraoral Taste Receptor Discovery: New Light on Ayurvedic Pharmacology

PubMed Central

2017-01-01

More and more research studies are revealing unexpectedly important roles of taste for health and pathogenesis of various diseases. Only recently it has been shown that taste receptors have many extraoral locations (e.g., stomach, intestines, liver, pancreas, respiratory system, heart, brain, kidney, urinary bladder, pancreas, adipose tissue, testis, and ovary), being part of a large diffuse chemosensory system. The functional implications of these taste receptors widely dispersed in various organs or tissues shed a new light on several concepts used in ayurvedic pharmacology (dravyaguna vijnana), such as taste (rasa), postdigestive effect (vipaka), qualities (guna), and energetic nature (virya). This review summarizes the significance of extraoral taste receptors and transient receptor potential (TRP) channels for ayurvedic pharmacology, as well as the biological activities of various types of phytochemical tastants from an ayurvedic perspective. The relative importance of taste (rasa), postdigestive effect (vipaka), and energetic nature (virya) as ethnopharmacological descriptors within Ayurveda boundaries will also be discussed. PMID:28642799

Preserved pharmacological activity of hepatocytes-treated extracts of valerian and St. John's wort.

PubMed

Simmen, Urs; Saladin, Caroline; Kaufmann, Priska; Poddar, Manisha; Wallimann, Christine; Schaffner, Willi

2005-07-01

The two herbal extracts valerian (Valeriana officinalis L.) and St. John's wort (Hypericum perforatum L.) were studied for their metabolic changes upon incubation with freshly prepared rat hepatocytes and subsequently analysed phytochemically as well as pharmacologically in vitro. Quantitative HPLC analysis of valerian extracts revealed considerable metabolic activities with regard to sesquiterpenes and iridoids. The amount of acetoxyvalerenic acid decreased 9-fold, while that of hydroxyvalerenic acid correspondingly increased 9-fold due to O-deacetylation. The valepotriates didrovaltrate, isovaltrate and valtrate decreased 2-, 18- and 16-fold, respectively. However, the binding affinities of the incubated extracts to the benzodiazepine and picrotoxin binding site of the GABA (A) receptor were quite similar to those of the non-incubated extracts. Neither valerenic acids nor valepotriates exhibited any significant effect on the two binding sites when tested as single compounds. Therefore, either other constituents represent the active ones or multiple compounds are necessary for the observed inhibitory and allosteric effects at the GABA (A) receptor. Extracts of St. John's wort were less potently metabolised than valerian. The amount of pseudohypericin and the main flavonoids (hyperoside, rutin, isoquercitrin, quercitrin, quercetin and I3,II8-biapigenin) slightly decreased during the 4-h incubation period. Both the antagonist effect at the corticotropin-releasing factor (CRF) type 1 receptor and the binding inhibition at the 5-HT transporter were attenuated during the metabolic treatment. The reduced antagonist effect correlates with the decreasing amount of pseudohypericin known to be a CRF (1) receptor antagonist. In conclusion, the incubation of plant extracts with freshly prepared rat hepatocytes represents a useful approach to study the pharmacological action of metabolised plant extracts. The consistent pharmacological activity of both valerian and St. John

[Pharmacology].

PubMed

González, José; Orero, Ana; Olmo, Vicente; Martínez, David; Prieto, José; Bahlsen, Jose Antonio; Zaragozá, Francisco; Honorato, Jesús

2011-06-01

Two of the main characteristics of western societies in the last fifty years have been the medicalization of the human life and the environmental degradation. The first one has forced human being to consider medicines use related to what would be rational, reasonable and well-reasoned. The second one brought us to a new ecologist conscience. In relation to the "human social system", the effects of medication can be considered very positive as a whole, particularly those related to the amazing increase of expectative and quality of life. But, along with those unquestionable beneficial effects, medicines have also caused some negative effects for other biotic and abiotic systems, such as microbian alterations and their undesirable consequences which have involved the massive use of antibiotics in medicine and veterinary, the uncontrolled elimination of millions of doses of all kind of drugs, additives and excipients, etc., as well as atmospheric contamination and degradation of forests and deep oceans which can have been caused by investigation and production of determinated drugs. In this context Pharmacology appears as a scientific discipline that studies the research (R), development (D), production (P), and utilization (U) of drugs and medical substances in relation to the environment. From a farmaecologic perspective the drugs utilization has its development in three main contexts, all of them closely related: prescription quality, farmaceutical care, and patient's active participation in his own disease and treatment.

Non-pharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) delivered in school settings: systematic reviews of quantitative and qualitative research.

PubMed Central

Richardson, Michelle; Moore, Darren A; Gwernan-Jones, Ruth; Thompson-Coon, Jo; Ukoumunne, Obioha; Rogers, Morwenna; Whear, Rebecca; Newlove-Delgado, Tamsin V; Logan, Stuart; Morris, Christopher; Taylor, Eric; Cooper, Paul; Stein, Ken; Garside, Ruth; Ford, Tamsin J

2015-01-01

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by age-inappropriate levels of inattention, impulsivity and hyperactivity. School can be particularly challenging for children with ADHD. Few reviews have considered non-pharmacological interventions in school settings. OBJECTIVES To assess the effectiveness of non-pharmacological interventions delivered in school settings for pupils with, or at risk of, ADHD and to explore the factors that may enhance, or limit, their delivery. DATA SOURCES Twenty electronic databases (including PsycINFO, MEDLINE, EMBASE, Education Resources Information Centre, The Cochrane Library and Education Research Complete) were searched from 1980 to February-August 2013. Three separate searches were conducted for four systematic reviews; they were supplemented with forward and backwards citation chasing, website searching, author recommendations and hand-searches of key journals. REVIEW METHODS The systematic reviews focused on (1) the effectiveness of school-based interventions for children with or at risk of ADHD; (2) quantitative research that explores attitudes towards school-based non-pharmacological interventions for pupils with ADHD; (3) qualitative research investigating the attitudes and experiences of children, teachers, parents and others using ADHD interventions in school settings; and (4) qualitative research exploring the experience of ADHD in school among pupils, their parents and teachers more generally. Methods of synthesis included a random-effects meta-analysis, meta-regression and narrative synthesis for review 1, narrative synthesis for review 2 and meta-ethnography and thematic analysis for reviews 3 and 4. RESULTS For review 1, 54 controlled trials met the inclusion criteria. For the 36 meta-analysed randomised controlled trials, beneficial effects (p < 0.05) were observed for several symptom and scholastic outcomes. Mean weighted effect sizes ranged from

Non-pharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) delivered in school settings: systematic reviews of quantitative and qualitative research.

PubMed

Richardson, Michelle; Moore, Darren A; Gwernan-Jones, Ruth; Thompson-Coon, Jo; Ukoumunne, Obioha; Rogers, Morwenna; Whear, Rebecca; Newlove-Delgado, Tamsin V; Logan, Stuart; Morris, Christopher; Taylor, Eric; Cooper, Paul; Stein, Ken; Garside, Ruth; Ford, Tamsin J

2015-06-01

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by age-inappropriate levels of inattention, impulsivity and hyperactivity. School can be particularly challenging for children with ADHD. Few reviews have considered non-pharmacological interventions in school settings. To assess the effectiveness of non-pharmacological interventions delivered in school settings for pupils with, or at risk of, ADHD and to explore the factors that may enhance, or limit, their delivery. Twenty electronic databases (including PsycINFO, MEDLINE, EMBASE, Education Resources Information Centre, The Cochrane Library and Education Research Complete) were searched from 1980 to February-August 2013. Three separate searches were conducted for four systematic reviews; they were supplemented with forward and backwards citation chasing, website searching, author recommendations and hand-searches of key journals. The systematic reviews focused on (1) the effectiveness of school-based interventions for children with or at risk of ADHD; (2) quantitative research that explores attitudes towards school-based non-pharmacological interventions for pupils with ADHD; (3) qualitative research investigating the attitudes and experiences of children, teachers, parents and others using ADHD interventions in school settings; and (4) qualitative research exploring the experience of ADHD in school among pupils, their parents and teachers more generally. Methods of synthesis included a random-effects meta-analysis, meta-regression and narrative synthesis for review 1, narrative synthesis for review 2 and meta-ethnography and thematic analysis for reviews 3 and 4. For review 1, 54 controlled trials met the inclusion criteria. For the 36 meta-analysed randomised controlled trials, beneficial effects (p < 0.05) were observed for several symptom and scholastic outcomes. Mean weighted effect sizes ranged from very small (d + < 0.20) to large (d + ≥ 0.80), but

Quantitative fluorescence tomography using a trimodality system: in vivo validation

PubMed Central

Lin, Yuting; Barber, William C.; Iwanczyk, Jan S.; Roeck, Werner W.; Nalcioglu, Orhan; Gulsen, Gultekin

2010-01-01

A fully integrated trimodality fluorescence, diffuse optical, and x-ray computed tomography (FT∕DOT∕XCT) system for small animal imaging is reported in this work. The main purpose of this system is to obtain quantitatively accurate fluorescence concentration images using a multimodality approach. XCT offers anatomical information, while DOT provides the necessary background optical property map to improve FT image accuracy. The quantitative accuracy of this trimodality system is demonstrated in vivo. In particular, we show that a 2-mm-diam fluorescence inclusion located 8 mm deep in a nude mouse can only be localized when functional a priori information from DOT is available. However, the error in the recovered fluorophore concentration is nearly 87%. On the other hand, the fluorophore concentration can be accurately recovered within 2% error when both DOT functional and XCT structural a priori information are utilized together to guide and constrain the FT reconstruction algorithm. PMID:20799770

Quantitative Evaluation Method of Each Generation Margin for Power System Planning

NASA Astrophysics Data System (ADS)

Su, Su; Tanaka, Kazuyuki

As the power system deregulation advances, the competition among the power companies becomes heated, and they seek more efficient system planning using existing facilities. Therefore, an efficient system planning method has been expected. This paper proposes a quantitative evaluation method for the (N-1) generation margin considering the overload and the voltage stability restriction. Concerning the generation margin related with the overload, a fast solution method without the recalculation of the (N-1) Y-matrix is proposed. Referred to the voltage stability, this paper proposes an efficient method to search the stability limit. The IEEE30 model system which is composed of 6 generators and 14 load nodes is employed to validate the proposed method. According to the results, the proposed method can reduce the computational cost for the generation margin related with the overload under the (N-1) condition, and specify the value quantitatively.

Altered pharmacology of native rodent spinal cord TRPV1 after phosphorylation

PubMed Central

Mogg, AJ; Mill, CEJ; Folly, EA; Beattie, RE; Blanco, MJ; Beck, JP; Broad, LM

2013-01-01

Background and Purpose Evidence suggests that phosphorylation of TRPV1 is an important component underlying its aberrant activation in pathological pain states. To date, the detailed pharmacology of diverse TRPV1 receptor agonists and antagonists has yet to be reported for native TRPV1 under phosphorylating conditions. Our goal was to optimize a relatively high-throughput methodology to allow pharmacological characterization of the native TRPV1 receptor using a spinal cord neuropeptide release assay under naive and phosphorylating states. Experimental Approach Herein, we describe characterization of rodent TRPV1 by measurement of CGRP release from acutely isolated lumbar (L1-L6) spinal cord using a 96-well technique that combines use of native, adult tissue with quantitation of CGRP release by elisa. Key Results We have studied a diverse panel of TRPV1 agonists and antagonists under basal and phosphorylating conditions. We show that TRPV1-mediated CGRP release is evoked, in a temperature-dependent manner, by a PKC activator, phorbol 12,13-dibutyrate (PDBu); and that treatment with PDBu increases the potency and efficacy of known TRPV1 chemical agonists, in an agonist-specific manner. We also show that the pharmacological profile of diverse TRPV1 antagonists is dependent on whether the stimulus is PDBu or capsaicin. Of note, HPPB was identified as an antagonist of capsaicin-evoked, but a potentiator of PDBu-evoked, CGRP release. Conclusions and Implications Our findings indicate that both TRPV1 agonist and antagonist profiles can be differentially altered by PKC activation. These findings may offer new insights for targeting TRPV1 in pain states. PMID:23062150

Lung Function Measurements in Rodents in Safety Pharmacology Studies

PubMed Central

Hoymann, Heinz Gerd

2012-01-01

The ICH guideline S7A requires safety pharmacology tests including measurements of pulmonary function. In the first step – as part of the “core battery” – lung function tests in conscious animals are requested. If potential adverse effects raise concern for human safety, these should be explored in a second step as a “follow-up study”. For these two stages of safety pharmacology testing, both non-invasive and invasive techniques are needed which should be as precise and reliable as possible. A short overview of typical in vivo measurement techniques is given, their advantages and disadvantages are discussed and out of these the non-invasive head-out body plethysmography and the invasive but repeatable body plethysmography in orotracheally intubated rodents are presented in detail. For validation purposes the changes in the respective parameters such as tidal midexpiratory flow (EF50) or lung resistance have been recorded in the same animals in typical bronchoconstriction models and compared. In addition, the technique of head-out body plethysmography has been shown to be useful to measure lung function in juvenile rats starting from day two of age. This allows safety pharmacology testing and toxicological studies in juvenile animals as a model for the young developing organism as requested by the regulatory authorities (e.g., EMEA Guideline 1/2008). It is concluded that both invasive and non-invasive pulmonary function tests are capable of detecting effects and alterations on the respiratory system with different selectivity and area of operation. The use of both techniques in a large number of studies in mice and rats in the last years have demonstrated that they provide useful and reliable information on pulmonary mechanics in safety pharmacology and toxicology testing, in investigations of respiratory disorders, and in pharmacological efficacy studies. PMID:22973226

Marine Pharmacology in 2009–2011: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action †

PubMed Central

Mayer, Alejandro M. S.; Rodríguez, Abimael D.; Taglialatela-Scafati, Orazio; Fusetani, Nobuhiro

2013-01-01

The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998–2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009–2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories. PMID:23880931

Current status and challenges of cytokine pharmacology

PubMed Central

Zídek, Z; Anzenbacher, P; Kmoníčková, E

2009-01-01

The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions. PMID:19371342

Targeting cancer metabolism: dietary and pharmacological interventions

PubMed Central

Vernieri, Claudio; Casola, Stefano; Foiani, Marco; Pietrantonio, Filippo; de Braud, Filippo; Longo, Valter

2016-01-01

Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacological approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this Review, we illustrate how dietary and pharmacological therapies differ in their effect on tumor growth, proliferation and metabolism, and discuss the available preclinical and clinical evidence in favor or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics. PMID:27872127

Recent advance in the pharmacology of dihydropyrimidinone.

PubMed

Wan, J-P; Pan, Y

2012-04-01

Dihydropyrimidinones (DHPMs) are a series of highly valuable small molecules possessing versatile pharmaceutical properties. Although the first one-pot synthesis of DHPMs had been reported more than 100 years ago, the fascinating achievement in DHPMs-based pharmacology during the past century promoted durative interests to the pharmacological and related studies of the scaffold, which lead to the discovery of many new biological functions of DHPMs. Recent pharmacological development on DHPMs-based molecules have been summarized in this review.

TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology.

PubMed

Abriel, Hugues; Syam, Ninda; Sottas, Valentin; Amarouch, Mohamed Yassine; Rougier, Jean-Sébastien

2012-10-01

The transient receptor potential channel (TRP) family comprises at least 28 genes in the human genome. These channels are widely expressed in many different tissues, including those of the cardiovascular system. The transient receptor potential channel melastatin 4 (TRPM4) is a Ca(2+)-activated non-specific cationic channel, which is impermeable to Ca(2+). TRPM4 is expressed in many cells of the cardiovascular system, such as cardiac cells of the conduction pathway and arterial and venous smooth muscle cells. This review article summarizes the recently described roles of TRPM4 in normal physiology and in various disease states. Genetic variants in the human gene TRPM4 have been linked to several cardiac conduction disorders. TRPM4 has also been proposed to play a crucial role in secondary hemorrhage following spinal cord injuries. Spontaneously hypertensive rats with cardiac hypertrophy were shown to over-express the cardiac TRPM4 channel. Recent studies suggest that TRPM4 plays an important role in cardiovascular physiology and disease, even if most of the molecular and cellular mechanisms have yet to be elucidated. We conclude this review article with a brief overview of the compounds that have been shown to either inhibit or activate TRPM4 under experimental conditions. Based on recent findings, the TRPM4 channel can be proposed as a future target for the pharmacological treatment of cardiovascular disorders, such as hypertension and cardiac arrhythmias. Copyright © 2012 Elsevier Inc. All rights reserved.

Strategic establishment of an International Pharmacology Specialty Laboratory in a resource-limited setting.

PubMed

Mtisi, Takudzwa J; Maponga, Charles; Monera-Penduka, Tsitsi G; Mudzviti, Tinashe; Chagwena, Dexter; Makita-Chingombe, Faithful; DiFranchesco, Robin; Morse, Gene D

2018-01-01

A growing number of drug development studies that include pharmacokinetic evaluations are conducted in regions lacking a specialised pharmacology laboratory. This necessitated the development of an International Pharmacology Specialty Laboratory (IPSL) in Zimbabwe. The aim of this article is to describe the development of an IPSL in Zimbabwe. The IPSL was developed collaboratively by the University of Zimbabwe and the University at Buffalo Center for Integrated Global Biomedical Sciences. Key stages included infrastructure development, establishment of quality management systems and collaborative mentorship in clinical pharmacology study design and chromatographic assay development and validation. Two high performance liquid chromatography instruments were donated by an instrument manufacturer and a contract research organisation. Laboratory space was acquired through association with the Zimbabwe national drug regulatory authority. Operational policies, standard operating procedures and a document control system were established. Scientists and technicians were trained in aspects relevant to IPSL operations. A high-performance liquid chromatography method for nevirapine was developed with the guidance of the Clinical Pharmacology Quality Assurance programme and approved by the assay method review programme. The University of Zimbabwe IPSL is engaged with the United States National Institute of Allergy and Infectious Diseases Division of AIDS research networks and is poised to begin drug assays and pharmacokinetic analyses. An IPSL has been successfully established in a resource-limited setting through the efforts of an external partnership providing technical guidance and motivated internal faculty and staff. Strategic partnerships were beneficial in navigating challenges leading to laboratory development and training new investigators. The IPSL is now engaged in clinical pharmacology research.

2015 Meeting of the National Directors of Graduate Studies in Pharmacology and Physiology

PubMed Central

McFalls, Ashley J.; Barnett, Joey V.

2016-01-01

Researchers trained in pharmacology and physiology must possess not only a comprehensive knowledge of chemistry and the nature of compounds but also a deep understanding of physiology and predict how these compounds function in a system or organism. However, graduate programs in pharmacology and physiology have increasingly begun to focus on more reductionist approaches to basic science, neglecting training in integrative/systems physiology. In response to a decline in the competency of recent pharmacology and physiology graduates, a biennial meeting, National Directors of Graduate Studies (NDOGS) in pharmacology and physiology, was conceived to address these concerns and improve the quality of graduate education. NDOGS functions as a forum for directors of pharmacology and physiology programs to exchange ideas and tackle the challenges facing graduate education. The 2015 meeting was held on the campus of the University of Cincinnati, and each day of the meeting was allocated for discussion of a broad topic. On Friday, talks were aimed at “enhancing the professional pipeline.” On Saturday, the theme of “fitting training to emerging needs” tackled ways that universities can respond to the emerging needs of a changing society. Sunday morning updated graduate program directors about changes to National Institutes of Health T32 Training Grant applications and provided a forum for program directors to share their experiences and concerns. Throughout the meeting, presentations and discussions highlighted challenges and opportunities that apply broadly to PhD training in the biomedical sciences and revealed best practices to improve training and career preparation of PhD trainees.

Quantitative analysis of eyes and other optical systems in linear optics.

PubMed

Harris, William F; Evans, Tanya; van Gool, Radboud D

2017-05-01

To show that 14-dimensional spaces of augmented point P and angle Q characteristics, matrices obtained from the ray transference, are suitable for quantitative analysis although only the latter define an inner-product space and only on it can one define distances and angles. The paper examines the nature of the spaces and their relationships to other spaces including symmetric dioptric power space. The paper makes use of linear optics, a three-dimensional generalization of Gaussian optics. Symmetric 2 × 2 dioptric power matrices F define a three-dimensional inner-product space which provides a sound basis for quantitative analysis (calculation of changes, arithmetic means, etc.) of refractive errors and thin systems. For general systems the optical character is defined by the dimensionally-heterogeneous 4 × 4 symplectic matrix S, the transference, or if explicit allowance is made for heterocentricity, the 5 × 5 augmented symplectic matrix T. Ordinary quantitative analysis cannot be performed on them because matrices of neither of these types constitute vector spaces. Suitable transformations have been proposed but because the transforms are dimensionally heterogeneous the spaces are not naturally inner-product spaces. The paper obtains 14-dimensional spaces of augmented point P and angle Q characteristics. The 14-dimensional space defined by the augmented angle characteristics Q is dimensionally homogenous and an inner-product space. A 10-dimensional subspace of the space of augmented point characteristics P is also an inner-product space. The spaces are suitable for quantitative analysis of the optical character of eyes and many other systems. Distances and angles can be defined in the inner-product spaces. The optical systems may have multiple separated astigmatic and decentred refracting elements. © 2017 The Authors Ophthalmic & Physiological Optics © 2017 The College of Optometrists.

Quantitative study of FORC diagrams in thermally corrected Stoner- Wohlfarth nanoparticles systems

NASA Astrophysics Data System (ADS)

De Biasi, E.; Curiale, J.; Zysler, R. D.

2016-12-01

The use of FORC diagrams is becoming increasingly popular among researchers devoted to magnetism and magnetic materials. However, a thorough interpretation of this kind of diagrams, in order to achieve quantitative information, requires an appropriate model of the studied system. For that reason most of the FORC studies are used for a qualitative analysis. In magnetic systems thermal fluctuations "blur" the signatures of the anisotropy, volume and particle interactions distributions, therefore thermal effects in nanoparticles systems conspire against a proper interpretation and analysis of these diagrams. Motivated by this fact, we have quantitatively studied the degree of accuracy of the information extracted from FORC diagrams for the special case of single-domain thermal corrected Stoner- Wohlfarth (easy axes along the external field orientation) nanoparticles systems. In this work, the starting point is an analytical model that describes the behavior of a magnetic nanoparticles system as a function of field, anisotropy, temperature and measurement time. In order to study the quantitative degree of accuracy of our model, we built FORC diagrams for different archetypical cases of magnetic nanoparticles. Our results show that from the quantitative information obtained from the diagrams, under the hypotheses of the proposed model, is possible to recover the features of the original system with accuracy above 95%. This accuracy is improved at low temperatures and also it is possible to access to the anisotropy distribution directly from the FORC coercive field profile. Indeed, our simulations predict that the volume distribution plays a secondary role being the mean value and its deviation the only important parameters. Therefore it is possible to obtain an accurate result for the inversion and interaction fields despite the features of the volume distribution.

Pharmacology Goes Concept-Based: Course Design, Implementation, and Evaluation.

PubMed

Lanz, Amelia; Davis, Rebecca G

Although concept-based curricula are frequently discussed in the nursing education literature, little information exists to guide the development of a concept-based pharmacology course. Traditionally, nursing pharmacology courses are taught with an emphasis on drug class where a prototype drug serves as an exemplar. When transitioning pharmacology to a concept-based course, special considerations are in order. How can educators successfully integrate essential pharmacological content into a curriculum structured around nursing concepts? This article presents one approach to the design and implementation of a concept-based undergraduate pharmacology course. Planning methods, supportive teaching strategies, and course evaluation procedures are discussed.

Promoting the safety performance of industrial radiography using a quantitative assessment system.

PubMed

Kardan, M R; Mianji, F A; Rastkhah, N; Babakhani, A; Azad, S Borhan

2006-12-01

The increasing number of industrial radiographers and their considerable occupational exposure has been one of the main concerns of the Iran Nuclear Regulatory Authority (INRA) in recent years. In 2002, a quantitative system of evaluating the safety performance of licensees and a complementary enforcement system was introduced by the National Radiation Protection Department (NRPD). Each parameter of the practice is given a weighting factor according to its importance to safety. Assessment of the licensees is done quantitatively by summing up their scores using prepared tables. Implementing this system of evaluation showed a considerable decrease in deficiencies in the various centres. Tables are updated regularly as a result of findings during the inspections. This system is used in addition to enforcement to promote safety performance and to increase the culture of safety in industrial radiography.

[Development of a pharmacological curriculum for general practice: Identifying and prescribing orally administered pharmacological substances with relevance for general practice].

PubMed

Straßner, Cornelia; Kaufmann-Kolle, Petra; Flum, Elisabeth; Schwill, Simon; Brandt, Bettina; Steinhäuser, Jost

2017-05-01

General practitioners (GPs) are among the specialists who prescribe the highest number of medication. Therefore the improvement of pharmacological competencies is an important part of the GP specialist training. The self-concept of general practice stating that GPs are the first contact persons for all health problems makes it challenging to define and acquire competencies for specialist training. While the "Competence-based Curriculum" developed by the German College of General Practitioners and Family Physicians defines diagnoses, reasons for counselling and competencies which are essential for general practice, a similar orientation guide is lacking for the pharmacological field. The aim of this study is to define and characterize pharmacological substances which every GP should know so well that he or she is able to conduct counselling and monitoring. We analysed private and public health insurance prescriptions of all general practices participating in the CONTENT project in the period from 2009 to 2014. The analysis was limited to substances with oral application which were prescribed at least once by at least 25 % (n = 11) of the practices. While the 100 most frequent prescriptions were included due to their frequency, less frequently prescribed substances were assessed concerning their relevance for general practice in a rating procedure. The substances included were classified by diagnoses and reasons for counselling. We analysed 1,912,896 prescriptions from 44 practices and 112,535 patients on the basis of the Anatomical Therapeutic Chemical (ATC) classification system. After applying the inclusion criteria, 453 substances were left, 302 of which were considered relevant for general practice and could be assigned to 45 diagnoses / reasons for counselling. The result of this study could be considered a working draft for a pharmacological curriculum for general practice, which may complement the "Competence-based Curriculum" in the medium term. Copyright

Pharmacologic Atrial Natriuretic Peptide Reduces Human Leg Capillary Filtration

NASA Technical Reports Server (NTRS)

Watenpaugh, Donald E.; Vissing, Susanne F.; Lane, Lynda D.; Buckey, Jay C.; Firth, Brian G.; Erdman, William; Hargens, Alan R.; Blomqvist, C. Gunnar

1995-01-01

Atrial natriuretic peptide (ANP) is produced and secreted by atrial cells. We measured calf capillary filtration rate with prolonged venous-occlusion plethysmography of supine healthy male subjects during pharmacologic infusion of ANP (48 pmol/kg/min for 15 min; n = 6) and during placebo infusion (n = 7). Results during infusions were compared to prior control measurements. ANP infusion increased plasma (ANP) from 30 +/- 4 to 2,568 +/- 595 pmol/L. Systemic hemoconcentration occurred during ANP infusion: mean hematocrit and plasma colloid osmotic pressure increased 4.6 and 11.3%, respectively, relative to preinfusion baseline values (p less than 0.05). Mean calf filtration, however, was significantly reduced from 0.15 to 0.08 ml/100 ml/min with ANP. Heart rate increased 20% with ANP infusion, whereas blood pressure was unchanged. Calf conductance (blood flow/ arterial pressure) and venous compliance were unaffected by ANP infusion. Placebo infusion had no effect relative to prior baseline control measurements. Although ANP induced systemic capillary filtration, in the calf, filtration was reduced with ANP. Therefore, pharmacologic ANP infusion enhances capillary filtration from the systemic circulation, perhaps at upper body or splanchnic sites or both, while having the opposite effect in the leg.

From gene networks to drugs: systems pharmacology approaches for AUD.

PubMed

Ferguson, Laura B; Harris, R Adron; Mayfield, Roy Dayne

2018-06-01

The alcohol research field has amassed an impressive number of gene expression datasets spanning key brain areas for addiction, species (humans as well as multiple animal models), and stages in the addiction cycle (binge/intoxication, withdrawal/negative effect, and preoccupation/anticipation). These data have improved our understanding of the molecular adaptations that eventually lead to dysregulation of brain function and the chronic, relapsing disorder of addiction. Identification of new medications to treat alcohol use disorder (AUD) will likely benefit from the integration of genetic, genomic, and behavioral information included in these important datasets. Systems pharmacology considers drug effects as the outcome of the complex network of interactions a drug has rather than a single drug-molecule interaction. Computational strategies based on this principle that integrate gene expression signatures of pharmaceuticals and disease states have shown promise for identifying treatments that ameliorate disease symptoms (called in silico gene mapping or connectivity mapping). In this review, we suggest that gene expression profiling for in silico mapping is critical to improve drug repurposing and discovery for AUD and other psychiatric illnesses. We highlight studies that successfully apply gene mapping computational approaches to identify or repurpose pharmaceutical treatments for psychiatric illnesses. Furthermore, we address important challenges that must be overcome to maximize the potential of these strategies to translate to the clinic and improve healthcare outcomes.

A Systematic Review of Quantitative Resilience Measures for Water Infrastructure Systems

DOE PAGES

Shin, Sangmin; Lee, Seungyub; Judi, David; ...

2018-02-07

Over the past few decades, the concept of resilience has emerged as an important consideration in the planning and management of water infrastructure systems. Accordingly, various resilience measures have been developed for the quantitative evaluation and decision-making of systems. There are, however, numerous considerations and no clear choice of which measure, if any, provides the most appropriate representation of resilience for a given application. This study provides a critical review of quantitative approaches to measure the resilience of water infrastructure systems, with a focus on water resources and distribution systems. A compilation of 11 criteria evaluating 21 selected resilience measuresmore » addressing major features of resilience is developed using the Axiomatic Design process. Existing gaps of resilience measures are identified based on the review criteria. The results show that resilience measures have generally paid less attention to cascading damage to interrelated systems, rapid identification of failure, physical damage of system components, and time variation of resilience. Concluding the paper, improvements to resilience measures are recommended. The findings contribute to our understanding of gaps and provide information to help further improve resilience measures of water infrastructure systems.« less

A Systematic Review of Quantitative Resilience Measures for Water Infrastructure Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, Sangmin; Lee, Seungyub; Judi, David

Over the past few decades, the concept of resilience has emerged as an important consideration in the planning and management of water infrastructure systems. Accordingly, various resilience measures have been developed for the quantitative evaluation and decision-making of systems. There are, however, numerous considerations and no clear choice of which measure, if any, provides the most appropriate representation of resilience for a given application. This study provides a critical review of quantitative approaches to measure the resilience of water infrastructure systems, with a focus on water resources and distribution systems. A compilation of 11 criteria evaluating 21 selected resilience measuresmore » addressing major features of resilience is developed using the Axiomatic Design process. Existing gaps of resilience measures are identified based on the review criteria. The results show that resilience measures have generally paid less attention to cascading damage to interrelated systems, rapid identification of failure, physical damage of system components, and time variation of resilience. Concluding the paper, improvements to resilience measures are recommended. The findings contribute to our understanding of gaps and provide information to help further improve resilience measures of water infrastructure systems.« less

Interoperability of Medication Classification Systems: Lessons Learned Mapping Established Pharmacologic Classes (EPCs) to SNOMED CT

PubMed Central

Nelson, Scott D; Parker, Jaqui; Lario, Robert; Winnenburg, Rainer; Erlbaum, Mark S.; Lincoln, Michael J.; Bodenreider, Olivier

2018-01-01

Interoperability among medication classification systems is known to be limited. We investigated the mapping of the Established Pharmacologic Classes (EPCs) to SNOMED CT. We compared lexical and instance-based methods to an expert-reviewed reference standard to evaluate contributions of these methods. Of the 543 EPCs, 284 had an equivalent SNOMED CT class, 205 were more specific, and 54 could not be mapped. Precision, recall, and F1 score were 0.416, 0.620, and 0.498 for lexical mapping and 0.616, 0.504, and 0.554 for instance-based mapping. Each automatic method has strengths, weaknesses, and unique contributions in mapping between medication classification systems. In our experience, it was beneficial to consider the mapping provided by both automated methods for identifying potential matches, gaps, inconsistencies, and opportunities for quality improvement between classifications. However, manual review by subject matter experts is still needed to select the most relevant mappings. PMID:29295234

Clinical Pharmacology & Therapeutics: Past, Present, and Future.

PubMed

Waldman, S A; Terzic, A

2017-03-01

Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation, and utilization continuum to catalyze, evolve, and disseminate discipline-transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation, and application ushering therapeutic innovation into modern healthcare. © 2017 American Society for Clinical Pharmacology and Therapeutics.

A Narrative Review of Pharmacologic and Non-pharmacologic Interventions for Disorders of Consciousness Following Brain Injury in the Pediatric Population

PubMed Central

Evanson, Nathan K.; Paulson, Andrea L.; Kurowski, Brad G.

2016-01-01

Traumatic brain injury (TBI) is the most common cause of long-term disability in the United States. A significant proportion of children who experience a TBI will have moderate or severe injuries, which includes a period of decreased responsiveness. Both pharmacological and non-pharmacological modalities are used for treating disorders of consciousness after TBI in children. However, the evidence supporting the use of potential therapies is relatively scant, even in adults, and overall, there is a paucity of study in pediatrics. The goal of this review is to describe the state of the science for use of pharmacologic and non-pharmacologic interventions for disorders of consciousness in the pediatric population. PMID:27280064

First Employment of British Pharmacology Graduates

ERIC Educational Resources Information Center

Hollingsworth, Michael; Markham, Anthony

2006-01-01

A survey was conducted in UK Universities to identify the employment of pharmacology graduates (BSc, MSc and PhD) 6 months after graduation in 2003. The aim was to provide data for the British Pharmacological Society (BPS) so they could offer advice to interested bodies and to University staff for careers information. 85% of 52 Universities…

Non Pharmacological Cognitive Enhancers – Current Perspectives

PubMed Central

Kumar, Kuldip; Anand, Kuljeet Singh

2015-01-01

Cognition refers to the mental processes involved in thinking, knowing, remembering, judging, and problem solving. Cognitive dysfunctions are an integral part of neuropsychiatric disorders as well as in healthy ageing. Cognitive Enhancers are molecules that help improve aspects of cognition like memory, intelligence, motivation, attention and concentration. Recently, Non Pharmacological Cognitive Enhancers have gained popularity as effective and safe alternative to various established drugs. Many of these Non Pharmacological Cognitive Enhancers seem to be more efficacious compared to currently available Pharmacological Cognitive Enhancers. This review describes and summarizes evidence on various Non Pharmacological Cognitive Enhancers such as physical exercise, sleep, meditation and yoga, spirituality, nutrients, computer training, brain stimulation, and music. We also discuss their role in ageing and different neuro-psychiatric disorders, and current status of Cochrane database recommendations. We searched the Pubmed database for the articles and reviews having the terms ‘non pharmacological and cognitive’ in the title, published from 2000 till 2014. A total of 11 results displayed, out of which 10 were relevant to the review. These were selected and reviewed. Appropriate cross-references within the articles along with Cochrane reviews were also considered and studied. PMID:26393186

Training in paediatric clinical pharmacology in the UK

PubMed Central

Choonara, Imti; Dewit, Odile; Harrop, Emily; Howarth, Sheila; Helms, Peter; Kanabar, Dipak; Lenney, Warren; Rylance, George; Vallance, Patrick

2004-01-01

Aims To produce a training programme in paediatric clinical pharmacology. Methods A working group, consisting of clinical pharmacologists (paediatric and adult), general paediatricians and the pharmaceutical industry was established to produce the training programme. Results Following a two year training programme in general paediatrics, a three year training programme in clinical pharmacology has been established. This includes one year of research in clinical pharmacology (paediatric or adult). The other two years involve training in different aspects of paediatric clinical pharmacology and general paediatrics. Conclusion The existence of a formal training programme should result in a significant increase in the number of paediatric clinical pharmacologists. PMID:15255806

Pharmacology of the lower urinary tract

PubMed Central

Hennenberg, Martin; Stief, Christian G.; Gratzke, Christian

2014-01-01

Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels. PMID:24744518

Nurses' knowledge of pharmacology behind drugs they commonly administer.

PubMed

Ndosi, Mwidimi E; Newell, Rob

2009-02-01

To determine if nurses had adequate pharmacology knowledge of the drugs they commonly administer. Literature suggests that nurses have insufficient pharmacology knowledge. We also know that nurses and teachers of pharmacology are not satisfied with the amount of pharmacology taught in preregistration programmes in the UK. There is a lack of primary research on nurses' knowledge of pharmacology for the purpose of drug administration. We used a non-experimental causal comparative and correlational design. We recruited a convenience sample of 42 nurses working in surgical wards of a foundation hospital in the North of England. Data were collected by structured interview and questionnaire methods. During the interview, the participants made a blinded selection of one out of four drugs they commonly administer and answered standard questions which focused on specific pharmacology knowledge. Their answers were given a score out of 10 (100%) to determine their actual pharmacology knowledge. The sample comprised of 18 (42.9%) junior nurses and 24 (57.1%) senior nurses. They had a median experience of 10.87 years postregistration. Their mean knowledge score was six ranging between two and nine (SD 1.9). Only 11 (26.1%) nurses scored eight or above and the majority 24 (57.2%) scored below seven, indicating inadequate knowledge. Knowledge of the mechanism of action and drug interactions was poor. There was a correlation between knowledge and experience. The results of this study suggest that nurses have inadequate knowledge of pharmacology. The results will contribute to the evidence of nurses' knowledge of pharmacology in the UK. This study supports the need for supplementary pharmacology education for nurses in clinical settings, focusing on common drugs they administer. This will increase nurses' knowledge and confidence in drug administration and safer medicines management.

A review of traditional pharmacological uses, phytochemistry, and pharmacological activities of Tribulus terrestris.

PubMed

Zhu, Wenyi; Du, Yijie; Meng, Hong; Dong, Yinmao; Li, Li

2017-07-11

Tribulus terrestris L. (TT) is an annual plant of the family Zygophyllaceae that has been used for generations to energize, vitalize, and improve sexual function and physical performance in men. The fruits and roots of TT have been used as a folk medicine for thousands of years in China, India, Sudan, and Pakistan. Numerous bioactive phytochemicals, such as saponins and flavonoids, have been isolated and identified from TT that are responsible alone or in combination for various pharmacological activities. This review provides a comprehensive overview of the traditional applications, phytochemistry, pharmacology and overuse of TT and provides evidence for better medicinal usage of TT.

[The Arabic pharmacology and the introduction to Europe: the background of the Arabic pharmacology - the legacy from Greece].

PubMed

Provençal, P

2001-01-01

When the Arabic-Islamic medicine evolved partly as a consequence of the wave of translations from mainly Greek medical books to Arabic in the 9th century the pharmacological works, which were available, were also translated. The books of Dioscurides and Galen on pharmacological matters became the decisive books of pharmacological translated literature and they formed the basis of the pharmacological understanding in the subsequent extensive literature on pharmacognosy and pharmacology written in Arabic. Nevertheless the Arabs united these two disciplines in a regular pharmacy and they evolved it as an independent discipline, which although attached to medicine was regarded as having its own praxis. The physicians and scientists rationalized and systematized their knowledge of medicinal plants and drugs and extended their knowledge by using original observations and research. Many books on medicaments were written, both as materia medica, i.e. records on simple drugs, and dispensatories, i.e. books on compounded drugs. These two kinds of books were always written separately as they were seen by the Arabs themselves as pertaining to two different subdisciplines, which meant that they were separated too in independent chapters or books in general Arabic works on medicine. When the extensive translations of Arabic medical literature to Latin took place in Italy and Spain in the 11th and 12th centuries, the Arabic pharmacological literature was of course also translated, and its decisive influence on later medieval European medical writings is easy to demonstrate. In the 18th century Peter Forsskaal was one of the first Europeans in the modern scientific tradition to collect and make notes on drugs used in Cairo and in Yemen.

Quantitative X-ray diffraction and fluorescence analysis of paint pigment systems : final report.

DOT National Transportation Integrated Search

1978-01-01

This study attempted to correlate measured X-ray intensities with concentrations of each member of paint pigment systems, thereby establishing calibration curves for the quantitative analyses of such systems.

Pharmacological screening technologies for venom peptide discovery.

PubMed

Prashanth, Jutty Rajan; Hasaballah, Nojod; Vetter, Irina

2017-12-01

Venomous animals occupy one of the most successful evolutionary niches and occur on nearly every continent. They deliver venoms via biting and stinging apparatuses with the aim to rapidly incapacitate prey and deter predators. This has led to the evolution of venom components that act at a number of biological targets - including ion channels, G-protein coupled receptors, transporters and enzymes - with exquisite selectivity and potency, making venom-derived components attractive pharmacological tool compounds and drug leads. In recent years, plate-based pharmacological screening approaches have been introduced to accelerate venom-derived drug discovery. A range of assays are amenable to this purpose, including high-throughput electrophysiology, fluorescence-based functional and binding assays. However, despite these technological advances, the traditional activity-guided fractionation approach is time-consuming and resource-intensive. The combination of screening techniques suitable for miniaturization with sequence-based discovery approaches - supported by advanced proteomics, mass spectrometry, chromatography as well as synthesis and expression techniques - promises to further improve venom peptide discovery. Here, we discuss practical aspects of establishing a pipeline for venom peptide drug discovery with a particular emphasis on pharmacology and pharmacological screening approaches. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

The Concise Guide to PHARMACOLOGY 2015/16: Overview.

PubMed

Alexander, Stephen Ph; Kelly, Eamonn; Marrion, Neil; Peters, John A; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Southan, Christopher; Buneman, O Peter; Catterall, William A; Cidlowski, John A; Davenport, Anthony P; Fabbro, Doriano; Fan, Grace; McGrath, John C; Spedding, Michael; Davies, Jamie A

2015-12-01

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease.

PubMed

Waters, Susanna; Tedroff, Joakim; Ponten, Henrik; Klamer, Daniel; Sonesson, Clas; Waters, Nicholas

2018-01-01

Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

Pharmacologic studies in vulnerable populations: Using the pediatric experience.

PubMed

Zimmerman, Kanecia; Gonzalez, Daniel; Swamy, Geeta K; Cohen-Wolkowiez, Michael

2015-11-01

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, pediatric thought leadership, and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women. Copyright © 2015 Elsevier Inc. All rights reserved.

Effectiveness of student-led objective tutorials in pharmacology teaching to medical students.

PubMed

Arora, Kriti; Hashilkar, Nayana Kamalnayan

2016-10-01

Current teaching in pharmacology is passive with less emphasis on clinical application. There is a need to incorporate newer instructional designs into pharmacology. Student-led objective tutorial (SLOT) is one of the novel designs to enhance interest among learners, provide opportunities for group learning, and facilitate self-directed learning. This study aims to assess the effectiveness of SLOTs over conventional tutorials (CTs) in pharmacology and to obtain feedback from the students regarding their perceptions about it. The regular batch of MBBS 2 nd professional in pharmacology was randomly divided into two groups. Five topics from central nervous system (CNS) were selected. One group received SLOT as the instructional strategy, whereas the other group went through CTs. At the end of the module, a written test was conducted to assess the effectiveness of both strategies. The students provided feedback regarding their experience using a prevalidated questionnaire. The mean scores of both the groups were analyzed using Mann-Whitney U-test. There was no significant difference in the mean scores of the end of the module test. However, the overall passing percentage was significantly higher in the intervention group ( P = 0.043). A total of 45.71% students favored it as a future tutorial method and expressed that SLOT enhanced their ability to learn independently. SLOT is an effective teaching-learning method to teach pharmacology to medical undergraduates. It enhances interest among learners and increases the ability to learn independently.

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system.

PubMed

St Pierre, Cristina; Guo, Jane; Shin, John D; Engstrom, Laura W; Lee, Hyun-Hee; Herbert, Alan; Surdi, Laura; Baker, James; Salmon, Michael; Shah, Sanjiv; Ellis, J Michael; Houshyar, Hani; Crackower, Michael A; Kleinschek, Melanie A; Jones, Dallas C; Hicks, Alexandra; Zaller, Dennis M; Alves, Stephen E; Ramadas, Ravisankar A

2017-01-01

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

Framework for a Quantitative Systemic Toxicity Model (FutureToxII)

EPA Science Inventory

EPA’s ToxCast program profiles the bioactivity of chemicals in a diverse set of ~700 high throughput screening (HTS) assays. In collaboration with L’Oreal, a quantitative model of systemic toxicity was developed using no effect levels (NEL) from ToxRefDB for 633 chemicals with HT...

An Overview of Clinical Pharmacology of Ibuprofen

PubMed Central

Bushra, Rabia; Aslam, Nousheen

2010-01-01

Ibuprofen was the first member of Propionic acid derivatives introduced in 1969. It is a popular domestic and over the counter analgesic and antipyretic for adults and children. Ibuprofen has been rated as the safest conventional NSAID by spontaneous adverse drug reaction reporting systems in the UK. This article summarizes the main pharmacological effects, therapeutical applications and adverse drug reactions, drug-drug interactions and food drug interactions of ibuprofen that have been reported especially during the last 10 years. PMID:22043330

Efficacy of Neurofeedback Versus Pharmacological Support in Subjects with ADHD.

PubMed

González-Castro, Paloma; Cueli, Marisol; Rodríguez, Celestino; García, Trinidad; Álvarez, Luis

2016-03-01

Behavioral training in neurofeedback has proven to be an essential complement to generalize the effects of pharmacological support in subjects who have attention deficit with hyperactivity disorder (ADHD). Therefore, this investigation attempts to analyze the efficacy of neurofeedback compared with pharmacological support and the combination of both. Participants were 131 students, classified into four groups: control (did not receive neurofeedback or pharmacological support), neurofeedback group, pharmacological support group, and combined group (neurofeedback + pharmacological support). Participants' executive control and cortical activation were assessed before and after treatment. Results indicate that the combined group obtained more benefits and that the neurofeedback group improved to a greater extent in executive control than the pharmacological support group. It is concluded that this kind of training may be an alternative to stimulate activation in subjects with ADHD.

Qualification of a Quantitative Laryngeal Imaging System Using Videostroboscopy and Videokymography

PubMed Central

Popolo, Peter S.; Titze, Ingo R.

2008-01-01

Objectives: We sought to determine whether full-cycle glottal width measurements could be obtained with a quantitative laryngeal imaging system using videostroboscopy, and whether glottal width and vocal fold length measurements were repeatable and reliable. Methods: Synthetic vocal folds were phonated on a laboratory bench, and dynamic images were obtained in repeated trials by use of videostroboscopy and videokymography (VKG) with an imaging system equipped with a 2-point laser projection device for measuring absolute dimensions. Video images were also obtained with an industrial videoscope system with a built-in laser measurement capability. Maximum glottal width and vocal fold length were compared among these 3 methods. Results: The average variation in maximum glottal width measurements between stroboscopic data and VKG data was 3.10%. The average variations in width measurements between the clinical system and the industrial system were 1.93% (stroboscopy) and 3.49% (VKG). The variations in vocal fold length were similarly small. The standard deviations across trials were 0.29 mm for width and 0.48 mm for length (stroboscopy), 0.18 mm for width (VKG), and 0.25 mm for width and 0.84 mm for length (industrial). Conclusions: For stable, periodic vibration, the full extent of the glottal width can be reliably measured with the quantitative videostroboscopy system. PMID:18646436

Development and validation of LC-MS/MS method for quantitative determination of (-)-securinine in mouse plasma.

PubMed

Wabuyele, Simuli L; Wald, David; Xu, Yan

2014-06-01

(-)-Securinine (SE) is a major alkaloid found in plant Securinega suffruticosa, which has a wide range of pharmacological activities including anticancer, anti-parasitic and central nervous system stimulating effects, etc. To aid the pharmacological study of SE, we developed an LC-MS/MS method for quantitative determination of SE in mouse plasma. In this method, plasma samples were first prepared with salting-out assisted liquid-liquid extraction using cold acetonitrile (-20°C) and 2.00 M ammonium acetate. Separation of SE and the internal standard (IS) from sample matrix was achieved on a Gemini Nx C18 column using 40% acetonitrile and 60% 10.0mM ammonium acetate at a flow rate of 0.200 mL min(-1). Quantification of SE was accomplished with positive electrospray ionization tandem mass spectrometry using mass transitions m/z 218.1→84.1 for SE, and m/z 204.1→70.2 for the IS. This method has a lower limit of quantitation (LLOQ) of 0.600 ng mL(-1) and a linear calibration range up to 600 ng mL(-1) in mouse plasma. The intra- and inter-run accuracy (%RE) and precision (%CV) were ≤ ± 6% and 6%, respectively. The IS normalized matrix factors from six lots of plasma matrices ranged 0.92-1.07, and the recoveries of plasma SE were 99-109%. The validated method has been applied to the measurement of SE in plasma samples of a mouse study. Copyright © 2014 Elsevier B.V. All rights reserved.

Confocal reflectance quantitative phase microscope system for cellular membranes dynamics study (Conference Presentation)

NASA Astrophysics Data System (ADS)

Singh, Vijay Raj; Yaqoob, Zahid; So, Peter T. C.

2017-02-01

Quantitative phase microscopy (QPM) techniques developed so far primarily belongs to high speed transmitted light based systems that has enough sensitivity to resolve membrane fluctuations and dynamics, but has no depth resolution. Therefore, most biomechanics studies using QPM today is confined to simple cells, such as RBCs, without internal organelles. An important instrument that will greatly extend the biomedical applications of QPM is to develop next generation microscope with 3D capability and sufficient temporal resolution to study biomechanics of complex eukaryotic cells including the mechanics of their internal compartments. For eukaryotic cells, the depth sectioning capability is critical and should be sufficient to distinguish nucleic membrane fluctuations from plasma membrane fluctuations. Further, this microscope must provide high temporal resolution since typical eukaryotes membranes are substantially stiffer than RBCs. A confocal reflectance quantitative phase microscope is presented based on multi-pinhole scanning, with the capabilities of higher temporal resolution and sensitivity for nucleic and plasma membranes of eukaryotic cells. System hardware is developed based on an array of confocal pinhole generated by using the `ON' state of subset of micro-mirrors of digital micro-mirror device (DMD, from Texas Instruments) and high-speed raster scanning provides 14ms imaging speed in wide-field mode. A common path interferometer is integrated at the imaging arm for detection of specimens' quantitative phase information. Theoretical investigation of quantitative phase reconstructed from system is investigated and application of system is presented for dimensional fluctuations measurements of both cellular plasma and nucleic membranes of embryonic stem cells.

Nursing students learning the pharmacology of diabetes mellitus with complexity-based computerized models: A quasi-experimental study.

PubMed

Dubovi, Ilana; Dagan, Efrat; Sader Mazbar, Ola; Nassar, Laila; Levy, Sharona T

2018-02-01

Pharmacology is a crucial component of medications administration in nursing, yet nursing students generally find it difficult and self-rate their pharmacology skills as low. To evaluate nursing students learning pharmacology with the Pharmacology Inter-Leaved Learning-Cells environment, a novel approach to modeling biochemical interactions using a multiscale, computer-based model with a complexity perspective based on a small set of entities and simple rules. This environment represents molecules, organelles and cells to enhance the understanding of cellular processes, and combines these cells at a higher scale to obtain whole-body interactions. Sophomore nursing students who learned the pharmacology of diabetes mellitus with the Pharmacology Inter-Leaved Learning-Cells environment (experimental group; n=94) or via a lecture-based curriculum (comparison group; n=54). A quasi-experimental pre- and post-test design was conducted. The Pharmacology-Diabetes-Mellitus questionnaire and the course's final exam were used to evaluate students' knowledge of the pharmacology of diabetes mellitus. Conceptual learning was significantly higher for the experimental than for the comparison group for the course final exam scores (unpaired t=-3.8, p<0.001) and for the Pharmacology-Diabetes-Mellitus questionnaire (U=942, p<0.001). The largest effect size for the Pharmacology-Diabetes-Mellitus questionnaire was for the medication action subscale. Analysis of complex-systems component reasoning revealed a significant difference for micro-macro transitions between the levels (F(1, 82)=6.9, p<0.05). Learning with complexity-based computerized models is highly effective and enhances the understanding of moving between micro and macro levels of the biochemical phenomena, this is then related to better understanding of medication actions. Moreover, the Pharmacology Inter-Leaved Learning-Cells approach provides a more general reasoning scheme for biochemical processes, which enhances

Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery☆

PubMed Central

Kell, Douglas B.; Goodacre, Royston

2014-01-01

Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology. PMID:23892182

Electronic cigarettes and nicotine clinical pharmacology.

PubMed

Schroeder, Megan J; Hoffman, Allison C

2014-05-01

To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products' ability to support and maintain nicotine dependence. Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products' impact on public health.

Electronic cigarettes and nicotine clinical pharmacology

PubMed Central

Schroeder, Megan J; Hoffman, Allison C

2014-01-01

Objective To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. Methods Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. Results Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products’ ability to support and maintain nicotine dependence. Conclusions Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products’ impact on public health. PMID:24732160

Introductory pharmacology for clinical practice.

PubMed

Corbett, Robin Webb; Owens, Laura Williford

2011-01-01

The average woman will take many medications, both prescription and nonprescription, as well as herbs or other dietary supplements over the course of her lifetime. These chemicals can produce therapeutic benefits but can also cause toxic effects. Pharmacokinetics, pharmacodynamics, pharmacotherapy, adverse drug reactions, and research in pharmacology are discussed as applied to women's health. Clinicians must have a firm understanding of the basic principles of pharmacology so that they can appropriately administer medications, monitor for anticipated effects and adverse reactions, and communicate as needed with women, their families, and other health care team members. © 2011 by the American College of Nurse-Midwives.

An Ibm PC/AT-Based Image Acquisition And Processing System For Quantitative Image Analysis

NASA Astrophysics Data System (ADS)

Kim, Yongmin; Alexander, Thomas

1986-06-01

In recent years, a large number of applications have been developed for image processing systems in the area of biological imaging. We have already finished the development of a dedicated microcomputer-based image processing and analysis system for quantitative microscopy. The system's primary function has been to facilitate and ultimately automate quantitative image analysis tasks such as the measurement of cellular DNA contents. We have recognized from this development experience, and interaction with system users, biologists and technicians, that the increasingly widespread use of image processing systems, and the development and application of new techniques for utilizing the capabilities of such systems, would generate a need for some kind of inexpensive general purpose image acquisition and processing system specially tailored for the needs of the medical community. We are currently engaged in the development and testing of hardware and software for a fairly high-performance image processing computer system based on a popular personal computer. In this paper, we describe the design and development of this system. Biological image processing computer systems have now reached a level of hardware and software refinement where they could become convenient image analysis tools for biologists. The development of a general purpose image processing system for quantitative image analysis that is inexpensive, flexible, and easy-to-use represents a significant step towards making the microscopic digital image processing techniques more widely applicable not only in a research environment as a biologist's workstation, but also in clinical environments as a diagnostic tool.

Automated, Quantitative Cognitive/Behavioral Screening of Mice: For Genetics, Pharmacology, Animal Cognition and Undergraduate Instruction

PubMed Central

Gallistel, C. R.; Balci, Fuat; Freestone, David; Kheifets, Aaron; King, Adam

2014-01-01

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and pharmacological manipulations on basic mechanisms of cognition and learning in mice. A standard polypropylene mouse housing tub is connected through an acrylic tube to a standard commercial mouse test box. The test box has 3 hoppers, 2 of which are connected to pellet feeders. All are internally illuminable with an LED and monitored for head entries by infrared (IR) beams. Mice live in the environment, which eliminates handling during screening. They obtain their food during two or more daily feeding periods by performing in operant (instrumental) and Pavlovian (classical) protocols, for which we have written protocol-control software and quasi-real-time data analysis and graphing software. The data analysis and graphing routines are written in a MATLAB-based language created to simplify greatly the analysis of large time-stamped behavioral and physiological event records and to preserve a full data trail from raw data through all intermediate analyses to the published graphs and statistics within a single data structure. The data-analysis code harvests the data several times a day and subjects it to statistical and graphical analyses, which are automatically stored in the "cloud" and on in-lab computers. Thus, the progress of individual mice is visualized and quantified daily. The data-analysis code talks to the protocol-control code, permitting the automated advance from protocol to protocol of individual subjects. The behavioral protocols implemented are matching, autoshaping, timed hopper-switching, risk assessment in timed hopper-switching, impulsivity measurement, and the circadian anticipation of food availability. Open-source protocol-control and data-analysis code makes the addition of new protocols simple. Eight test environments fit in a 48 in x 24 in x 78 in cabinet; two such cabinets (16 environments) may be

Automated, quantitative cognitive/behavioral screening of mice: for genetics, pharmacology, animal cognition and undergraduate instruction.

PubMed

Gallistel, C R; Balci, Fuat; Freestone, David; Kheifets, Aaron; King, Adam

2014-02-26

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and pharmacological manipulations on basic mechanisms of cognition and learning in mice. A standard polypropylene mouse housing tub is connected through an acrylic tube to a standard commercial mouse test box. The test box has 3 hoppers, 2 of which are connected to pellet feeders. All are internally illuminable with an LED and monitored for head entries by infrared (IR) beams. Mice live in the environment, which eliminates handling during screening. They obtain their food during two or more daily feeding periods by performing in operant (instrumental) and Pavlovian (classical) protocols, for which we have written protocol-control software and quasi-real-time data analysis and graphing software. The data analysis and graphing routines are written in a MATLAB-based language created to simplify greatly the analysis of large time-stamped behavioral and physiological event records and to preserve a full data trail from raw data through all intermediate analyses to the published graphs and statistics within a single data structure. The data-analysis code harvests the data several times a day and subjects it to statistical and graphical analyses, which are automatically stored in the "cloud" and on in-lab computers. Thus, the progress of individual mice is visualized and quantified daily. The data-analysis code talks to the protocol-control code, permitting the automated advance from protocol to protocol of individual subjects. The behavioral protocols implemented are matching, autoshaping, timed hopper-switching, risk assessment in timed hopper-switching, impulsivity measurement, and the circadian anticipation of food availability. Open-source protocol-control and data-analysis code makes the addition of new protocols simple. Eight test environments fit in a 48 in x 24 in x 78 in cabinet; two such cabinets (16 environments) may be

Pharmacological profiling of the TRPV3 channel in recombinant and native assays.

PubMed

Grubisha, Olivera; Mogg, Adrian J; Sorge, Jessica L; Ball, Laura-Jayne; Sanger, Helen; Ruble, Cara L A; Folly, Elizabeth A; Ursu, Daniel; Broad, Lisa M

2014-05-01

Transient receptor potential vanilloid subtype 3 (TRPV3) is implicated in nociception and certain skin conditions. As such, it is an attractive target for pharmaceutical research. Understanding of endogenous TRPV3 function and pharmacology remains elusive as selective compounds and native preparations utilizing higher throughput methodologies are lacking. In this study, we developed medium-throughput recombinant and native cellular assays to assess the detailed pharmacological profile of human, rat and mouse TRPV3 channels. Medium-throughput cellular assays were developed using a Ca(2+) -sensitive dye and a fluorescent imaging plate reader. Human and rat TRPV3 pharmacology was examined in recombinant cell lines, while the mouse 308 keratinocyte cell line was used to assess endogenous TRPV3 activity. A recombinant rat TRPV3 cellular assay was successfully developed after solving a discrepancy in the published rat TRPV3 protein sequence. A medium-throughput, native, mouse TRPV3 keratinocyte assay was also developed and confirmed using genetic approaches. Whereas the recombinant human and rat TRPV3 assays exhibited similar agonist and antagonist profiles, the native mouse assay showed important differences, namely, TRPV3 activity was detected only in the presence of potentiator or during agonist synergy. Furthermore, the native assay was more sensitive to block by some antagonists. Our findings demonstrate similarities but also notable differences in TRPV3 pharmacology between recombinant and native systems. These findings offer insights into TRPV3 function and these assays should aid further research towards developing TRPV3 therapies. © 2013 The British Pharmacological Society.

Towards a genealogy of pharmacological practice.

PubMed

Camargo, Ricardo; Ried, Nicolás

2016-03-01

Following Foucault's work on disciplinary power and biopolitics, this article maps an initial cartography of the research areas to be traced by a genealogy of pharmacological practice. Pharmacology, as a practical activity, refers to the creation, production and sale of drugs/medication. This work identifies five lines of research that, although often disconnected from each other, may be observed in the specialized literature: (1) pharmaceuticalization; (2) regulation of the pharmaceutical industry; (3) the political-economic structure of the pharmaceutical industry; (4) consumption/consumerism of medications; (5) and bio-knowledge. The article suggests that a systematic analysis of these areas leads one to consider pharmacological practice a sui generis apparatus of power, which reaches beyond the purely disciplinary and biopolitical levels to encompass molecular configurations, thereby giving rise not only to new types of government over life, but also to new struggles for life, extending from molecular to population-wide levels.

Mining Molecular Pharmacological Effects from Biomedical Text: a Case Study for Eliciting Anti-Obesity/Diabetes Effects of Chemical Compounds.

PubMed

Dura, Elzbieta; Muresan, Sorel; Engkvist, Ola; Blomberg, Niklas; Chen, Hongming

2014-05-01

In the pharmaceutical industry, efficiently mining pharmacological data from the rapidly increasing scientific literature is very crucial for many aspects of the drug discovery process such as target validation, tool compound selection etc. A quick and reliable way is needed to collect literature assertions of selected compounds' biological and pharmacological effects in order to assist the hypothesis generation and decision-making of drug developers. INFUSIS, the text mining system presented here, extracts data on chemical compounds from PubMed abstracts. It involves an extensive use of customized natural language processing besides a co-occurrence analysis. As a proof-of-concept study, INFUSIS was used to search in abstract texts for several obesity/diabetes related pharmacological effects of the compounds included in a compound dictionary. The system extracts assertions regarding the pharmacological effects of each given compound and scores them by the relevance. For each selected pharmacological effect, the highest scoring assertions in 100 abstracts were manually evaluated, i.e. 800 abstracts in total. The overall accuracy for the inferred assertions was over 90 percent. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Botany, ethnomedicines, phytochemistry and pharmacology of Himalayan paeony (Paeonia emodi Royle.).

PubMed

Ahmad, Mushtaq; Malik, Khafsa; Tariq, Akash; Zhang, Guolin; Yaseen, Ghulam; Rashid, Neelam; Sultana, Shazia; Zafar, Muhammad; Ullah, Kifayat; Khan, Muhammad Pukhtoon Zada

2018-06-28

submission and most of the studies (90%) without validation of taxonomic names using recognized databases. In reported methods, 67% studies without characterization of extracts, 25% lack proper dose, 40% without duration and 31% reports lack information on proper controls. Similarly, only 18% studies reports active compound(s) responsible for pharmacological activities, 14% studies show minimal active concentration, only 2.5% studies report mechanism of action on target while none of the reports mentioned in silico approach. P. emodi is endemic to Himalayan region (Pakistan, China, India and Nepal) with diverse traditional therapeutic uses. Majority of reviewed studies showed confusion in its taxonomic validity, incomplete methodologies and ambiguous findings. Keeping in view the immense uses of P. emodi in various traditional medicinal systems, holistic pharmacological approaches in combination with reverse pharmacology, system biology, and "omics" technologies are recommended to improve the quality of research which leads to natural drug discovery development at global perspectives. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical pharmacology in Russia-historical development and current state.

PubMed

Zagorodnikova Goryachkina, Ksenia; Burbello, Aleksandra; Sychev, Dmitry; Frolov, Maxim; Kukes, Vladimir; Petrov, Vladimir

2015-02-01

Clinical pharmacology in Russia has long history and is currently active, but rather unrecognized internationally. It is governmentally approved as a teaching/scientific specialty since 1983 and as a medical specialty since 1997. Courses of clinical pharmacology are included in the undergraduate curricula in the 5th and/or 6th year of education at all medical schools in the Russian Federation. Postgraduate education includes initial specialization in internal medicine with further residency in clinical pharmacology. Governmental legislation recommends that every healthcare institution has either a department or a single position of clinical pharmacologist. Major routine duties include information about and monitoring of medication use, consultations in difficult clinical situations, pharmacogenetic counseling, therapeutic drug monitoring, pharmacovigilance, and participation in drug and therapeutics (formulary) committees. There are official experts in clinical pharmacology in Russia responsible for coordinating relevant legislative issues. The chief expert clinical pharmacologist represents the discipline directly at the Ministry of Health. Research in clinical pharmacology in Russia is extensive and variable, but only some of it is published internationally. Russia is a participant of international societies of clinical pharmacology and therapeutics and collaboration is actively ongoing. There are still certain problems related to the development of the discipline in Russia-some healthcare institutions do not see the need for clinical pharmacology. However, the number of clinical pharmacologists in Russia is increasing as well as their role in physicians' education, national healthcare, and research.

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution.

PubMed

Denoyer, Delphine; Pearson, Helen B; Clatworthy, Sharnel A S; Smith, Zoe M; Francis, Paul S; Llanos, Roxana M; Volitakis, Irene; Phillips, Wayne A; Meggyesy, Peter M; Masaldan, Shashank; Cater, Michael A

2016-06-14

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed.

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

PubMed Central

Denoyer, Delphine; Pearson, Helen B.; Clatworthy, Sharnel A.S.; Smith, Zoe M.; Francis, Paul S.; Llanos, Roxana M.; Volitakis, Irene; Phillips, Wayne A.; Meggyesy, Peter M.; Masaldan, Shashank; Cater, Michael A.

2016-01-01

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed. PMID:27175597

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

PubMed Central

van Rijn, Richard M.; DeFriel, Julia N.; Whistler, Jennifer L.

2013-01-01

Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders, and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR selective drugs are in clinical trials, but no DOR selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. This review will discuss the existing literature focusing on four aspects: 1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands 2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. 3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. 4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. These combined features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands. PMID:23649885

Transdermal patches: history, development and pharmacology.

PubMed

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-05-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. © 2015 The British Pharmacological Society.

Patterns, Probabilities, and People: Making Sense of Quantitative Change in Complex Systems

ERIC Educational Resources Information Center

Wilkerson-Jerde, Michelle Hoda; Wilensky, Uri J.

2015-01-01

The learning sciences community has made significant progress in understanding how people think and learn about complex systems. But less is known about how people make sense of the quantitative patterns and mathematical formalisms often used to study these systems. In this article, we make a case for attending to and supporting connections…

Pharmacological Potential of Sea Cucumbers

PubMed Central

Khotimchenko, Yuri

2018-01-01

This review presents a detailed analysis of published research data focused on the pharmacological activity exerted by biologically active compounds isolated from sea cucumbers belonging to the class of Holothuroidea, phylum Echinodermata. The review contains descriptions of the structure, physico-chemical properties and pharmacological effects of these active substances. Particular attention is given to compounds with anticoagulant, antithrombotic, antioxidant, anticancer, anti-infectious, immune-stimulating and anti-ACE (angiotensin converting enzyme) activities as well as to the substances exerting a regulating influence on lipid and carbohydrate metabolism. All these compounds may be considered as prototypes for development of new pharmaceutical substances and medicines. PMID:29724051

Non-pharmacological approaches to alleviate distress in dementia care.

PubMed

Mitchell, Gary; Agnelli, Joanne

2015-11-25

Distress is one of the most common clinical manifestations associated with dementia. Pharmacological intervention may be appropriate in managing distress in some people. However, best practice guidelines advocate non-pharmacological interventions as the preferred first-line treatment. The use of non-pharmacological interventions encourages healthcare professionals to be more person-centred in their approach, while considering the causes of distress. This article provides healthcare professionals with an overview of some of the non-pharmacological approaches that can assist in alleviating distress for people living with dementia including: reminiscence therapy, reality orientation, validation therapy, music therapy, horticultural therapy, doll therapy and pet therapy. It provides a summary of their use in clinical practice and links to the relevant literature.

[The non-pharmacological management of chronic pain].

PubMed

Berlemont, Christine

2017-05-01

Pain management is not limited to the putting in place of pharmacological, surgical, physiotherapy or psychological strategies. Non-pharmacological therapies can also be proposed, notably in relation to chronic pain. Appreciated by patients and developed by caregivers, they require appropriate regulatory guidelines and specific training in order for them to be implemented safely. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Breastfeeding information in pharmacology textbooks: a content analysis.

PubMed

Amir, Lisa H; Raval, Manjri; Hussainy, Safeera Y

2013-07-01

Women often need to take medicines while breastfeeding and pharmacists need to provide accurate information in order to avoid undue caution about the compatibility of medicines and breastfeeding. The objective of this study was to review information provided about breastfeeding in commonly used pharmacology textbooks. We asked 15 Australian universities teaching pharmacy courses to provide a list of recommended pharmacology textbooks in 2011. Ten universities responded, generating a list of 11 textbooks that we analysed for content relating to breastfeeding. Pharmacology textbooks outline the mechanisms of actions of medicines and their use: however, only a small emphasis is placed on the safety/compatibility of medicines for women during breastfeeding. Current pharmacology textbooks recommended by Australian universities have significant gaps in their coverage of medicine use in breastfeeding. Authors of textbooks should address this gap, so academic staff can recommend texts with the best lactation content.

Measuring the effectiveness of pharmacology teaching in undergraduate medical students.

PubMed

Urrutia-Aguilar, Maria Esther; Martinez-Gonzalez, Adrian; Rodriguez, Rodolfo

2012-03-01

Information overload and recent curricular changes are viewed as important contributory factors to insufficient pharmacological education of medical students. This study was designed to assess the effectiveness of pharmacology teaching in our medical school. The study subjects were 455 second-year medical students, class of 2010, and 26 pharmacology teachers at the National University of Mexico Medical School. To assess pharmacological knowledge, students were required to take 3 multiple-choice exams (70 questions each) as part of their evaluation in the pharmacology course. A 30-item questionnaire was used to explore the students' opinion on teaching. Pharmacology professors evaluated themselves using a similar questionnaire. Students and teachers rated each statement on a 5-point Likert scale. The groups' exam scores ranged from 54.5% to 90.0% of correct responses, with a mean score of 77.3%. Only 73 (16%) of 455 students obtained an exam score of 90% and higher. Students' evaluations of faculty and professor self-ratings were very high (90% and 96.2%, of the maximal response, respectively). Student and professor ratings were not correlated with exam scores (r = 0.291). Our study shows that knowledge on pharmacology is incomplete in a large proportion of second-year medical students and indicates that there is an urgent need to review undergraduate training in pharmacology. The lack of relationship between the subjective ratings of teacher effectiveness and objective exam scores suggests the use of more demanding measures to assess the effectiveness of teaching.

Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review.

PubMed

Wang, Ting; Guo, Rixin; Zhou, Guohong; Zhou, Xidan; Kou, Zhenzhen; Sui, Feng; Li, Chun; Tang, Liying; Wang, Zhuju

2016-07-21

Panax notoginseng (Burk.) F.H. Chen is a widely used traditional Chinese medicine known as Sanqi or Tianqi in China. This plant, which is distributed primarily in the southwest of China, has wide-ranging pharmacological effects and can be used to treat cardiovascular diseases, pain, inflammation and trauma as well as internal and external bleeding due to injury. This paper provides up-to-date information on investigations of this plant, including its botany, ethnopharmacology, phytochemistry, pharmacology and toxicology. The possible uses and perspectives for future investigation of this plant are also discussed. The relevant information on Panax notoginseng (Burk.) F.H. Chen was collected from numerous resources, including classic books about Chinese herbal medicine, and scientific databases, including Pubmed, SciFinder, ACS, Ebsco, Elsevier, Taylor, Wiley and CNKI. More than 200 chemical compounds have been isolated from Panax notoginseng (Burk.) F.H. Chen, including saponins, flavonoids and cyclopeptides. The plant has pharmacological effects on the cardiovascular system, immune system as well as anti-inflammatory, anti-atherosclerotic, haemostatic and anti-tumour activities, etc. Panax notoginseng is a valuable traditional Chinese medical herb with multiple pharmacological effects. This review summarizes the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of P. notoginseng, and presents the constituents and their corresponding chemical structures found in P. notoginseng comprehensively for the first time. Future research into its phytochemistry of bio-active components should be performed by using bioactivity-guided isolation strategies. Further work on elucidation of the structure-function relationship among saponins, understanding of multi-target network pharmacology of P. notoginseng, as well as developing its new clinical usage and comprehensive utilize will enhance the therapeutic potentials of P. notoginseng. Copyright © 2016

Citri Reticulatae Pericarpium (Chenpi): Botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional Chinese medicine.

PubMed

Yu, Xin; Sun, Shuang; Guo, Yuyan; Liu, Yan; Yang, Dayu; Li, Guoyu; Lü, Shaowa

2018-06-28

Citri Reticulatae Pericarpium (Rutaceae, CRP), commonly called as Chenpi () in Chinese, is most frequently used as a qi-regulating drug in thousands of Chinese medicine prescriptions. CRP is found mainly in major citrus-producing areas such as the Guangdong, Guangxi, Sichuan, Fujian, and Zhejiang Provinces of China. Since thousands of years in China, CRP has been used widely in clinical practice to treat nausea, vomiting, indigestion, anepithymia, diarrhea, cough, expectoration, and so on. Currently, CRP is listed in the Pharmacopoeia of the People's Republic of China. The present paper reviews the botany, ethnopharmacology, phytochemistry, pharmacology, quality control, and toxicology of CRP. Information on CRP was gathered from various sources including the books on traditional Chinese herbal medicine; scientific databases including Elsevier, PubMed, and ScienceDirect; Baidu Scholar; CNKI; and others and from different professional websites. Approximately 140 chemical compounds have been isolated and identified from CRP. Among them, volatile oils and flavonoids are generally considered as the main bioactive and characteristic ingredients. CRP possesses wide pharmacological effects such as having a beneficial effect on the cardiovascular, digestive, and respiratory systems, antitumor, antioxidant, and anti-inflammatory properties; and a protective effect on the liver and nerve. Moreover, hesperidin is chosen as an indicator in the quantitative determination of CRP, and the quantity of aflatoxin in CRP must not exceed the standard limit mentioned in the pharmacopoeia. In brief, CRP has a warming nature, and hence, it can be used in harmony with a lot of medicines. CRP not only exhibits its effects individually but also aids other medicines exhibit a better effect. CRP can be consumed with tea, food, alcohol, and medicine. Irrespective of the form it is being consumed, CRP not only shows a synergistic effect but also has strengths on its own. Modern pharmacological

Developing and delivering clinical pharmacology in pharmaceutical companies.

PubMed

Richards, Duncan

2012-06-01

The challenges of developing new medicines are well known. Effective application of clinical pharmacology expertise is vital to the successful evaluation of potential new medicines. In drug development, this depends on effective integration of diverse skills. Many of these are currently in short supply, but through innovative partnerships between industry and academia there is an opportunity to reinvigorate the discipline by nurturing these key skills to the benefit of both partners. Specific areas of focus should be experimental medicine, modelling and simulation, and translational skills. © 2012 The Author. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

How research in behavioral pharmacology informs behavioral science.

PubMed

Branch, Marc N

2006-05-01

Behavioral pharmacology is a maturing science that has made significant contributions to the study of drug effects on behavior, especially in the domain of drug-behavior interactions. Less appreciated is that research in behavioral pharmacology can have, and has had, implications for the experimental analysis of behavior, especially its conceptualizations and theory. In this article, I outline three general strategies in behavioral pharmacology research that have been employed to increase understanding of behavioral processes. Examples are provided of the general characteristics of the strategies and of implications of previous research for behavior theory. Behavior analysis will advance as its theories are challenged.

Recent Pharmacology Studies on the International Space Station

NASA Technical Reports Server (NTRS)

Wotring, Virginia

2014-01-01

The environment on the International Space Station (ISS) includes a variety of potential stressors including the absence of Earth's gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. The effects of this extreme environment on pharmacokinetics, pharmacodynamics, and even on stored medication doses, are not yet understood. Dr. Wotring will discuss recent analyses of medication doses that experienced long duration storage on the ISS and a recent retrospective examination of medication use during long-duration spaceflights. She will also describe new pharmacology experiments that are scheduled for upcoming ISS missions. Dr. Virginia E. Wotring is a Senior Scientist in the Division of Space Life Sciences in the Universities Space Research Association, and Pharmacology Discipline Lead at NASA's Johnson Space Center, Human Heath and Countermeasures Division. She received her doctorate in Pharmacological and Physiological Science from Saint Louis University after earning a B.S. in Chemistry at Florida State University. She has published multiple studies on ligand gated ion channels in the brain and spinal cord. Her research experience includes drug mechanisms of action, drug receptor structure/function relationships and gene & protein expression. She joined USRA (and spaceflight research) in 2009. In 2012, her book reviewing pharmacology in spaceflight was published by Springer: Space Pharmacology, Space Development Series.

Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology".

PubMed

Insel, Paul A; Amara, Susan G; Blaschke, Terrence F; Meyer, Urs A

2017-01-06

Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

Pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance identifies very early cardiac involvement in systemic sclerosis patients of recent onset.

PubMed

Giacomelli, Roberto; Di Cesare, Ernesto; Cipriani, Paola; Ruscitti, Piero; Di Sibio, Alessandra; Liakouli, Vasiliki; Gennarelli, Antonio; Carubbi, Francesco; Splendiani, Alessandra; Berardicurti, Onorina; Di Benedetto, Paola; Ciccia, Francesco; Guggino, Giuliana; Radchenko, Ganna; Triolo, Giovanni; Masciocchi, Carlo

2017-09-01

To evaluate occult cardiac involvement in asymptomatic systemic sclerosis (SSc) patients by pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance (CMR), for a very early identification of patients at higher risk of cardiac-related mortality. Sixteen consecutive patients with definite SSc, fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria in less than 1 year from the onset of Raynaud's phenomenon, underwent pharmacological stress, rest perfusion and delayed enhancement CMR. At enrollment, no patient showed signs and/or symptoms suggestive for cardiac involvement. No patient showed traditional cardiovascular risk factors. Both the 12-lead electrocardiogram examination and echocardiographic evaluation did not show any alterations in our cohort. Stress perfusion defects of left ventricle were detected in six out of 16 (37.5%) patients and these defects did not match with the coronary flow distribution. The results showed the presence of two different patterns of stress perfusion defects: sub-endocardial and/or a midmyocardial. The presence of stress perfusion defects did not correlate with any clinical feature of enrolled patients. Myocardial stress perfusion defects may be detected early by pharmacological stress perfusion CMR, a reliable and sensitive technique for the noninvasive evaluation of SSc heart disease, in patients with SSc of recent onset. These defects seem to be independent from traditional risk factors and associated comorbidities, suggesting they are a specific hallmark of the disease. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Marine pharmacology in 2005–6: Marine Compounds with Anthelmintic, Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiprotozoal, Antituberculosis, and Antiviral Activities; affecting the Cardiovascular, Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M. S.; Rodriguez, Abimael D.; Berlinck, Roberto G. S.; Hamann, Mark T.

2009-01-01

BACKGROUND The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors’ 1998–2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented. RESULTS Anthelminthic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. CONCLUSIONS Marine pharmacology research during 2005–2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents. SIGNIFICANCE Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity and will probably result in novel therapeutic agents for the treatment of multiple disease categories. PMID:19303911

Pharmacological management of acute radiation morbidity.

PubMed

Zimmermann, J S; Kimmig, B

1998-11-01

The acute radiation morbidity may be a serious problem for the patient and may be decreased by pharmacological approaches. A database research (Medline, Cancerlit, DIMDI, etc.) was performed in order to obtain pharmacological approaches to decrease the acute radiation morbidity. The evaluation was focused on therapeutic principles but not on special drugs. Different approaches may be chosen to protect healthy tissues from the effects of ionizing radiation: 1. administration of cyto- or radioprotective agents prior to irradiation, 2. administration of agents to avoid additional secondary toxicity by inflammation or superinfection during the treatment cycle (supportive care) and 3. administration of rescue agents, such as bone marrow CSFs or hyperbaric oxygen (HBO), after therapy. For radioprotection, there are reports on cellular protection by vitamine E, vitamine C, beta carotene, ribose-cysteine, glutamine, Mgcl2/adenosine triphosphate and WR-2721 (amifostine). In general, preclinical studies show that the combination of pretreatment with amifostine, irradiation, and G-CSF after radiation enhances hematologic recovery. Assessment of these combined effects, including local supportive therapies, merits further clinical investigation. There are data from prospective studies as well as from empirical clinical experience, that radioprotection and clinical supportive care may reduce the treatment related morbidity by 10 to 30% either. A further improvement of the therapeutic ratio is to be expected by systemically combined application of radioprotectors, supportive care and rescue agents.

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

PubMed Central

Pirazzini, Marco; Rossetto, Ornella; Eleopra, Roberto

2017-01-01

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. PMID:28356439

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.

PubMed

Pirazzini, Marco; Rossetto, Ornella; Eleopra, Roberto; Montecucco, Cesare

2017-04-01

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. Copyright © 2017 by The Author(s).

A review on ethnobotany, phytochemistry and pharmacology of Fumaria indica (Fumitory)

PubMed Central

Gupta, Prakash Chandra; Sharma, Nisha; Rao, Ch V

2012-01-01

Fumaria indica (Hausskn.) Pugsley (Fumariaceae), known as “Fumitory”, is an annual herb found as a common weed all over the plains of India and Pakistan. The whole plant is widely used in traditional and folkloric systems of medicine. In traditional systems of medicine, the plant is reputed for its anthelmintic, diuretic, diaphoretic, laxative, cholagogue, stomachic and sedative activities and is used to purify blood and in liver obstruction in ethnopharmacology. The whole plant is ascribed to possess medicinal virtues in Ayurvedic and Unani systems of medicine and is also used in preparation of important Ayurvedic medicinal preparations and polyherbal liver formulations. The review reveals that phytochemical constituents of wide range have been separated from the plants and it possesses important pharmacological activities like smooth muscle relaxant, spasmogenic and spasmolytic, analgesic, anti-inflammatory, neuropharmacological and antibacterial activities. The separation of hepatoprotective and antifungal constituents from this plant was also reported newly. This review highlights the traditional, ethnobotanical, phytochemical, pharmacological information available on Fumaria indica, which might be helpful for scientists and researchers to find out new chemical entities responsible for its claimed traditional uses. PMID:23569991

Non-pharmacological interventions on cognitive functions in older people with mild cognitive impairment (MCI).

PubMed

Teixeira, Camila Vieira Ligo; Gobbi, Lilian Teresa Bucken; Corazza, Danilla Icassatti; Stella, Florindo; Costa, José Luiz Riani; Gobbi, Sebastião

2012-01-01

Mild cognitive impairment (MCI) can be a stage of pre-dementia. There is no consensus about pharmacological treatment for this population, so it is important to structure non-pharmacological interventions for increasing their cognitive reserve. We intended to analyze the effects of non-pharmacological interventions in the cognitive functions in older people with MC, in form of a systemic review. Data sources were the Web of Science, Biological Abstracts, Medline, Pub Med, EBSCHost, Scirus and Google Scholar. All studies were longitudinal trials, with MCI sample, aged>60 years, community-dwelling, and having cognitive functions as dependent variable. Seven studies, from 91 previously selected ones, were identified according to the inclusion criteria. Six studies used cognitive intervention, improving memory and one study used physical activity as intervention, improving executive functions. The results show evidence that physical activity and cognitive exercise may improve memory and executive functions in older people with MCI. But yet, more controlled studies are needed to establish a protocol of recommendations regarding the systemization of exercise, necessary to produce benefits in the cognitive functioning in older people with MCI. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Marine Pharmacology in 2000: Marine Compounds with Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiplatelet, Antituberculosis, and Antiviral Activities; Affecting the Cardiovascular, Immune, and Nervous Systems and Other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M. S.; Hamann, Mark T.

2016-01-01

During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States. This current review, a sequel to the authors’ 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria. Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals. An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties. Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes. Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories. PMID:14583811

Preclinical pharmacology of midazolam.

PubMed

Pieri, L

1983-01-01

Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. Midazolam was slightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in 'encéphale isolé' rats. This depression was reversed by Ro 15-1788, a recently discovered selective benzodiazepine antagonist. Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. Midazolam had one-third the potency of diazepam in displacing 3H-flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. The animal data suggest the usefulness of midazolam as an oral sleep-inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water-soluble injection form.

Computer system for definition of the quantitative geometry of musculature from CT images.

PubMed

Daniel, Matej; Iglic, Ales; Kralj-Iglic, Veronika; Konvicková, Svatava

2005-02-01

The computer system for quantitative determination of musculoskeletal geometry from computer tomography (CT) images has been developed. The computer system processes series of CT images to obtain three-dimensional (3D) model of bony structures where the effective muscle fibres can be interactively defined. Presented computer system has flexible modular structure and is suitable also for educational purposes.

How Research in Behavioral Pharmacology Informs Behavioral Science

ERIC Educational Resources Information Center

Branch, Marc N.

2006-01-01

Behavioral pharmacology is a maturing science that has made significant contributions to the study of drug effects on behavior, especially in the domain of drug-behavior interactions. Less appreciated is that research in behavioral pharmacology can have, and has had, implications for the experimental analysis of behavior, especially its…

Trends in safety pharmacology: posters presented at the annual meetings of the Safety Pharmacology Society 2001-2010.

PubMed

Redfern, William S; Valentin, Jean-Pierre

2011-01-01

The inaugural meeting of the Safety Pharmacology Society (SPS) was in 2001, soon after ICH S7A had been adopted. The 10th anniversary is an appropriate milestone at which to analyse trends in the science and themes of safety pharmacology, as reflected in posters presented at the annual meetings. The source information was the poster abstract booklets from each of the first ten annual meetings. The number of posters rose steadily from 34 in 2001 to 201 in 2010. The proportion of posters containing in vitro data has remained constant throughout the decade at ~30%. In terms of organ functions, themes relating to the cardiovascular system (CVS) have always generated the majority of posters, remaining above 60% of the total for the last 9years. The dominant theme has been around 'QT liability'. This peaked in 2003 at 68% of all posters presented, around the time of the ICHS7B discussions, and has remained above 30% thereafter. Apart from 2003 (dipping to 4%), CNS-related posters have remained steady at 11-17% throughout the decade. Respiratory-related posters have remained at 5-8% over the last 5years. Gastrointestinal (GI)-related posters have contributed 2-6% throughout the decade, and renal-related posters 1-3%. Posters on combined organ assessments have appeared in recent years. The relative emphasis on the different organ functions is broadly proportional to the causes of candidate drug attrition preclinically, whereas both CNS and GI are under-represented when considering their contribution to significant adverse effects during clinical development. Trends are either regulatory-driven (e.g. increase in posters on abuse-dependence liability since EMEA/CHMP/SWP/94227/2004), technology-driven (e.g. automated hERG assay; left ventricular function; non-invasive CVS measurements; stem cells, etc.), or relate to the predictive ability of safety pharmacology data (e.g. clinical translation initiatives; concordance between in vitro and in vivo preclinical data; integrated

Combining Machine Learning Systems and Multiple Docking Simulation Packages to Improve Docking Prediction Reliability for Network Pharmacology

PubMed Central

Hsin, Kun-Yi; Ghosh, Samik; Kitano, Hiroaki

2013-01-01

Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate. PMID:24391846

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease.

PubMed

Bhattacharya, Indranil; Manukyan, Zorayr; Chan, Phylinda; Heatherington, Anne; Harnisch, Lutz

2017-10-12

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10 -4 L/[h·kg]; central volume of distribution 457 × 10 -4 L/kg; maximum elimination rate 17.5 × 10 -4 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10 -4 h -1 ; complex removal rate 90 × 10 -4 h -1 ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD. © 2017, The American College of Clinical Pharmacology.

Review of pharmacological therapy for tinnitus.

PubMed

Patterson, Matthew B; Balough, Ben J

2006-01-01

This article provides a review of studies investigating the pharmacological treatment of tinnitus. Tinnitus continues to be a significant and costly health problem without a uniformly accepted treatment. A wide variety of studies exploring prescription, supplement, and vitamin therapies are assessed for efficacy of treatment and for establishing consistencies in symptom definition, assessment, and outcome measures. This review reveals no compelling evidence suggesting the efficacy of any pharmacological agent in the treatment of tinnitus. Analysis of prior investigations provides insight to appropriate methods for future work, which are outlined.

Operational models of pharmacological agonism.

PubMed

Black, J W; Leff, P

1983-12-22

The traditional receptor-stimulus model of agonism began with a description of drug action based on the law of mass action and has developed by a series of modifications, each accounting for new experimental evidence. By contrast, in this paper an approach to modelling agonism is taken that begins with the observation that experimental agonist-concentration effect, E/[A], curves are commonly hyperbolic and develops using the deduction that the relation between occupancy and effect must be hyperbolic if the law of mass action applies at the agonist-receptor level. The result is a general model that explicitly describes agonism by three parameters: an agonist-receptor dissociation constant, KA; the total receptor concentration, [R0]; and a parameter, KE, defining the transduction of agonist-receptor complex, AR, into pharmacological effect. The ratio, [R0]/KE, described here as the 'transducer ratio', tau, is a logical definition for the efficacy of an agonist in a system. The model may be extended to account for non-hyperbolic E/[A] curves with no loss of meaning. Analysis shows that an explicit formulation of the traditional receptor-stimulus model is one particular form of the general model but that it is not the simplest. An alternative model is proposed, representing the cognitive and transducer functions of a receptor, that describes agonist action with one fewer parameter than the traditional model. In addition, this model provides a chemical definition of intrinsic efficacy making this parameter experimentally accessible in principle. The alternative models are compared and contrasted with regard to their practical and conceptual utilities in experimental pharmacology.

Phage Therapy: Eco-Physiological Pharmacology

PubMed Central

Abedon, Stephen T.

2014-01-01

Bacterial virus use as antibacterial agents, in the guise of what is commonly known as phage therapy, is an inherently physiological, ecological, and also pharmacological process. Physiologically we can consider metabolic properties of phage infections of bacteria and variation in those properties as a function of preexisting bacterial states. In addition, there are patient responses to pathogenesis, patient responses to phage infections of pathogens, and also patient responses to phage virions alone. Ecologically, we can consider phage propagation, densities, distribution (within bodies), impact on body-associated microbiota (as ecological communities), and modification of the functioning of body “ecosystems” more generally. These ecological and physiological components in many ways represent different perspectives on otherwise equivalent phenomena. Comparable to drugs, one also can view phages during phage therapy in pharmacological terms. The relatively unique status of phages within the context of phage therapy as essentially replicating antimicrobials can therefore result in a confluence of perspectives, many of which can be useful towards gaining a better mechanistic appreciation of phage therapy, as I consider here. Pharmacology more generally may be viewed as a discipline that lies at an interface between organism-associated phenomena, as considered by physiology, and environmental interactions as considered by ecology. PMID:25031881

[Non-pharmacological diabetes therapy].

PubMed

Martin, Stephan; Kolb, Hubert

2008-02-01

Diabetes mellitus type 2 is a life-style disease that is triggered by obesity and lack of physical activity. The pathophysiological basis of the disease is a reduction of insulin sensitivity, that is caused by the trigger factors. Glucose metabolic disorders appear if overproduction of insulin can not compensate the insulin resistance. In early phases postprandial blood glucose is increased, in late phases elevation of fasting blood glucose is noted. In the general awareness manifestation of type 2 diabetes is associated with an initiation of a pharmacological therapy. This is not the case, as described in detail in this review. Next to epidemiological studies, which indicate trigger factors, intervention trials will be discussed that led to a shift in paradigm in the diabetology. Non-pharmacological interventions are a therapeutical alternative in a lot of patients or are able to reduce the amount of antidiabetic agents significantly.

Pharmacological enhancement of treatment for amblyopia

PubMed Central

Rashad, Mohammad A

2012-01-01

Background The purpose of this study was to compare a weight-adjusted dose of carbidopa- levodopa as treatment adjunctive to occlusion therapy with occlusion therapy alone in children and adults with different types of amblyopia. Methods This prospective study included 63 patients with amblyopia classified into two groups, ie, an occlusion group which included 35 patients who received occlusion therapy only and a pharmacological enhancement group which included 28 patients who received oral carbidopa-levodopa together with occlusion therapy for 6 weeks. Results The mean logarithm of the minimal angle of resolution (logMAR) of the eyes with amblyopia was not significantly different in the occlusion group (0.52, 0.52, and 0.51) than in the pharmacological enhancement group (0.58, 0.49, and 0.56) at three follow-up visits (at months 1, 3, and 12, respectively). There was a highly significant improvement in mean logMAR of amblyopic eyes compared with baseline in both occlusion groups (from 0.68 to 0.52, from 0.68 to 0.52, and from 0.68 to 0.51) and in the pharmacological enhancement group (from 0.81 to 0.58, from 0.81 to 0.49, and from 0.81 to 0.56) at the month 1, 3, and 12 visits (P = 0.01, P = 0.01, and P = 0.001, respectively). The improvement of mean logMAR in the subgroup of patients older than 12 years was greater in the pharmacological enhancement group (42.5%) than in the occlusion group (30%). The improvement of mean logMAR in the subgroup of patients with severe amblyopia was greater in the pharmacological enhancement group (34.3%) than in the occlusion group (22%). Conclusion Significant improvement was reported in both groups at all follow-up visits over 1 year. Regardless of the etiology of amblyopia, levodopa-carbidopa may be added to part-time occlusion in older patients as a means of increasing the plasticity of the visual cortex. Levodopa may add to the effect of occlusion in severe amblyopia and bilateral amblyopia. PMID:22536029

Safety pharmacology investigations on the nervous system: An industry survey.

PubMed

Authier, Simon; Arezzo, Joseph; Delatte, Marcus S; Kallman, Mary-Jeanne; Markgraf, Carrie; Paquette, Dominique; Pugsley, Michael K; Ratcliffe, Sian; Redfern, William S; Stevens, Joanne; Valentin, Jean-Pierre; Vargas, Hugo M; Curtis, Michael J

2016-01-01

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing. Copyright © 2016 Elsevier Inc. All rights reserved.

[Pharmacological treatment].

PubMed

Arriola Manchola, Enrique; Álaba Trueba, Javier

2016-06-01

Alzheimer's disease (AD) is a chronic degenerative and inflammatory process leading to synapticdysfunction and neuronal death. A review about the pharmacological treatment alternatives is made: acetylcholinesterase inhibitors (AChEI), a nutritional supplement (Souvenaid) and Ginkgo biloba. A special emphasis on Ginkgo biloba due to the controversy about its use and the approval by the European Medicines Agency is made. Copyright © 2016 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

Geriatric pharmacology and pharmacotherapy education for health professionals and students: a systematic review

PubMed Central

Keijsers, Carolina J P W; van Hensbergen, Larissa; Jacobs, Lotte; Brouwers, Jacobus R B J; de Wildt, Dick J; ten Cate, Olle Th J; Jansen, Paul A F

2012-01-01

AIMS Given the reported high rates of medication errors, especially in elderly patients, we hypothesized that current curricula do not devote enough time to the teaching of geriatric pharmacology. This review explores the quantity and nature of geriatric pharmacology education in undergraduate and postgraduate curricula for health professionals. METHODS Pubmed, Embase and PsycINFO databases were searched (from 1 January 2000 to 11 January 2011), using the terms ‘pharmacology’ and ‘education’ in combination. Articles describing content or evaluation of pharmacology education for health professionals were included. Education in general and geriatric pharmacology was compared. RESULTS Articles on general pharmacology education (252) and geriatric pharmacology education (39) were included. The number of publications on education in general pharmacology, but not geriatric pharmacology, has increased over the last 10 years. Articles on undergraduate and postgraduate education for 12 different health disciplines were identified. A median of 24 h (from 15 min to 4956 h) devoted to pharmacology education and 2 h (1–935 h) devoted to geriatric pharmacology were reported. Of the articles on education in geriatric pharmacology, 61.5% evaluated the teaching provided, mostly student satisfaction with the course. The strength of findings was low. Similar educational interventions were not identified, and evaluation studies were not replicated. CONCLUSIONS Recently, interest in pharmacology education has increased, possibly because of the high rate of medication errors and the recognized importance of evidence-based medical education. Nevertheless, courses on geriatric pharmacology have not been evaluated thoroughly and none can be recommended for use in training programmes. Suggestions for improvements in education in general and geriatric pharmacology are given. PMID:22416832

[Implementation of a computerized pharmacological database for pediatric use].

PubMed

Currò, V; Grimaldi, V; Polidori, G; Cascioli, E; Lanni, R; De Luca, F; D'Atri, A; Bernabei, A

1990-01-01

The authors present a pharmacological database to support teaching and care activity carried out in the Divisional Paediatric Ambulatory of the Catholic University of Rome. This database is included in a integrated system, ARPIA (Ambulatory and Research in Pediatric by Information Assistance), devoted to manage ambulatory paediatric data. ARPIA has been implemented by using a relational DBMS, very cheap and highly diffused on personal computers. The database specifies: active ingredient and code number related to it, clinical uses, doses, contra-indications and precautions, adverse effects, besides the possible wrapping available on the market. All this is showed on a single for that appears on the screen and allows a fast reading of the most important elements characterizing every drug. The search of the included drugs can be made on the basis of three different detailed lists: active ingredient, proprietary preparation and clinical use. It is, besides, possible to have a complete report about the drugs requested by the user. This system allows the user, without modifying the program, to interact with the included data modifying each element of the form. In the system there is also a fast consultation handbook containing for every active ingredient, the complete list of italian proprietary medicines. This system aims to give a better knowledge of the most commonly used drugs, not only limited to the paediatrician but also to the ambulatory health staff; an improvement of the therapy furthering, a more effective use of several pharmacological agents and first of all a training device not only to specialists but also to students.

[PHYSIOLOGY AND PHARMACOLOGICAL PROPERTIES OF NANOMATERIALS].

PubMed

Chekman, I S

2015-01-01

Literature data and results of our department studies on theoretical and practical basics of nanoscience were summarized in the article. Much attention is paid to research in the field of physical, chemical, biological, medical, physiological, pharmacological, and toxicological properties of nanomaterials with the aim of their wider implementation into practice lately. The discovery of new quantum/wave properties of nanoparticles is of particular importance. The author of the article advances an idea: wave properties of nanomaterials play greater role with a decrease in particle size. The preponderance of wave properties compared with corpuscular ones in nanostructures determines a great change in their physical. chemical properties and an increase in physical, mechanical biological, physiological, pharmacological, and toxicologica activity. The idea advanced in the article hasn't been verified by theoretical or experimental studies for now. Joined efforts of scientists of different scientific fields are needed. A confirmation of hypothesis by specific findings will be of great importance for physiology, medicine, pharmacology and promote an implementation of new efficacious preparations into clinical practice. New fundamental discoveries could be made only by multidisciplinary approach.

Teaching the pharmacology of antiarrhythmic drugs.

PubMed

Zdanowicz, Martin M; Lynch, Launa M J

2011-09-10

To provide doctor of pharmacy (PharmD) students with highly integrated, comprehensive and up-to-date instruction related to the pharmacology of antiarrhythmic drugs. Students were taught the medicinal chemistry, pharmacology, and therapeutics of antiarrhythmic agents in the cardiology module presented in quarter 7 of the PharmD curriculum. Important foundational information for this topic was presented to students in prerequisite physiology courses and pathophysiology courses offered earlier in the curriculum. Emphasis was placed on student critical thinking and active involvement. Weekly recitation sessions afforded students the opportunity to apply the information they learned regarding arrhythmia pharmacotherapy to comprehensive patient cases. Student comprehension was measured using class exercises, short quizzes, case write-ups, comprehensive examinations, group exercises, and classroom discussion. Students were afforded the opportunity to evaluate the course, and the instructors as well as rate the degree to which the course achieved its educational outcomes. Students learned about cardiac arrhythmias through a high-quality, interdisciplinary series of classes presented by faculty members with extensive experience related to the pharmacology and pharmacotherapy of cardiac arrhythmias.

Pharmacology of midazolam.

PubMed

Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

1981-01-01

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

[Study on characteristics of pharmacological effects of traditional Chinese medicines distributing along stomach meridian based on medicinal property combination].

PubMed

Zhang, Bai-Xia; Gu, Hao; Guo, Hong-Ling; Ma, Li; Wang, Yun; Qiao, Yan-Jiang

2014-07-01

At present, studies on traditional Chinese medicine (TCM) properties are mostly restricted to a single or two kinds of medicinal properties, but deviated from the holism of the theoretical system of TCMs. In this paper, the characteristics of pharmacological effects of different property combinations of TCMs distributing in the stomach meridian were take as the study objective. The data of properties of TCMs distributing in the stomach meridian was collected from the Pharmacopoeia of the People's Republic of China (2005). The data of pharmacological effects of TCMs distributing in the stomach meridian was collected from all of literatures recorded in Chinese Journal Full-text Database (CNKI) since 1980, Science of Chinese Materia Medica (Yan Zhenghua, People's Medical Publishing House, 2006) and Clinical Science of Chinese Materia Medica (Gao Xuemin, Zhong Gansheng, Hebei Science and Technology Publishing House, 2005). The corresponding pharmacological effects of property combinations of TCMs distributing in the stomach meridian was mined by the method of association rules. The results of the association rules were consistent with the empirical knowledge, and showed that different medicinal property combinations had respective pharmacological characteristics, including differences and similarities in pharmacological effects of different medicinal property combinations. Medicinal property combinations with identical four properties or five tastes showed similar pharmacological effects; whereas medicinal property combinations with different four properties or five tastes showed differentiated pharmacological effects. However, medicinal property combinations with different four properties or five tastes could also show similar pharmacological effects. In this study, the medicinal property theory and the pharmacological effects of TCMs were combined to reveal the main characteristics and regularity of pharmacological effects of TCMs distributing in the stomach meridian

Methods of quantitative risk assessment: The case of the propellant supply system

NASA Astrophysics Data System (ADS)

Merz, H. A.; Bienz, A.

1984-08-01

As a consequence of the disastrous accident in Lapua (Finland) in 1976, where an explosion in a cartridge loading facility killed 40 and injured more than 70 persons, efforts were undertaken to examine and improve the safety of such installations. An ammunition factory in Switzerland considered the replacement of the manual supply of propellant hoppers by a new pneumatic supply system. This would reduce the maximum quantity of propellant in the hoppers to a level, where an accidental ignition would no longer lead to a detonation, and this would drastically limit the effects on persons. A quantitative risk assessment of the present and the planned supply system demonstrated that, in this particular case, the pneumatic supply system would not reduce the risk enough to justify the related costs. In addition, it could be shown that the safety of the existing system can be improved more effectively by other safety measures at considerably lower costs. Based on this practical example, the advantages of a strictly quantitative risk assessment for the safety planning in explosives factories are demonstrated. The methodological background of a risk assessment and the steps involved in the analysis are summarized. In addition, problems of quantification are discussed.

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview.

PubMed

Alexander, Stephen Ph; Kelly, Eamonn; Marrion, Neil V; Peters, John A; Faccenda, Elena; Harding, Simon D; Pawson, Adam J; Sharman, Joanna L; Southan, Christopher; Buneman, O Peter; Cidlowski, John A; Christopoulos, Arthur; Davenport, Anthony P; Fabbro, Doriano; Spedding, Michael; Striessnig, Jörg; Davies, Jamie A

2017-12-01

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate. © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Fibromyalgia syndrome: prevalence, pharmacological and non-pharmacological interventions in outpatient health care. An analysis of statutory health insurance data.

PubMed

Sauer, Kristin; Kemper, Claudia; Glaeske, Gerd

2011-01-01

Fibromyalgia syndrome (FMS) is a chronic pain condition impacting on quality of life, causing physical and psychological impairment resulting in limited participation in professional and social life. The objective of this study was to assess the prevalence, recommended pharmacological and non-pharmacological interventions of FMS, patients' characteristics and to compare findings to current research. About 1.6 Mio patients of a German statutory health insurance company (GEK) in 2007 were analyzed for: (a) the prevalence of FMS (ICD-10: M79.7); (b) and comorbid depression (ICD-10: F32/33); (c) the recommended pharmacological and non-pharmacological intervention rates; (d) and characteristics of patients associated with being prescribed recommended interventions. The (a) standardized prevalence of FMS in 2007 was 0.05% in men and 0.4% in women. (b) 51.9% of the patients with prevalent FMS had a comorbid depression in 2007 (88.2% female). (c) 66% of FMS patients received the recommended pharmacological treatment, 59% physical therapy, 6.1% cognitive-behavioural therapy and 3.4% a combination of these (multi-component therapy, MCT). (d) One year increase in age was associated with a 3% decrease in the predicted odds of receiving MCT (95%, CI 0.95-0.99). The current data indicate an FMS-prevalence that differs from epidemiological surveys and screenings, probably due to methodological differences. Especially females with comorbid depression are affected. The likelihood of receiving MCT is not associated with gender, but with younger age. Yet, the findings seem to indicate insufficient and inadequate treatment, but FMS warrants more research. Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Pharmacological Management of Cardiorenal Syndromes

PubMed Central

House, Andrew A.; Haapio, Mikko; Lassus, Johan; Bellomo, Rinaldo; Ronco, Claudio

2011-01-01

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted. PMID:21660311

[Military pharmacology education outside the imperial school of medicine].

PubMed

Yildirim, N

1998-01-01

In 1870, just after starting medical education in Turkish at the Imperial School of Medicine (Mekeb-i Tibbiye-i Sahani) favor in the pharmacology and surgery courses decreased; and even pharmacology graduates continued their education to be physicians. This change gave rise to the shortage of pharmacists and surgeons in the army, and consquently in 1873 the branch of surgery and in 1876 pharmacology were inaugurated at the Haydarpasa Military Hospital. Those who had studied at this Hospital for three years were given a diploma for pharmacy practice (ameliyat eczaciligi sehadetnamesi) and were appointed to the army and to military hospitals. The years of education was raised to four years in 1888, and it was reduced to three years again in 1891. According to Charles Bonkowski, the chemist of Sultan Abdulhamid II, the instruction of military pharmacology was independent from the School of Medicine; he suggested the foundation of a higher school of pharmacy in Istanbul on the standards of the Paris Higher School of Pharmacology (Ecole Superieur de Pharmacie de Paris) where he had studied and graduated in 1865. Unfortunately this advice was not realised; but a department of pharmacology was opened within the Military High School for Veterinarians (Baytar Rustiye-i Askeriyesi) in Eyup in order to educate the students properly. This institution, renamed as the Military High School for Veterinarians and Pharmacists (Baytar ve Eczact Mekteb-i Rustiye-i Askeriyesi), had sent its graduates to the Imperial School of Medicine for many years. Since this process had proved to be useful, the Pharmacology Branch at the Haydarpasa Military Hospital was closed in 1892. In 1895, another military school which was called Eczaci ve Timarci Sibyan Mektebi started instruction on the Naval Hospital. Graduates of this school were appointed to the naval offices for minor operations.

Pharmacological treatment for memory disorder in multiple sclerosis.

PubMed

He, Dian; Zhang, Yun; Dong, Shuai; Wang, Dongfeng; Gao, Xiangdong; Zhou, Hongyu

2013-12-17

This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review

Veterinary pharmacology: history, current status and future prospects.

PubMed

Lees, P; Fink-Gremmels, J; Toutain, P L

2013-04-01

Veterinary therapeutics, based on the art of Materia Medica, has been practised for countless centuries, but the science of veterinary pharmacology is of very recent origin. This review traces the contribution of Materia Medica to veterinary therapeutics from the Egyptian period through to the Age of Enlightenment. The first tentative steps in the development of the science of veterinary pharmacology were taken in the 18th century, but it was not until the mid 20th century that the science replaced the art of Materia Medica. This review traces the 20th century developments in veterinary pharmacology, with emphasis on the explosion of knowledge in the 35 year period to 2010. The range of factors which have influenced the current status of the discipline are reviewed. Future developments are considered from the perspectives of what might be regarded as desirable and those innovations that might be anticipated. We end with words of encouragement for young colleagues intent upon pursuing a career in veterinary pharmacology. © 2013 Blackwell Publishing Ltd.

Pharmacological profiling of the TRPV3 channel in recombinant and native assays

PubMed Central

Grubisha, Olivera; Mogg, Adrian J; Sorge, Jessica L; Ball, Laura-Jayne; Sanger, Helen; Ruble, Cara L A; Folly, Elizabeth A; Ursu, Daniel; Broad, Lisa M

2014-01-01

Background and Purpose Transient receptor potential vanilloid subtype 3 (TRPV3) is implicated in nociception and certain skin conditions. As such, it is an attractive target for pharmaceutical research. Understanding of endogenous TRPV3 function and pharmacology remains elusive as selective compounds and native preparations utilizing higher throughput methodologies are lacking. In this study, we developed medium-throughput recombinant and native cellular assays to assess the detailed pharmacological profile of human, rat and mouse TRPV3 channels. Experimental Approach Medium-throughput cellular assays were developed using a Ca2+-sensitive dye and a fluorescent imaging plate reader. Human and rat TRPV3 pharmacology was examined in recombinant cell lines, while the mouse 308 keratinocyte cell line was used to assess endogenous TRPV3 activity. Key Results A recombinant rat TRPV3 cellular assay was successfully developed after solving a discrepancy in the published rat TRPV3 protein sequence. A medium-throughput, native, mouse TRPV3 keratinocyte assay was also developed and confirmed using genetic approaches. Whereas the recombinant human and rat TRPV3 assays exhibited similar agonist and antagonist profiles, the native mouse assay showed important differences, namely, TRPV3 activity was detected only in the presence of potentiator or during agonist synergy. Furthermore, the native assay was more sensitive to block by some antagonists. Conclusions and Implications Our findings demonstrate similarities but also notable differences in TRPV3 pharmacology between recombinant and native systems. These findings offer insights into TRPV3 function and these assays should aid further research towards developing TRPV3 therapies. Linked Articles This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:23848361

Holistic Management of Schizophrenia Symptoms Using Pharmacological and Non-pharmacological Treatment.

PubMed

Ganguly, Pronab; Soliman, Abdrabo; Moustafa, Ahmed A

2018-01-01

Individuals with schizophrenia lead a poor quality of life, due to poor medical attention, homelessness, unemployment, financial constraints, lack of education, and poor social skills. Thus, a review of factors associated with the holistic management of schizophrenia is of paramount importance. The objective of this review is to improve the quality of life of individuals with schizophrenia, by addressing the factors related to the needs of the patients and present them in a unified manner. Although medications play a role, other factors that lead to a successful holistic management of schizophrenia include addressing the following: financial management, independent community living, independent living skill, relationship, friendship, entertainment, regular exercise for weight gained due to medication administration, co-morbid health issues, and day-care programmes for independent living. This review discusses the relationship between different symptoms and problems individuals with schizophrenia face (e.g., homelessness and unemployment), and how these can be managed using pharmacological and non-pharmacological methods. Thus, the target of this review is the carers of individuals with schizophrenia, public health managers, counselors, case workers, psychiatrists, and clinical psychologists aiming to enhance the quality of life of individuals with schizophrenia.

Quantitative measurement of feline colonic transit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krevsky, B.; Somers, M.B.; Maurer, A.H.

1988-10-01

Colonic transit scintigraphy, a method for quantitatively evaluating the movement of the fecal stream in vivo, was employed to evaluate colonic transit in the cat. Scintigraphy was performed in duplicate in five cats and repeated four times in one cat. After instillation of an 111In marker into the cecum through a surgically implanted silicone cecostomy tube, colonic movement of the instillate was quantitated for 24 h using gamma scintigraphy. Antegrade and retrograde motion of radionuclide was observed. The cecum and ascending colon emptied rapidly, with a half-emptying time of 1.68 +/- 0.56 h (mean +/- SE). After 24 h, 25.1more » +/- 5.2% of the activity remained in the transverse colon. The progression of the geometric center was initially rapid, followed later by a delayed phase. Geometric center reproducibility was found to be high when analyzed using simple linear regression (slope = 0.92; r = 0.73; P less than 0.01). Atropine (0.1 mg/kg im) was found to delay cecum and ascending colon emptying and delay progression of the geometric center. These results demonstrate both 1) the ability of colonic transit scintigraphy to detect changes in transit induced by pharmacological manipulation and 2) the fact that muscarinic blockade inhibits antegrade transit of the fecal stream. We conclude that feline colonic transit may be studied in a quantitative and reproducible manner with colonic transit scintigraphy.« less

Systems analysis of thrombus formation

PubMed Central

Diamond, Scott L.

2016-01-01

The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient-specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. Additionally, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs. PMID:27126646

The Quantitative Basis of the Arabidopsis Innate Immune System to Endemic Pathogens Depends on Pathogen Genetics

PubMed Central

Corwin, Jason A.; Copeland, Daniel; Feusier, Julie; Subedy, Anushriya; Eshbaugh, Robert; Palmer, Christine; Maloof, Julin; Kliebenstein, Daniel J.

2016-01-01

The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used the Arabidopsis-Botrytis pathosystem to explore the quantitative genetic architecture underlying host innate immune system in a population of Arabidopsis thaliana. By infecting a diverse panel of Arabidopsis accessions with four phenotypically and genotypically distinct isolates of the fungal necrotroph B. cinerea, we identified a total of 2,982 genes associated with quantitative resistance using lesion area and 3,354 genes associated with camalexin production as measures of the interaction. Most genes were associated with resistance to a specific Botrytis isolate, which demonstrates the influence of pathogen genetic variation in analyzing host quantitative resistance. While known resistance genes, such as receptor-like kinases (RLKs) and nucleotide-binding site leucine-rich repeat proteins (NLRs), were found to be enriched among associated genes, they only account for a small fraction of the total genes associated with quantitative resistance. Using publically available co-expression data, we condensed the quantitative resistance associated genes into co-expressed gene networks. GO analysis of these networks implicated several biological processes commonly connected to disease resistance, including defense hormone signaling and ROS production, as well as novel processes, such as leaf development. Validation of single gene T-DNA knockouts in a Col-0 background demonstrate a high success rate (60%) when accounting for differences in environmental and Botrytis genetic variation. This study shows that the genetic architecture underlying host innate immune system is extremely complex and is likely able to sense and respond to differential virulence among pathogen genotypes. PMID:26866607

The Quantitative Basis of the Arabidopsis Innate Immune System to Endemic Pathogens Depends on Pathogen Genetics.

PubMed

Corwin, Jason A; Copeland, Daniel; Feusier, Julie; Subedy, Anushriya; Eshbaugh, Robert; Palmer, Christine; Maloof, Julin; Kliebenstein, Daniel J

2016-02-01

The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used the Arabidopsis-Botrytis pathosystem to explore the quantitative genetic architecture underlying host innate immune system in a population of Arabidopsis thaliana. By infecting a diverse panel of Arabidopsis accessions with four phenotypically and genotypically distinct isolates of the fungal necrotroph B. cinerea, we identified a total of 2,982 genes associated with quantitative resistance using lesion area and 3,354 genes associated with camalexin production as measures of the interaction. Most genes were associated with resistance to a specific Botrytis isolate, which demonstrates the influence of pathogen genetic variation in analyzing host quantitative resistance. While known resistance genes, such as receptor-like kinases (RLKs) and nucleotide-binding site leucine-rich repeat proteins (NLRs), were found to be enriched among associated genes, they only account for a small fraction of the total genes associated with quantitative resistance. Using publically available co-expression data, we condensed the quantitative resistance associated genes into co-expressed gene networks. GO analysis of these networks implicated several biological processes commonly connected to disease resistance, including defense hormone signaling and ROS production, as well as novel processes, such as leaf development. Validation of single gene T-DNA knockouts in a Col-0 background demonstrate a high success rate (60%) when accounting for differences in environmental and Botrytis genetic variation. This study shows that the genetic architecture underlying host innate immune system is extremely complex and is likely able to sense and respond to differential virulence among pathogen genotypes.

Clinical Pharmacology & Therapeutics: Past, Present and Future

PubMed Central

Waldman, SA; Terzic, A

2016-01-01

Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation and utilization continuum to catalyze, evolve and disseminate discipline-transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation and application ushering therapeutic innovation into modern health care. PMID:28194770

Evolving pharmacology of orphan GPCRs: IUPHAR Commentary.

PubMed

Davenport, Anthony P; Harmar, Anthony J

2013-10-01

The award of the 2012 Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka for their work on the structure and function of GPCRs, spanning a period of more than 20 years from the cloning of the human β2 -adrenoceptor to determining the crystal structure of the same protein, has earned both researchers a much deserved place in the pantheon of major scientific discoveries. GPCRs comprise one of the largest families of proteins, controlling many major physiological processes and have been a major focus of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) since its inception in 1987. We report here recent efforts by the British Pharmacological Society and NC-IUPHAR to define the endogenous ligands of 'orphan' GPCRs and to place authoritative and accessible information about these crucial therapeutic targets online. © 2013 The British Pharmacological Society.

Pharmacological versus sensory factors in the satiation of chocolate craving.

PubMed

Michener, W; Rozin, P

1994-09-01

This is the first experimental study directed at differentiating between physiological or sensory accounts of the satiation of nondrug cravings, using chocolate craving, the most common craving in North America. At the onset of craving, chocolate cravers consumed a chocolate bar, the caloric equivalent in "white chocolate" (containing none of the pharmacological components of chocolate), the pharmacological equivalent in cocoa capsules, placebo, and no treatment conditions had virtually no effect. White chocolate produced partial abatement, unchanged by the addition of all the pharmacological factors in cocoa. This result indicates no role for pharmacological effects in the satisfaction of chocolate craving. It also suggests a role for aroma independent of sweetness, texture, and calories.

Auditory cortical plasticity induced by intracortical microstimulation under pharmacological blockage of inhibitory synapses.

PubMed

Yokota, R; Takahashi, H; Funamizu, A; Uchihara, M; Suzurikawa, J; Kanzaki, R

2006-01-01

Electrical stimulation that can reorganize our neural system has a potential for promising neurorehabilitation. We previously demonstrated that temporally controlled intracortical microstimulation (ICMS) could induce the spike time-dependant plasticity and modify tuning properties of cortical neurons as desired. A 'pairing' ICMS following tone-induced excitatory post-synaptic potentials (EPSPs) produced potentiation in response to the paired tones, while an 'anti-pairing' ICMS preceding the tone-induced EPSPs resulted in depression. However, the conventional ICMS affected both excitatory and inhibitory synapses, and thereby could not quantify net excitatory synaptic effects. In the present work, we evaluated the ICMS effects under a pharmacological blockage of inhibitory inputs. The pharmacological blockage enhanced the ICMS effects, suggesting that inhibitory inputs determine a plastic degree of the neural system. Alternatively, the conventional ICMS had an inadequate timing to control excitatory synaptic inputs, because inhibitory synapse determined the latency of total neural inputs.

Quantitative computational models of molecular self-assembly in systems biology

PubMed Central

Thomas, Marcus; Schwartz, Russell

2017-01-01

Molecular self-assembly is the dominant form of chemical reaction in living systems, yet efforts at systems biology modeling are only beginning to appreciate the need for and challenges to accurate quantitative modeling of self-assembly. Self-assembly reactions are essential to nearly every important process in cell and molecular biology and handling them is thus a necessary step in building comprehensive models of complex cellular systems. They present exceptional challenges, however, to standard methods for simulating complex systems. While the general systems biology world is just beginning to deal with these challenges, there is an extensive literature dealing with them for more specialized self-assembly modeling. This review will examine the challenges of self-assembly modeling, nascent efforts to deal with these challenges in the systems modeling community, and some of the solutions offered in prior work on self-assembly specifically. The review concludes with some consideration of the likely role of self-assembly in the future of complex biological system models more generally. PMID:28535149

Quantitative computational models of molecular self-assembly in systems biology.

PubMed

Thomas, Marcus; Schwartz, Russell

2017-05-23

Molecular self-assembly is the dominant form of chemical reaction in living systems, yet efforts at systems biology modeling are only beginning to appreciate the need for and challenges to accurate quantitative modeling of self-assembly. Self-assembly reactions are essential to nearly every important process in cell and molecular biology and handling them is thus a necessary step in building comprehensive models of complex cellular systems. They present exceptional challenges, however, to standard methods for simulating complex systems. While the general systems biology world is just beginning to deal with these challenges, there is an extensive literature dealing with them for more specialized self-assembly modeling. This review will examine the challenges of self-assembly modeling, nascent efforts to deal with these challenges in the systems modeling community, and some of the solutions offered in prior work on self-assembly specifically. The review concludes with some consideration of the likely role of self-assembly in the future of complex biological system models more generally.

Physicochemical and Pharmacological Characterization of Permanently Charged Opioids.

PubMed

Mazak, Karoly; Noszal, Bela; Hosztafi, Sandor

2017-01-01

The main aim of synthesizing permanently charged opioids is to ensure that they do not enter the central nervous system. Such drugs can provide analgesic activity with reduced sedation and other side effects on the central nervous system. We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field. The present review focuses on the characterization of permanently charged opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity, morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity are also reviewed. The last part of our study concentrates on sulfate conjugates of morphine derivatives that display unique pharmacological properties because they carry a negative charge at any pH value in the human body. In conclusion, the findings of this review confirm the importance of permanently charged opioids in the investigated fields of pharmacology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Resolving anaphoras for the extraction of drug-drug interactions in pharmacological documents

PubMed Central

2010-01-01

Background Drug-drug interactions are frequently reported in the increasing amount of biomedical literature. Information Extraction (IE) techniques have been devised as a useful instrument to manage this knowledge. Nevertheless, IE at the sentence level has a limited effect because of the frequent references to previous entities in the discourse, a phenomenon known as 'anaphora'. DrugNerAR, a drug anaphora resolution system is presented to address the problem of co-referring expressions in pharmacological literature. This development is part of a larger and innovative study about automatic drug-drug interaction extraction. Methods The system uses a set of linguistic rules drawn by Centering Theory over the analysis provided by a biomedical syntactic parser. Semantic information provided by the Unified Medical Language System (UMLS) is also integrated in order to improve the recognition and the resolution of nominal drug anaphors. Besides, a corpus has been developed in order to analyze the phenomena and evaluate the current approach. Each possible case of anaphoric expression was looked into to determine the most effective way of resolution. Results An F-score of 0.76 in anaphora resolution was achieved, outperforming significantly the baseline by almost 73%. This ad-hoc reference line was developed to check the results as there is no previous work on anaphora resolution in pharmalogical documents. The obtained results resemble those found in related-semantic domains. Conclusions The present approach shows very promising results in the challenge of accounting for anaphoric expressions in pharmacological texts. DrugNerAr obtains similar results to other approaches dealing with anaphora resolution in the biomedical domain, but, unlike these approaches, it focuses on documents reflecting drug interactions. The Centering Theory has proved being effective at the selection of antecedents in anaphora resolution. A key component in the success of this framework is the

New Therapeutic Approaches and Prognostic Assays for Breast Cancer: Radiolabeled Ligands and Antibodies and Quantitative PCR..

DTIC Science & Technology

1997-11-01

and Quantitative PCR PRINCIPAL INVESTIGATOR: Indra Poola, Ph.D. CONTRACTING ORGANIZATION: Howard university Washington, DC 20059 REPORT DATE... Howard University Washington, DC 20059 8. PERFORMING ORGANIZATION REPORT NUMBER 8. SPONSORING f MONITORING AGENCY NAME(S) AND ADDRESS(ES) U.S...Stollar J.A. Hanover B.L. Vallee C.B. Hirschberg November 21, 1997 Indra Poola Dept. of Pharmacology Howard University School of Medicine 520 W

Blues for the Lecture Theatre--The Pharmacology Songbook

ERIC Educational Resources Information Center

MacDonald, Ewen; Saarti, Jarmo

2006-01-01

In 2005, we were able to digitally record the so-called pharmacology songbook; a set of songs with lyrics devoted to pharmacological topics. A CD was prepared entitled The Beta-blocker Blues and its contents are now all freely available in mp3 format from our web page (Ewen MacDonald & friends, 2005). The web page also contains the lyrics and…

Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review.

PubMed

Maciulaitis, R; Kontrimaviciute, V; Bressolle, F M M; Briedis, V

2008-03-01

Ibogaine is an indole alkaloid derived from the bark of the root of the African shrub Tabernanthe iboga. Psychoactive properties of ibogaine have been known for decades. More recently, based on experimental data from animals and anectodal reports in human, it has been found that this drug has anti-addictive effects. Several patents were published between 1969 and 1995. The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously. However, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood. Ibogaine is rapidly metabolized in the body in noribogaine. The purpose of this article was to review data from the literature concerning physicochemical properties, bio-analytical methods, and pharmacology of ibogaine; this article will be focused on the use of this drug as anti-addictive agent.

A robust rotorcraft flight control system design methodology utilizing quantitative feedback theory

NASA Technical Reports Server (NTRS)

Gorder, Peter James

1993-01-01

Rotorcraft flight control systems present design challenges which often exceed those associated with fixed-wing aircraft. First, large variations in the response characteristics of the rotorcraft result from the wide range of airspeeds of typical operation (hover to over 100 kts). Second, the assumption of vehicle rigidity often employed in the design of fixed-wing flight control systems is rarely justified in rotorcraft where rotor degrees of freedom can have a significant impact on the system performance and stability. This research was intended to develop a methodology for the design of robust rotorcraft flight control systems. Quantitative Feedback Theory (QFT) was chosen as the basis for the investigation. Quantitative Feedback Theory is a technique which accounts for variability in the dynamic response of the controlled element in the design robust control systems. It was developed to address a Multiple-Input Single-Output (MISO) design problem, and utilizes two degrees of freedom to satisfy the design criteria. Two techniques were examined for extending the QFT MISO technique to the design of a Multiple-Input-Multiple-Output (MIMO) flight control system (FCS) for a UH-60 Black Hawk Helicopter. In the first, a set of MISO systems, mathematically equivalent to the MIMO system, was determined. QFT was applied to each member of the set simultaneously. In the second, the same set of equivalent MISO systems were analyzed sequentially, with closed loop response information from each loop utilized in subsequent MISO designs. The results of each technique were compared, and the advantages of the second, termed Sequential Loop Closure, were clearly evident.

Clinical Pharmacology in Sleep Medicine

PubMed Central

Proctor, Ashley; Bianchi, Matt T.

2012-01-01

The basic treatment goals of pharmacological therapies in sleep medicine are to improve waking function by either improving sleep or by increasing energy during wakefulness. Stimulants to improve waking function include amphetamine derivatives, modafinil, and caffeine. Sleep aids encompass several classes, from benzodiazepine hypnotics to over-the-counter antihistamines. Other medications used in sleep medicine include those initially used in other disorders, such as epilepsy, Parkinson's disease, and psychiatric disorders. As these medications are prescribed or encountered by providers in diverse fields of medicine, it is important to recognize the distribution of adverse effects, drug interaction profiles, metabolism, and cytochrome substrate activity. In this paper, we review the pharmacological armamentarium in the field of sleep medicine to provide a framework for risk-benefit considerations in clinical practice. PMID:23213564

Fesoterodine: Pharmacological properties and clinical implications.

PubMed

Gamé, Xavier; Peyronnet, Benoit; Cornu, Jean-Nicolas

2018-05-24

Fesoterodine (as one of three drugs: dutasteride, finasteride and fesoterodine) was classified B (beneficial) by LUTS-FORTA 2014, indicating that it is a medicinal product with proven or obvious efficacy in the elderly, with limited side effects and/or safety concerns. A systematic literature review was undertaken in January 2018 using the PubMed and Google Scholar databases with the following individual and combined keywords: "fesoterodine", "pharmacology", "overactive bladder" and "antimuscarinics". The aim of the review was to determine which of fesoterodine's pharmacological properties explains its clinical benefits in general patient populations with OAB and the elderly in particular. The articles in the results were then selected by publication language (English and French only), methodology (off-topic studies, reported cases and literature reviews were excluded), relevance to the subject matter and publication date prior to 31 January 2018. A total of 205 articles was initially obtained, with 115 read and 45 selected. It appears that the association of four pharmacological properties specific to fesoterodine can explain that this drug has a good balance between efficacy and tolerability. These properties are namely the drug's high and nearly equal affinity for both the M2 and M3 muscarinic receptors, poor penetration of the blood-brain barrier, lack of hepatic first-pass activation -fesoterodine being rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine, by ubiquitous esterases-, and its extended-release formulation. Fesoterodine's pharmacological profile is optimal for the treatment of overactive bladder. It is now recognized as one of the leading first-line treatment for this indication. Copyright © 2018 Elsevier B.V. All rights reserved.

The genus Caesalpinia L. (Caesalpiniaceae): phytochemical and pharmacological characteristics.

PubMed

Zanin, João L Baldim; de Carvalho, Bianca A; Martineli, Paloma Salles; dos Santos, Marcelo Henrique; Lago, João Henrique G; Sartorelli, Patrícia; Viegas, Cláudio; Soares, Marisi G

2012-06-29

The genus Caesalpinia (Caesalpiniaceae) has more than 500 species, many of which have not yet been investigated for potential pharmacological activity. Several classes of chemical compounds, such as flavonoids, diterpenes, and steroids, have been isolated from various species of the genus Caesalpinia. It has been reported in the literature that these species exhibit a wide range of pharmacological properties, including antiulcer, anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antirheumatic activities that have proven to be efficacious in ethnomedicinal practices. In this review we present chemical and pharmacological data from recent phytochemical studies on various plants of the genus Caesalpinia.

Pharmacological Effects of Biotin in Animals.

PubMed

Riveron-Negrete, Leticia; Fernandez-Mejia, Cristina

2017-01-01

In recent decades, it was found that vitamins affect biological functions in ways other than their long-known functions; niacin is the best example of a water-soluble vitamin known to possess multiple actions. Biotin, also known as vitamin B7 or vitamin H, is a water-soluble B-complex vitamin that serves as a covalently-bound coenzyme of carboxylases. It is now well documented that biotin has actions other than participating in classical enzyme catalysis reactions. Several lines of evidence have demonstrated that pharmacological concentrations of biotin affect glucose and lipid metabolism, hypertension, reproduction, development, and immunity. The effect of biotin on these functions is related to its actions at the transcriptional, translational, and post-translational levels. The bestsupported mechanism involved in the genetic effects of biotin is the soluble guanylate cyclase/protein kinase G (PKG) signaling cascade. Although there are commercially-available products containing pharmacological concentrations of biotin, the toxic effects of biotin have been poorly studied. This review summarizes the known actions and molecular mechanisms of pharmacological doses of biotin in animals and current information regarding biotin toxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The endocannabinoid system and emotional processing: a pharmacological fMRI study with ∆9-tetrahydrocannabinol.

PubMed

Bossong, Matthijs G; van Hell, Hendrika H; Jager, Gerry; Kahn, René S; Ramsey, Nick F; Jansma, J Martijn

2013-12-01

Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ∆9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative ('fearful faces') or a positive content ('happy faces') were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Pharmacology for the treatment of premature ejaculation.

PubMed

Giuliano, François; Clèment, Pierre

2012-07-01

Male sexual response comprises four phases: excitement, including erection; plateau; ejaculation, usually accompanied by orgasm; and resolution. Ejaculation is a complex sexual response involving a sequential process consisting of two phases: emission and expulsion. Ejaculation, which is basically a spinal reflex, requires a tight coordination between sympathetic, parasympathetic, and somatic efferent pathways originating from different segments and area in the spinal cord and innervating pelvi-perineal anatomical structures. A major relaying and synchronizing role is played by a group of lumbar neurons described as the spinal generator of ejaculation. Excitatory and inhibitory influences from sensory genital and cerebral stimuli are integrated and processed in the spinal cord. Premature ejaculation (PE) can be defined by ≤1-min ejaculatory latency, an inability to delay ejaculation, and negative personal consequences. Because there is no physiological impairment in PE, any pharmacological agent with central or peripheral mechanism of action that is delaying the ejaculation is a drug candidate for the treatment of PE. Ejaculation is centrally mediated by a variety of neurotransmitter systems, involving especially serotonin and serotonergic pathways but also dopaminergic and oxytocinergic systems. Pharmacological delay of ejaculation can be achieved either by inhibiting excitatory or reinforcing inhibitory pathways from the brain or the periphery to the spinal cord. PE can be treated with long-term use of selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants. Dapoxetine, a short-acting SSRI, is the first treatment registered for the on-demand treatment of PE. Anesthetics applied on the glans penis have the ability to lengthen the time to ejaculation. Targeting oxytocinergic, neurokinin-1, dopaminergic, and opioid receptors represent future avenues to delaying ejaculation.

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

PubMed

Butterworth, R F; Poignant, J C; Barbeau, A

1975-01-01

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less

Calotropis gigantiea (L.) R. Br (Apocynaceae): a phytochemical and pharmacological review.

PubMed

Kadiyala, Madhuri; Ponnusankar, S; Elango, Kannan

2013-10-28

Calotropis gigantiea (L.) R. Br (Apocynaceae) commonly called as "crown flower" or "giant milk weed" is a well-known weed to many cultures for treating various disorders related to central nervous system, skin diseases, digestive system, respiratory system, reproductive system etc. Indigenous groups made the plant as a part of their lives since they use the fruit fibre to make ropes, household items, for weaving clothes and flowers for garlands apart from usage for various indications. The study aims at far-reaching review on phytochemistry, pharmacological activities, ethnopharmacology, intellectual property transfer on pharmacological therapies, toxicity which aids to provide scientific evidence for the ethnobotanical claims and to identify gaps required to be conducted as a future research prerequisite. A systematic literature search was performed using different databases such as Scopus, Science direct, PubMed and Sciverse with no timeline limit set during the search. All the available abstracts and full text articles were included in the systematic review. Most of the folkloric uses were validated by the scientific studies such as analgesic, anti-arthritic, anti-asthmatic, anti-bacterial, anti-convulsant, anti-pyretic, central nervous system disorders, contraceptive, anti-ulcer and wound healing. In addition other studies such as anti-diabetic, anti-diarrhoeal, anti-helminthic, anti-histamine, anti-inflammatory, anti-microbial, anti-oxidant, cardio-protective studies, cytotoxicity, hepatoprotectivity, fibrinolytic, mosquitocidal, nerve muscle activity, vasodilation and skeletal muscle activities were also reported for the plant. Isolated compounds such as calotropin, frugoside and 4'-O-β-D-glucopyranosyl frugoside were tested for the cytotoxicity efficacy against both human and rat cell lines out of which calotropin showed potent activity (IC50-15 ng/ml). However there were no clinical trials reported on the plant which is one of the major lacunas. This

Pharmacological MRI in animal models: a useful tool for 5-HT research?

PubMed

Martin, Chris; Sibson, Nicola R

2008-11-01

Pharmacological magnetic resonance imaging (phMRI) offers the potential to provide novel insights into the functioning of neurotransmitter systems and drug action in the central nervous system. To date, much of the neuropharmacological research that has applied phMRI techniques has focused on the dopaminergic system with relatively few studies into serotonergic function. In this article, we discuss the current capabilities of, and future potential for phMRI to address fundamental questions in serotonergic research using animal models. Firstly we review existing literature on the application of phMRI to the serotonergic system by exploring 3 broad research themes: (i) the functional anatomy of the serotonergic system; (ii) drug-receptor targeting and distribution; and (iii) disease models and drug development. Subsequently, we discuss the interpretation of phMRI data in terms of neuropharmacological action with a focus on issues specific to neuroimaging studies of the serotonergic system. Unlike other neuroimaging approaches such as positron emission tomography, phMRI methods do not currently offer sensitivity to markers of specific pharmacological action. However, they can provide in vivo markers of the neuropharmacological modulation of neuronal activity across the whole brain with unparalleled spatial and temporal resolution. Furthermore, due to the non-invasive nature of MRI, these markers are readily translatable to human studies. Whilst there are a number of constraints and limitations to phMRI methods that necessitate careful data interpretation, we argue that phMRI could become a valuable research tool in neuropharmacological studies of the serotonergic system.

Achieving the World Health Organization's vision for clinical pharmacology

PubMed Central

Henry, David; Gray, Jean; Day, Richard; Bochner, Felix; Ferro, Albert; Pirmohamed, Munir; Mörike, Klaus; Schwab, Matthias

2015-01-01

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence‐based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co‐morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need. PMID:26466826

Yin and Yang of ginseng pharmacology: ginsenosides vs gintonin

PubMed Central

Im, Dong-soon; Nah, Seung-yeol

2013-01-01

Ginseng, the root of Panax ginseng, has been used in traditional Chinese medicine as a tonic herb that provides many beneficial effects. Pharmacologic studies in the last decades have shown that ginsenosides (ginseng saponins) are primarily responsible for the actions of ginseng. However, the effects of ginseng are not fully explained by ginsenosides. Recently, another class of active ingredients called gintonin was identified. Gintonin is a complex of glycosylated ginseng proteins containing lysophosphatidic acids (LPAs) that are the intracellular lipid mitogenic mediator. Gintonin specifically and potently activates the G protein-coupled receptors (GPCRs) for LPA. Thus, the actions of ginseng are now also linked to LPA and its GPCRs. This linkage opens new dimensions for ginseng pharmacology and LPA therapeutics. In the present review, we evaluate the pharmacology of ginseng with the traditional viewpoint of Yin and Yang components. Furthermore, we will compare ginsenoside and gintonin based on the modern view of molecular pharmacology in terms of ion channels and GPCRs. PMID:24122014

Fundamentals of Clinical Pharmacology With Application for Pregnant Women.

PubMed

Patil, Avinash S; Sheng, Jessica; Dotters-Katz, Sarah K; Schmoll, Maria S; Onslow, Mitchell; Pierson, Rebecca C

2017-05-01

Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy. © 2017 by the American College of Nurse-Midwives.

Human Behavioral Pharmacology, Past, Present, and Future: Symposium Presented at the 50th Annual Meeting of the Behavioral Pharmacology Society

PubMed Central

Comer, Sandra D.; Bickel, Warren K.; Yi, Richard; de Wit, Harriet; Higgins, Stephen T.; Wenger, Galen R.; Johanson, Chris-Ellyn; Kreek, Mary Jeanne

2010-01-01

A symposium held at the 50th annual meeting of the Behavioral Pharmacology Society in May 2007 reviewed progress in the human behavioral pharmacology of drug abuse. Studies on drug self-administration in humans are reviewed that assessed reinforcing and subjective effects of drugs of abuse. The close parallels observed between studies in humans and laboratory animals using similar behavioral techniques have broadened our understanding of the complex nature of the pharmacological and behavioral factors controlling drug self-administration. The symposium also addressed the role that individual differences, such as gender, personality, and genotype play in determining the extent of self-administration of illicit drugs in human populations. Knowledge of how these factors influence human drug self-administration has helped validate similar differences observed in laboratory animals. In recognition that drug self-administration is but one of many choices available in the lives of humans, the symposium addressed the ways in which choice behavior can be studied in humans. These choice studies in human drug abusers have opened up new and exciting avenues of research in laboratory animals. Finally, the symposium reviewed behavioral pharmacology studies conducted in drug abuse treatment settings and the therapeutic benefits that have emerged from these studies. PMID:20664330

How do the top 12 pharmaceutical companies operate safety pharmacology?

PubMed

Ewart, Lorna; Gallacher, David J; Gintant, Gary; Guillon, Jean-Michel; Leishman, Derek; Levesque, Paul; McMahon, Nick; Mylecraine, Lou; Sanders, Martin; Suter, Willi; Wallis, Rob; Valentin, Jean-Pierre

2012-09-01

How does safety pharmacology operate in large pharmaceutical companies today? By understanding our current position, can we prepare safety pharmacology to successfully navigate the complex process of drug discovery and development? A short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 12 pharmaceutical companies, as defined by 2009 revenue figures. A series of multiple choice questions was designed to explore group size, accountabilities, roles and responsibilities of group members, outsourcing policy and publication record. A 92% response rate was obtained. Six out of 11 companies have 10 to 30 full time equivalents in safety pharmacology, who hold similar roles and responsibilities; although the majority of members are not qualified at PhD level or equivalent. Accountabilities were similar across companies and all groups have accountability for core battery in vivo studies and problem solving activities but differences do exist for example with in vitro safety screening and pharmacodynamic/pharmokinetic modeling (PK/PD). The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced activity. Finally, safety pharmacology groups are publishing 1 to 4 articles each year. This short survey has highlighted areas of similarity and differences in the way large pharmaceutical companies operate safety pharmacology. Copyright © 2012 Elsevier Inc. All rights reserved.

A new cross-correlation algorithm for the analysis of "in vitro" neuronal network activity aimed at pharmacological studies.

PubMed

Biffi, E; Menegon, A; Regalia, G; Maida, S; Ferrigno, G; Pedrocchi, A

2011-08-15

Modern drug discovery for Central Nervous System pathologies has recently focused its attention to in vitro neuronal networks as models for the study of neuronal activities. Micro Electrode Arrays (MEAs), a widely recognized tool for pharmacological investigations, enable the simultaneous study of the spiking activity of discrete regions of a neuronal culture, providing an insight into the dynamics of networks. Taking advantage of MEAs features and making the most of the cross-correlation analysis to assess internal parameters of a neuronal system, we provide an efficient method for the evaluation of comprehensive neuronal network activity. We developed an intra network burst correlation algorithm, we evaluated its sensitivity and we explored its potential use in pharmacological studies. Our results demonstrate the high sensitivity of this algorithm and the efficacy of this methodology in pharmacological dose-response studies, with the advantage of analyzing the effect of drugs on the comprehensive correlative properties of integrated neuronal networks. Copyright © 2011 Elsevier B.V. All rights reserved.

Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

PubMed Central

Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

2016-01-01

Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

An Integrated Approach to Instruction in Pharmacology and Therapeutics

ERIC Educational Resources Information Center

Talbert, Robert L.; Walton, Charles A.

1976-01-01

The impact of the clinical faculty on the content of the pharmacology course is described in a discussion of trends in pharmacology instruction. Interfaculty communication and development of course objectives are reviewed, and descriptions of two baccalaureate courses at the University of Texas College of Pharmacy are appended. (LBH)

Quantitative metrics for evaluating the phased roll-out of clinical information systems.

PubMed

Wong, David; Wu, Nicolas; Watkinson, Peter

2017-09-01

We introduce a novel quantitative approach for evaluating the order of roll-out during phased introduction of clinical information systems. Such roll-outs are associated with unavoidable risk due to patients transferring between clinical areas using both the old and new systems. We proposed a simple graphical model of patient flow through a hospital. Using a simple instance of the model, we showed how a roll-out order can be generated by minimising the flow of patients from the new system to the old system. The model was applied to admission and discharge data acquired from 37,080 patient journeys at the Churchill Hospital, Oxford between April 2013 and April 2014. The resulting order was evaluated empirically and produced acceptable orders. The development of data-driven approaches to clinical Information system roll-out provides insights that may not necessarily be ascertained through clinical judgment alone. Such methods could make a significant contribution to the smooth running of an organisation during the roll-out of a potentially disruptive technology. Unlike previous approaches, which are based on clinical opinion, the approach described here quantitatively assesses the appropriateness of competing roll-out strategies. The data-driven approach was shown to produce strategies that matched clinical intuition and provides a flexible framework that may be used to plan and monitor Clinical Information System roll-out. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Pharmacological Strategies to Retard Cardiovascular Aging

PubMed Central

Alfaras, Irene; Di Germanio, Clara; Bernier, Michel; Csiszar, Anna; Ungvari, Zoltan; Lakatta, Edward G.; de Cabo, Rafael

2016-01-01

Aging is the major risk factor for cardiovascular diseases (CVD), which are the leading cause of death in the United States. Traditionally, the effort to prevent CVD has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat CVD. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the pro-longevity benefits of various therapeutic strategies that support cardiovascular health. PMID:27174954

The role of clinical pharmacology in molecular genetics

NASA Technical Reports Server (NTRS)

Robertson, D.

1997-01-01

PROBLEM: Discovering the causes of unusual phenotypes in human subjects is an important aspect of patient-oriented research. MATERIAL: The tools of clinical pharmacology are uniquely useful in addressing these problems. PATIENTS, SUBJECTS, OR CASE HISTORIES: We evaluated a 42-year-old patient with lifelong orthostatic hypotension and ptosis of the eyelids. He underwent a series of biochemical, physiological, and pharmacological tests outlined in this article. RESULTS: These studies indicated that sympathetic innervation was intact but that the sympathetic neurotransmitter was dopamine rather than norepinephrine. These results demonstrated that dopamine-beta-hydroxylase deficiency underlies the clinical abnormalities of this patient. CONCLUSION: In selected individuals with unusual phenotypes, the techniques of clinical chemistry and clinical pharmacology can define the nature of the defect at almost the resolution of the human genome.

Effective non-pharmacological birth interventions.

PubMed

Davis, Jude

2015-02-01

Midwifery expertise is in 'normal' birth. What constitutes 'normal' is debatable, but well embedded within 'normal' are the birth plans of women who aspire to give birth without using drugs. To give birth without drugs for many may seem undesirable or intolerable, especially to those whose cultural references to birth have been overwhelmingly negative, fearful or risk-obsessed. However, significant numbers of women have confidence in their innate ability to birth their babies and are rightfully concerned about the undesirable side effects of pharmacological interventions. As well as providing wider choice for women, looking for alternative ways of addressing pain and progress in labour enhances birth attendants' knowledge and becomes a delightful journey of discovering the ancient and modern arts of midwifery. Shared here are a collection of ideas to contribute to the toolkit of knowledge about non-pharmacological interventions.

A novel quantitative assay of mitophagy: Combining high content fluorescence microscopy and mitochondrial DNA load to quantify mitophagy and identify novel pharmacological tools against pathogenic heteroplasmic mtDNA.

PubMed

Diot, Alan; Hinks-Roberts, Alex; Lodge, Tiffany; Liao, Chunyan; Dombi, Eszter; Morten, Karl; Brady, Stefen; Fratter, Carl; Carver, Janet; Muir, Rebecca; Davis, Ryan; Green, Charlotte J; Johnston, Iain; Hilton-Jones, David; Sue, Carolyn; Mortiboys, Heather; Poulton, Joanna

2015-10-01

Mitophagy is a cellular mechanism for the recycling of mitochondrial fragments. This process is able to improve mitochondrial DNA (mtDNA) quality in heteroplasmic mtDNA disease, in which mutant mtDNA co-exists with normal mtDNA. In disorders where the load of mutant mtDNA determines disease severity it is likely to be an important determinant of disease progression. Measuring mitophagy is technically demanding. We used pharmacological modulators of autophagy to validate two techniques for quantifying mitophagy. First we used the IN Cell 1000 analyzer to quantify mitochondrial co-localisation with LC3-II positive autophagosomes. Unlike conventional fluorescence and electron microscopy, this high-throughput system is sufficiently sensitive to detect transient low frequency autophagosomes. Secondly, because mitophagy preferentially removes pathogenic heteroplasmic mtDNA mutants, we developed a heteroplasmy assay based on loss of m.3243A>G mtDNA, during culture conditions requiring oxidative metabolism ("energetic stress"). The effects of the pharmacological modulators on these two measures were consistent, confirming that the high throughput imaging output (autophagosomes co-localising with mitochondria) reflects mitochondrial quality control. To further validate these methods, we performed a more detailed study using metformin, the most commonly prescribed antidiabetic drug that is still sometimes used in Maternally Inherited Diabetes and Deafness (MIDD). This confirmed our initial findings and revealed that metformin inhibits mitophagy at clinically relevant concentrations, suggesting that it may have novel therapeutic uses. Copyright © 2015. Published by Elsevier Ltd.

Evidence-based pharmacological treatment of substance use disorders and pathological gambling.

PubMed

van den Brink, Wim

2012-03-01

This review summarizes our current knowledge of the pharmacological treatment of substance use disorders and pathological gambling using data mainly from randomized controlled trials and meta-analyses regarding these randomized controlled trials. The review is restricted to the selection of first and second line pharmacological treatments for smoking, alcohol dependence, opioid dependence, cocaine dependence, cannabis dependence and pathological gambling. It is concluded that great progress has been made in the last three decades and that currently evidence-based pharmacological treatments are available for smoking cessation, alcohol and opioid dependence and pathological gambling. At the same time a series of existing and new pharmacological compounds are being tested in cocaine and cannabis dependence. The review concludes with a summary of additional strategies to increase the effect size of already available pharmacological interventions, including polypharmacy, combining pharmacotherapy with psychotherapy and psychosocial support, and improved patient-treatment matching.

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety.

PubMed

Moreira, Rute; Pereira, David M; Valentão, Patrícia; Andrade, Paula B

2018-06-05

Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA.

A Review of Pharmacologic Treatment for Compulsive Buying Disorder.

PubMed

Soares, Célia; Fernandes, Natália; Morgado, Pedro

2016-04-01

At present, no treatment recommendations can be made for compulsive buying disorder. Recent studies have found evidence for the efficacy of psychotherapeutic options, but less is known regarding the best pharmacologic treatment. The purpose of this review is to present and analyze the available published evidence on the pharmacological treatment of compulsive buying disorder. To achieve this, we conducted a review of studies focusing on the pharmacological treatment of compulsive buying by searching the PubMed/MEDLINE database. Selection criteria were applied, and 21 studies were identified. Pharmacological classes reported included antidepressants, mood stabilizers, opioid antagonists, second-generation antipsychotics, and N-methyl-D-aspartate receptor antagonists. We found only placebo-controlled trials for fluvoxamine; none showed effectiveness against placebo. Three open-label trials reported clinical improvement with citalopram; one was followed by a double-blind discontinuation. Escitalopram was effective in an open-label trial but did not show efficacy in the double-blind phase. Memantine was identified as effective in a pilot open-label study. Fluoxetine, bupropion, nortriptyline, clomipramine, topiramate and naltrexone were only reported to be effective in clinical cases. According to the available literature, there is no evidence to propose a specific pharmacologic agent for compulsive buying disorder. Future research is required for a better understanding of both pathogenesis and treatment of this disorder.

Pharmacologic Conversion during Dofetilide Treatment for Persistent Atrial Fibrillation.

PubMed

Steinberg, Jonathan S; Shah, Yash; Szepietowska, Barbara

2017-06-01

Dofetilide is a pure I Kr blocker and is one of the few drugs specifically studied and approved in the United States for the management of persistent atrial fibrillation (AF). Dofetilide has been noted to have a high rate of pharmacologic conversion during initial dosing in prior smaller studies. The intent of the study was to examine the safety of an inpatient loading strategy, and the incidence and patterns of pharmacologic conversion by dofetilide during the treatment of persistent AF in a large consecutive cohort. This is a retrospective analysis of 308 consecutive patients with persistent AF electively admitted for inpatient dofetilide loading. The initiation dose of dofetilide was determined by the creatinine clearance. Overall, 88% (n = 271) successfully completed initiation of dofetilide and were discharged in sinus rhythm. The most common reason for failure to complete initiation of dofetilide loading was QTc prolongation in 24 patients (7.8%), and torsade de pointes occurred in three patients (1%). Pharmacologic conversion was observed in 56% (n = 151) after a median of two doses. The rate of pharmacologic conversion based on the final dose was 75%, 9%, and 0% for 500 mcg, 250 mcg, and 125 mcg, respectively (P < 0.05). Dofetilide is a well-tolerated antiarrhythmic drug with a low incidence of proarrhythmia and an especially high rate of pharmacologic conversion in patients with persistent AF. © 2017 Wiley Periodicals, Inc.

Pharmacological and Chemical Effects of Cigarette Additives

PubMed Central

Rabinoff, Michael; Caskey, Nicholas; Rissling, Anthony; Park, Candice

2007-01-01

We investigated tobacco industry documents and other sources for evidence of possible pharmacological and chemical effects of tobacco additives. Our findings indicated that more than 100 of 599 documented cigarette additives have pharmacological actions that camouflage the odor of environmental tobacco smoke emitted from cigarettes, enhance or maintain nicotine delivery, could increase the addictiveness of cigarettes, and mask symptoms and illnesses associated with smoking behaviors. Whether such uses were specifically intended for these agents is unknown. Our results provide a clear rationale for regulatory control of tobacco additives. PMID:17666709

Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics

NASA Technical Reports Server (NTRS)

Lathers, C. M.; Charles, J. B.; Bungo, M. W.

1989-01-01

The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.

The current status and trend of clinical pharmacology in developing countries

PubMed Central

2013-01-01

Background Several international forums for promoting clinical pharmacology in developing countries have been held since 1980, and several clinical pharmacology programmes targeting developing countries were instituted such that the status of clinical pharmacology in developing countries is not where it was 50 years ago. Therefore, a survey and an appraisal of the literature on the current status of clinical pharmacology in developing countries were undertaken with a hope that it would enable development of appropriate strategies for further promotion of clinical pharmacology in these countries. Methods First, nine determinants (or enabling factors) for running a successful clinical pharmacology programme were identified, i.e., disease burden, drug situation, economic growth, clinical pharmacology activities, recognition, human capital, government support, international collaboration, and support for traditional/alternative medicines. These factors were then evaluated with regard to their current status in the developing countries that responded to an electronic questionnaire, and their historical perspective, using the literature appraisal. From these, a projected trend was constructed with recommendations on the way forward. Results Clinical pharmacology services, research and teaching in developing countries have improved over the past 50 years with over 90% of countries having the appropriate policies for regulation and rational use of medicines in place. Unfortunately, policy implementation remains a challenge, owing to a worsening disease burden and drug situation, versus fewer clinical pharmacologists and other competing priorities for the national budgets. This has led to a preference for training ‘a physician clinical pharmacologist’ in programmes emphasizing local relevancy and for a shorter time, and the training of other professionals in therapeutics for endemic diseases (task shifting), as the most promising strategies of ensuring rational use of

Quantitative Reactivity Scales for Dynamic Covalent and Systems Chemistry.

PubMed

Zhou, Yuntao; Li, Lijie; Ye, Hebo; Zhang, Ling; You, Lei

2016-01-13

Dynamic covalent chemistry (DCC) has become a powerful tool for the creation of molecular assemblies and complex systems in chemistry and materials science. Herein we developed for the first time quantitative reactivity scales capable of correlation and prediction of the equilibrium of dynamic covalent reactions (DCRs). The reference reactions are based upon universal DCRs between imines, one of the most utilized structural motifs in DCC, and a series of O-, N-, and S- mononucleophiles. Aromatic imines derived from pyridine-2-carboxyaldehyde exhibit capability for controlling the equilibrium through distinct substituent effects. Electron-donating groups (EDGs) stabilize the imine through quinoidal resonance, while electron-withdrawing groups (EWGs) stabilize the adduct by enhancing intramolecular hydrogen bonding, resulting in curvature in Hammett analysis. Notably, unique nonlinearity induced by both EDGs and EWGs emerged in Hammett plot when cyclic secondary amines were used. This is the first time such a behavior is observed in a thermodynamically controlled system, to the best of our knowledge. Unified quantitative reactivity scales were proposed for DCC and defined by the correlation log K = S(N) (R(N) + R(E)). Nucleophilicity parameters (R(N) and S(N)) and electrophilicity parameters (R(E)) were then developed from DCRs discovered. Furthermore, the predictive power of those parameters was verified by successful correlation of other DCRs, validating our reactivity scales as a general and useful tool for the evaluation and modeling of DCRs. The reactivity parameters proposed here should be complementary to well-established kinetics based parameters and find applications in many aspects, such as DCR discovery, bioconjugation, and catalysis.

Towards a Moral Ecology of Pharmacological Cognitive Enhancement in British Universities.

PubMed

Vagwala, Meghana Kasturi; Bicquelet, Aude; Didziokaite, Gabija; Coomber, Ross; Corrigan, Oonagh; Singh, Ilina

2017-01-01

Few empirical studies in the UK have examined the complex social patterns and values behind quantitative estimates of the prevalence of pharmacological cognitive enhancement (PCE). We conducted a qualitative investigation of the social dynamics and moral attitudes that shape PCE practices among university students in two major metropolitan areas in the UK. Our thematic analysis of eight focus groups ( n  = 66) suggests a moral ecology that operates within the social infrastructure of the university. We find that PCE resilience among UK university students is mediated by normative and cultural judgments disfavoring competitiveness and prescription drug taking. PCE risk can be augmented by social factors such as soft peer pressure and normalization of enhancement within social and institutional networks. We suggest that moral ecological dynamics should be viewed as key mechanisms of PCE risk and resilience in universities. Effective PCE governance within universities should therefore attend to developing further understanding of the moral ecologies of PCE.

Marine pharmacology in 2003-4: marine compounds with anthelmintic antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action.

PubMed

Mayer, Alejandro M S; Rodríguez, Abimael D; Berlinck, Roberto G S; Hamann, Mark T

2007-05-01

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998-2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003-2004, research on the pharmacology of marine natural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea, Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for novel therapeutic agents with broad spectrum activity.

Marine pharmacology in 2003-4: Marine Compounds with Anthelminthic, Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiplatelet, Antiprotozoal, Antituberculosis, and Antiviral Activities; affecting the Cardiovascular, Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M.S.; Rodriguez, Abimael D.; Berlinck, Roberto G.S.; Hamann, Mark T.

2007-01-01

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998-2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelminthic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003-2004, research on the pharmacology of marine natural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea, Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for novel therapeutic agents with broad spectrum activity. PMID:17392033

Marine pharmacology in 2001–2002: Marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action

PubMed Central

Mayer, Alejandro M.S.; Hamann, Mark T.

2016-01-01

During 2001–2002, research on the pharmacology of marine chemicals continued to be global in nature involving investigators from Argentina, Australia, Brazil, Canada, China, Denmark, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Pakistan, the Philippines, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, and the United States. This current article, a sequel to the authors’ 1998, 1999 and 2000 marine pharmacology reviews, classifies 106 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria, on the basis of peer-reviewed preclinical pharmacology. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 56 marine chemicals. An additional 19 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as to possess anti-inflammatory and antidiabetic effects. Finally, 31 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2001–2002 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads for the ongoing global search for therapeutic agents for the treatment of multiple disease categories. PMID:15919242

A web-based quantitative signal detection system on adverse drug reaction in China.

PubMed

Li, Chanjuan; Xia, Jielai; Deng, Jianxiong; Chen, Wenge; Wang, Suzhen; Jiang, Jing; Chen, Guanquan

2009-07-01

To establish a web-based quantitative signal detection system for adverse drug reactions (ADRs) based on spontaneous reporting to the Guangdong province drug-monitoring database in China. Using Microsoft Visual Basic and Active Server Pages programming languages and SQL Server 2000, a web-based system with three software modules was programmed to perform data preparation and association detection, and to generate reports. Information component (IC), the internationally recognized measure of disproportionality for quantitative signal detection, was integrated into the system, and its capacity for signal detection was tested with ADR reports collected from 1 January 2002 to 30 June 2007 in Guangdong. A total of 2,496 associations including known signals were mined from the test database. Signals (e.g., cefradine-induced hematuria) were found early by using the IC analysis. In addition, 291 drug-ADR associations were alerted for the first time in the second quarter of 2007. The system can be used for the detection of significant associations from the Guangdong drug-monitoring database and could be an extremely useful adjunct to the expert assessment of very large numbers of spontaneously reported ADRs for the first time in China.

Pharmacology of P2X channels.

PubMed

Gever, Joel R; Cockayne, Debra A; Dillon, Michael P; Burnstock, Geoffrey; Ford, Anthony P D W

2006-08-01

Significant progress in understanding the pharmacological characteristics and physiological importance of homomeric and heteromeric P2X channels has been achieved in recent years. P2X channels, gated by ATP and most likely trimerically assembled from seven known P2X subunits, are present in a broad distribution of tissues and are thought to play an important role in a variety of physiological functions, including peripheral and central neuronal transmission, smooth muscle contraction, and inflammation. The known homomeric and heteromeric P2X channels can be distinguished from each other on the basis of pharmacological differences when expressed recombinantly in cell lines, but whether this pharmacological classification holds true in native cells and in vivo is less well-established. Nevertheless, several potent and selective P2X antagonists have been discovered in recent years and shown to be efficacious in various animal models including those for visceral organ function, chronic inflammatory and neuropathic pain, and inflammation. The recent advancement of drug candidates targeting P2X channels into human trials, confirms the medicinal exploitability of this novel target family and provides hope that safe and effective medicines for the treatment of disorders involving P2X channels may be identified in the near future.

Some pharmacological aspects of drug dependence.

PubMed

Chesher, G B

1975-12-06

The self-administration of drugs to achieve altered states of consciousness is recognized as normal human behaviour. Community attitudes towards drug use vary according to the drug and often bear little relationship to the known pharmacological and toxicological effects of the drug. For an objective assessment of the potential dangers associated with drug use, a distinction is made between drug use and drug abuse. It is stressed that the progression from drug use to drug abuse involves social and psychological factors in addition to the pharmacological factors which are outlined in this paper. The sequential development of drug dependency is described under the headings: Induction; continued consumption; compulsive consumption; withdrawal; abstinence; reinduction. Man uses psychotropic drugs because he finds the effects rewarding. Some experimental models to explore the neurophysiological basis of the reward are described. Experiments employing inhibitors of protein synthesis suggest that the phenomena of tolerance and physical dependence involve the synthesis of new protein. It has been suggested that the new protein might be new receptor molecules for the drug or neurotransmitter substances. These new receptors might constitute a "drug memory" and provide a possible explanation for high relapse rate of drug dependent subjects. A pharmacological basis for the methadone maintenance programme of management of narcotic dependent subjects is briefly outlined.

[Non-Pharmacological Interventions for Pregnancy-Related Sleep Disturbances].

PubMed

Hung, Hsuan-Man; Chiang, Hsiao-Ching

2017-02-01

Most women experience the worse sleep quality of their life during pregnancy and the early postpartum period. Although pregnancy typically accounts for a relatively short part of a woman's life, the related sleep disturbances may have a significant and negative impact on her long-term health. Approximately 78-80% of pregnant women experience sleep disturbances, including interruptions in deep sleep, decreased total sleep time, poor subjective sleep quality, frequent night waking, and reduced sleep efficacy. Sleep disturbances during pregnancy start during the first trimester and become prevalent during the third trimester. Related factors include physiological and psychosocial changes and an unhealthy lifestyle. As non-pharmacological interventions have the potential to improve sleep quality in 70% to 80% of patients with insomnia, this is the main approached that is currently used to treat pregnancy-related sleep disturbances. Examples of these non-pharmacological interventions include music therapy, aerobic exercise, massage, progressive muscle relaxation, multi-modal interventions, and the use of a maternity support belt. The efficacy and safety of other related non-pharmacological interventions such as auricular acupressure, cognitive therapy, tai chi, and aromatherapy remain uncertain, with more empirical research required. Additionally, non-pharmacological interventions do not effectively treat sleep disturbances in all pregnant women.

A Web-based e-learning course: integration of pathophysiology into pharmacology.

PubMed

Tse, Mimi M Y; Lo, Lisa W L

2008-11-01

The Internet is becoming the preferred place to find information. Millions of people go online in search of health and medical information. Likewise, the demand for Web-based courses is growing. This paper presents the development, utilization, and evaluation of a Web-based e-learning course for nursing students, entitled Integration of Pathophysiology into Pharmacology. The pathophysiology component included cardiovascular, respiratory, central nervous and immune system diseases, while the pharmacology component was developed based on 150 commonly used drugs. One hundred and nineteen Year 1 nursing students took part in the course. The Web-based e-learning course materials were uploaded to a WebCT for students' self-directed learning and attempts to pass two scheduled online quizzes. At the end of the semester, students were given a questionnaire to measure the e-learning experience. Their experience in the e-learning course was a positive one. Students stated that they were able to understand rather than memorize the subject content, and develop their problem solving and critical thinking abilities. Online quizzes yielded satisfactory results. In the focus group interview, students indicated that they appreciated the time flexibility and convenience associated with Web-based learning, and also made good suggestions for enhancing Web-based learning. The Web-based approach is promising for teaching and learning pathophysiology and pharmacology for nurses and other healthcare professionals.

Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters.

PubMed

Smit, Cornelis; De Hoogd, Sjoerd; Brüggemann, Roger J M; Knibbe, Catherijne A J

2018-03-01

The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

System-Wide Quantitative Proteomics of the Metabolic Syndrome in Mice: Genotypic and Dietary Effects.

PubMed

Terfve, Camille; Sabidó, Eduard; Wu, Yibo; Gonçalves, Emanuel; Choi, Meena; Vaga, Stefania; Vitek, Olga; Saez-Rodriguez, Julio; Aebersold, Ruedi

2017-02-03

Advances in mass spectrometry have made the quantitative measurement of proteins across multiple samples a reality, allowing for the study of complex biological systems such as the metabolic syndrome. Although the deregulation of lipid metabolism and increased hepatic storage of triacylglycerides are known to play a part in the onset of the metabolic syndrome, its molecular basis and dependency on dietary and genotypic factors are poorly characterized. Here, we used an experimental design with two different mouse strains and dietary and metabolic perturbations to generate a compendium of quantitative proteome data using three mass spectrometric techniques. The data reproduce known properties of the metabolic system and indicate differential molecular adaptation of the two mouse strains to perturbations, contributing to a better understanding of the metabolic syndrome. We show that high-quality, high-throughput proteomic data sets provide an unbiased broad overview of the behavior of complex systems after perturbation.

Effects of Heart Failure and its Pharmacological Management on Sleep

PubMed Central

Jiménez, Jessica A.; Greenberg, Barry H.; Mills, Paul J.

2011-01-01

Heart failure (HF) patients have a high prevalence of disturbed sleep. Optimal pharmacological management of HF includes the use of angiotensin converting enzyme inhibitors and β-blockers, which have been associated with decreased severity of central sleep apnea, which is likely secondary to improvements in cardiac performance. There is also evidence, however, indicating that other pharmacological treatments for HF might adversely affect sleep. This brief review introduces the topic of disturbed sleep in HF and examines the extent to which its standard pharmacological management impacts sleep quality. PMID:22125571

Pharmacological and biotechnological advances with Rosmarinus officinalis L.

PubMed

Neves, Josynaria Araújo; Neves, Josyanne Araújo; Oliveira, Rita de Cassia Meneses

2018-05-01

Rosmarinus officinalis L. is an aromatic plant with a number of biological properties. Recently, has been studied regarding its therapeutic potential. The objective of this study was to perform a systematic review on R. officinalis essential oil for its pharmacological properties and biotechnological applications. Areas covered: The databases were searched for articles (Science Direct, Pub Med and Web of Science) and patents (INPI, WIPO and EPO) with publications on R. officinalis and associations with essential oil (EO-Ro), cardiovascular system, hypertension and cyclodextrin. We selected 305 articles on EO-Ro in the most diverse subjects and six articles with of R. officinalis associated with hypertension. 59 patents were analyzed. The results demonstrate how extensive the studies are on the biological activities with the extract and EO-Ro. These have shown effects antibacterial, antifungal, anti-inflammatory, antitumor and other. The properties exhibited by EO-Ro reinforce the use of this plant as a phytotherapeutic agent. Expert opinion: Although there are several pharmacological properties, studies on the prevention or treatment of cardiovascular diseases with EO-Ro are scarce, especially to evaluate the antihypertensive activity of EO-Ro. It has also become clear that EO-Ro can be exploited in different commercial products as supplement, cosmetics and new formulations.

Cholinesterases, a target of pharmacology and toxicology.

PubMed

Pohanka, Miroslav

2011-09-01

Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

Nanoparticles: pharmacological and toxicological significance

PubMed Central

Medina, C; Santos-Martinez, M J; Radomski, A; Corrigan, O I; Radomski, M W

2007-01-01

Nanoparticles are tiny materials (<1000 nm in size) that have specific physicochemical properties different to bulk materials of the same composition and such properties make them very attractive for commercial and medical development. However, nanoparticles can act on living cells at the nanolevel resulting not only in biologically desirable, but also in undesirable effects. In contrast to many efforts aimed at exploiting desirable properties of nanoparticles for medicine, there are limited attempts to evaluate potentially undesirable effects of these particles when administered intentionally for medical purposes. Therefore, there is a pressing need for careful consideration of benefits and side effects of the use of nanoparticles in medicine. This review article aims at providing a balanced update of these exciting pharmacological and potentially toxicological developments. The classes of nanoparticles, the current status of nanoparticle use in pharmacology and therapeutics, the demonstrated and potential toxicity of nanoparticles will be discussed. PMID:17245366

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

PubMed

Billaud, Eliane M; Guillemain, Romain; Berge, Maud; Amrein, Catherine; Lefeuvre, Sandrine; Louët, Agnès Lillo-Le; Boussaud, Véronique; Chevalier, Patrick

2010-11-01

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Establishment of a Quantitative Medical Technology Evaluation System and Indicators within Medical Institutions.

PubMed

Wu, Suo-Wei; Chen, Tong; Pan, Qi; Wei, Liang-Yu; Wang, Qin; Li, Chao; Song, Jing-Chen; Luo, Ji

2018-06-05

The development and application of medical technologies reflect the medical quality and clinical capacity of a hospital. It is also an effective approach in upgrading medical service and core competitiveness among medical institutions. This study aimed to build a quantitative medical technology evaluation system through questionnaire survey within medical institutions to perform an assessment to medical technologies more objectively and accurately, and promote the management of medical quality technologies and ensure the medical safety of various operations among the hospitals. A two-leveled quantitative medical technology evaluation system was built through a two-round questionnaire survey of chosen experts. The Delphi method was applied in identifying the structure of evaluation system and indicators. The judgment of the experts on the indicators was adopted in building the matrix so that the weight coefficient and maximum eigenvalue (λ max), consistency index (CI), and random consistency ratio (CR) could be obtained and collected. The results were verified through consistency tests, and the index weight coefficient of each indicator was conducted and calculated through analytical hierarchy process. Twenty-six experts of different medical fields were involved in the questionnaire survey, 25 of whom successfully responded to the two-round research. Altogether, 4 primary indicators (safety, effectiveness, innovativeness, and benefits), as well as 13 secondary indicators, were included in the evaluation system. The matrix is built to conduct the λ max, CI, and CR of each expert in the survey, and the index weight coefficients of primary indicators were 0.33, 0.28, 0.27, and 0.12, respectively, and the index weight coefficients of secondary indicators were conducted and calculated accordingly. As the two-round questionnaire survey of experts and statistical analysis were performed and credibility of the results was verified through consistency evaluation test, the

A meta-analysis to determine the effect of pharmacological and non-pharmacological treatments on fibromyalgia symptoms comprising OMERACT-10 response criteria.

PubMed

Papadopoulou, Despoina; Fassoulaki, Argyro; Tsoulas, Christos; Siafaka, Ioanna; Vadalouca, Athina

2016-03-01

Fibromyalgia is characterized by widespread pain, sleep problems, fatigue, functional impairment, psychological distress, and cognitive dysfunction. The objective of this meta-analysis is to synthesize the available data on the effectiveness of pharmacological and non-pharmacological interventions across all domains included in the Outcome Measures in Rheumatology Clinical Trials (OMERACT-10) fibromyalgia response definitions, and to examine response based on these definitions. We searched Cochrane, PubMed, Scopus, and the reference lists of articles for randomized controlled trials of any drug formulation or non-pharmacological intervention used for fibromyalgia treatment. We extracted efficacy data regarding pain, sleep, physical function, fatigue, anxiety, depression, and cognition. The available data were insufficient to draw definite conclusions regarding response. Indirect evidence indicates that it may be expected with the use of serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NRIs), and multidisciplinary treatment.

Pharmacology education in North American dental schools: the basic science survey series.

PubMed

Gautam, Medha; Shaw, David H; Pate, Ted D; Lambert, H Wayne

2013-08-01

As part of the Basic Science Survey Series (BSSS) for Dentistry, members of the American Dental Education Association (ADEA) Physiology, Pharmacology, and Therapeutics Section surveyed course directors of basic pharmacology courses in North American dental schools. The survey was designed to assess, among other things, faculty affiliation and experience of course directors, teaching methods, general course content and emphasis, extent of interdisciplinary (shared) instruction, and impact of recent curricular changes. Responses were received from forty-nine of sixty-seven (73.1 percent) U.S. and Canadian dental schools. The findings suggest the following: 1) substantial variation exists in instructional hours, faculty affiliation, placement within curriculum, class size, and interdisciplinary nature of pharmacology courses; 2) pharmacology course content emphasis is similar among schools; 3) the number of contact hours in pharmacology has remained stable over the past three decades; 4) recent curricular changes were often directed towards enhancing the integrative and clinically relevant aspects of pharmacology instruction; and 5) a trend toward innovative content delivery, such as use of computer-assisted instruction applications, is evident. Data, derived from this study, may be useful to pharmacology course directors, curriculum committees, and other dental educators with an interest in integrative and interprofessional education.

Teaching clinical opioid pharmacology with the Human Patient Simulator.

PubMed

Hassan, Zaki; DiLorenzo, Amy; Sloan, Paul

2010-01-01

Postoperative pain should be aggressively treated to decrease the development of chronic postsurgical pain. There has been an increase in the use of Human Patient Simulator (HPS) for teaching advanced courses in pharmacology to medical students, residents, and nurses. The aim of this educational investigation was to pilot the HPS for the training of medical students and surgical recovery room staff nurses in the pharmacology of opioids for the management of postoperative pain. The computerized HPS mannequin is fully monitored with appropriate displays and includes a voice speaker mounted in the head. Medical students and Postanesthesia care unit nurses, led by faculty in the Department of Anesthesiology in small groups of 4-6, participated in a 2- to 3-hour HPS course on the use of opioids for the management of acute postoperative pain. Trainees were asked to treat the acute and severe postoperative pain of a simulated patient. Opioid effects and side effects (such as respiratory depression) were presented on the mannequin in real time to the participants. Side effects of naloxone to reverse opioid depression were presented as a crisis in real time to the participants. Participants completed a 10-item course evaluation using a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree). Twenty-two nurses and nine medical students completed the HPS opioid pharmacology scenario. Almost all participants rated the HPS course very highly and rated every item as either agree or strongly agree. Most participants agreed that the simulator session improved their understanding of opioid pharmacology including opioid side effects and management of opioid complications. Course participants felt most strongly (median, interquartile range) that the simulator session improved their understanding of naloxone pharmacology (5, 0), simulators serve as a useful teaching tool (5, 0), and that they would be pleased to participate in any additional HPS teaching sessions (5, 0). The

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin on vasoconstriction.

PubMed

Yin, Anyue; Yamada, Akihiro; Stam, Wiro B; van Hasselt, Johan G C; van der Graaf, Piet H

2018-06-02

Development of combination therapies has received significant interest in recent years. Previously a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction, and performed inter-species scaling to humans using this mechanism-based model. Contractile data was obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pre-treatment with the irreversible α-adrenoceptor antagonist, phenoxybenzamine. Data was analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. With receptor affinities set to literature values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error ≤ 20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments. This article is protected by copyright. All rights reserved.

A systems-pharmacology analysis of herbal medicines used in health improvement treatment: predicting potential new drugs and targets.

PubMed

Liu, Jianling; Pei, Mengjie; Zheng, Chunli; Li, Yan; Wang, Yonghua; Lu, Aiping; Yang, Ling

2013-01-01

For thousands of years, tonic herbs have been successfully used all around the world to improve health, energy, and vitality. However, their underlying mechanisms of action in molecular/systems levels are still a mystery. In this work, two sets of tonic herbs, so called Qi-enriching herbs (QEH) and Blood-tonifying herbs (BTH) in TCM, were selected to elucidate why they can restore proper balance and harmony inside body, organ and energy system. Firstly, a pattern recognition model based on artificial neural network and discriminant analysis for assessing the molecular difference between QEH and BTH was developed. It is indicated that QEH compounds have high lipophilicity while BTH compounds possess high chemical reactivity. Secondly, a systematic investigation integrating ADME (absorption, distribution, metabolism, and excretion) prediction, target fishing and network analysis was performed and validated on these herbs to obtain the compound-target associations for reconstructing the biologically-meaningful networks. The results suggest QEH enhance physical strength, immune system and normal well-being, acting as adjuvant therapy for chronic disorders while BTH stimulate hematopoiesis function in body. As an emerging approach, the systems pharmacology model might facilitate to understand the mechanisms of action of the tonic herbs, which brings about new development for complementary and alternative medicine.

New approaches to pharmacological treatment of osteoporosis.

PubMed Central

Akesson, Kristina

2003-01-01

Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb.et Zucc.: a review.

PubMed

Peng, Wei; Qin, Rongxin; Li, Xiaoli; Zhou, Hong

2013-07-30

Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum), also known as Reynoutria japonica Houtt and Huzhang in China, is a traditional and popular Chinese medicinal herb. Polygonum cuspidatum with a wide spectrum of pharmacological effects has been used for treatment of inflammation, favus, jaundice, scald, and hyperlipemia, etc. The present paper reviews the traditional applications as well as advances in botany, phytochemistry, pharmacodynamics, pharmacokinetics and toxicology of this plant. Finally, the tendency and perspective for future investigation of this plant are discussed, too. A systematic review of literature about Polygonum cuspidatum is carried out using resources including classic books about Chinese herbal medicine, and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science and others. Polygonum cuspidatum is widely distributed in the world and has been used as a traditional medicine for a long history in China. Over 67 compounds including quinones, stilbenes, flavonoids, counmarins and ligans have been isolated and identified from this plant. The root of this plant is used as the effective agent in pre-clinical and clinical practice for regulating lipids, anti-endotoxic shock, anti-infection and anti-inflammation, anti-cancer and other diseases in China and Japan. As an important traditional Chinese medicine, Polygonum cuspidatum has been used for treatment of hyperlipemia, inflammation, infection and cancer, etc. Because there is no enough systemic data about the chemical constituents and their pharmacological effects or toxicities, it is important to investigate the pharmacological effects and molecular mechanisms of this plant based on modern realization of diseases' pathophysiology. Drug target-guided and bioactivity-guided isolation and purification of the chemical constituents from this plant and subsequent evaluation of their pharmacologic effects will promote the development of new drug and make sure which

A review of quantitative structure-property relationships for the fate of ionizable organic chemicals in water matrices and identification of knowledge gaps.

PubMed

Nolte, Tom M; Ragas, Ad M J

2017-03-22

Many organic chemicals are ionizable by nature. After use and release into the environment, various fate processes determine their concentrations, and hence exposure to aquatic organisms. In the absence of suitable data, such fate processes can be estimated using Quantitative Structure-Property Relationships (QSPRs). In this review we compiled available QSPRs from the open literature and assessed their applicability towards ionizable organic chemicals. Using quantitative and qualitative criteria we selected the 'best' QSPRs for sorption, (a)biotic degradation, and bioconcentration. The results indicate that many suitable QSPRs exist, but some critical knowledge gaps remain. Specifically, future focus should be directed towards the development of QSPR models for biodegradation in wastewater and sediment systems, direct photolysis and reaction with singlet oxygen, as well as additional reactive intermediates. Adequate QSPRs for bioconcentration in fish exist, but more accurate assessments can be achieved using pharmacologically based toxicokinetic (PBTK) models. No adequate QSPRs exist for bioconcentration in non-fish species. Due to the high variability of chemical and biological species as well as environmental conditions in QSPR datasets, accurate predictions for specific systems and inter-dataset conversions are problematic, for which standardization is needed. For all QSPR endpoints, additional data requirements involve supplementing the current chemical space covered and accurately characterizing the test systems used.

Pharmacology Experiments on the Computer.

ERIC Educational Resources Information Center

Keller, Daniel

1990-01-01

A computer program that replaces a set of pharmacology and physiology laboratory experiments on live animals or isolated organs is described and illustrated. Five experiments are simulated: dose-effect relationships on smooth muscle, blood pressure and catecholamines, neuromuscular signal transmission, acetylcholine and the circulation, and…

Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Chin-Rang

Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complementmore » Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.« less

Pharmacological Strategies to Retard Cardiovascular Aging.

PubMed

Alfaras, Irene; Di Germanio, Clara; Bernier, Michel; Csiszar, Anna; Ungvari, Zoltan; Lakatta, Edward G; de Cabo, Rafael

2016-05-13

Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health. © 2016 American Heart Association, Inc.

The quantitative control and matching of an optical false color composite imaging system

NASA Astrophysics Data System (ADS)

Zhou, Chengxian; Dai, Zixin; Pan, Xizhe; Li, Yinxi

1993-10-01

Design of an imaging system for optical false color composite (OFCC) capable of high-precision density-exposure time control and color balance is presented. The system provides high quality FCC image data that can be analyzed using a quantitative calculation method. The quality requirement to each part of the image generation system is defined, and the distribution of satellite remote sensing image information is analyzed. The proposed technology makes it possible to present the remote sensing image data more effectively and accurately.

Pharmacologic Treatments for Binge-Eating Disorder.

PubMed

McElroy, Susan L

2017-01-01

Binge-eating disorder (BED) is the most common eating disorder and is associated with poor physical and mental health outcomes. Psychological and behavioral interventions have been a mainstay of treatment for BED, but as understanding of this disorder has grown, pharmacologic agents have become promising treatment options for some patients. At this time, only one drug-the stimulant prodrug lisdexamfetamine-is approved for the treatment of BED. Numerous classes of medications including antidepressants, anticonvulsants, and antiobesity drugs have been explored as off-label treatments for BED with variable success. Although not all patients with BED may be suitable candidates for pharmacotherapy, all patients should be considered for and educated about pharmacologic treatment options. © Copyright 2017 Physicians Postgraduate Press, Inc.

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

PubMed

Russo, Ethan B; Marcu, Jahan

2017-01-01

The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed "pharmacological treasure trove." © 2017 Elsevier Inc. All rights reserved.

Phytochemical and Pharmacological Properties of Gymnema sylvestre: An Important Medicinal Plant

PubMed Central

Tiwari, Pragya; Mishra, B. N.; Sangwan, Neelam S.

2014-01-01

Gymnema sylvestre (Asclepiadaceae), popularly known as “gurmar” for its distinct property as sugar destroyer, is a reputed herb in the Ayurvedic system of medicine. The phytoconstituents responsible for sweet suppression activity includes triterpene saponins known as gymnemic acids, gymnemasaponins, and a polypeptide, gurmarin. The herb exhibits a broad range of therapeutic effects as an effective natural remedy for diabetes, besides being used for arthritis, diuretic, anemia, osteoporosis, hypercholesterolemia, cardiopathy, asthma, constipation, microbial infections, indigestion, and anti-inflammatory. G. sylvestre has good prospects in the treatment of diabetes as it shows positive effects on blood sugar homeostasis, controls sugar cravings, and promotes regeneration of pancreas. The herbal extract is used in dietary supplements since it reduces body weight, blood cholesterol, and triglyceride levels and holds great prospects in dietary as well as pharmacological applications. This review explores the transition of a traditional therapeutic to a modern contemporary medication with an overview of phytochemistry and pharmacological activities of the herb and its phytoconstituents. PMID:24511547

Phytochemical and pharmacological properties of Gymnema sylvestre: an important medicinal plant.

PubMed

Tiwari, Pragya; Mishra, B N; Sangwan, Neelam S

2014-01-01

Gymnema sylvestre (Asclepiadaceae), popularly known as "gurmar" for its distinct property as sugar destroyer, is a reputed herb in the Ayurvedic system of medicine. The phytoconstituents responsible for sweet suppression activity includes triterpene saponins known as gymnemic acids, gymnemasaponins, and a polypeptide, gurmarin. The herb exhibits a broad range of therapeutic effects as an effective natural remedy for diabetes, besides being used for arthritis, diuretic, anemia, osteoporosis, hypercholesterolemia, cardiopathy, asthma, constipation, microbial infections, indigestion, and anti-inflammatory. G. sylvestre has good prospects in the treatment of diabetes as it shows positive effects on blood sugar homeostasis, controls sugar cravings, and promotes regeneration of pancreas. The herbal extract is used in dietary supplements since it reduces body weight, blood cholesterol, and triglyceride levels and holds great prospects in dietary as well as pharmacological applications. This review explores the transition of a traditional therapeutic to a modern contemporary medication with an overview of phytochemistry and pharmacological activities of the herb and its phytoconstituents.

Status of Undergraduate Pharmacology Laboratories in Colleges of Pharmacy in the United States

ERIC Educational Resources Information Center

Katz, Norman L.; And Others

1978-01-01

U.S. colleges of pharmacy were surveyed in 1976 to determine whether a trend exists in continuing, discontinuing, or restructuring laboratory time in pharmaceutical education. Data regarding core undergraduate pharmacology courses, undergraduate pharmacology laboratory status, and pharmacology faculty are presented. (LBH)

An Endocrine Pharmacology Course for the Clinically-Oriented Pharmacy Curriculum

ERIC Educational Resources Information Center

Rahwan, Ralf G.

1976-01-01

In view of trends in clinical pharmacy education, the role of the traditional basic sciences has to be reassessed. An endocrine pharmacology course comprised of 49 clock-hours and open for professional undergraduate and graduate credit is described that blends basic and applied pharmacology. (LBH)

The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

PubMed

White, C Michael

2017-03-01

This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.

A thermodynamic assay to test pharmacological chaperones for Fabry disease.

PubMed

Andreotti, Giuseppina; Citro, Valentina; Correra, Antonella; Cubellis, Maria Vittoria

2014-03-01

The majority of the disease-causing mutations affect protein stability, but not functional sites and are amenable, in principle, to be treated with pharmacological chaperones. These drugs enhance the thermodynamic stability of their targets. Fabry disease, a disorder caused by mutations in the gene encoding lysosomal alpha-galactosidase, represents an excellent model system to develop experimental protocols to test the efficiency of such drugs. The stability of lysosomal alpha-galactosidase under different conditions was studied by urea-induced unfolding followed by limited proteolysis and Western blotting. We measured the concentration of urea needed to obtain half-maximal unfolding because this parameter represents an objective indicator of protein stability. Urea-induced unfolding is a versatile technique that can be adapted to cell extracts containing tiny amounts of wild-type or mutant proteins. It allows testing of protein stability as a function of pH, in the presence or in the absence of drugs. Results are not influenced by the method used to express the protein in transfected cells. Scarce and dispersed populations pose a problem for the clinical trial of drugs for rare diseases. This is particularly true for pharmacological chaperones that must be tested on each mutation associated with a given disease. Diverse in vitro tests are needed. We used a method based on chemically induced unfolding as a tool to assess whether a particular Fabry mutation is responsive to pharmacological chaperones, but, by no means is our protocol limited to this disease. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

The Pharmacological Potential of Mushrooms

PubMed Central

2005-01-01

This review describes pharmacologically active compounds from mushrooms. Compounds and complex substances with antimicrobial, antiviral, antitumor, antiallergic, immunomodulating, anti-inflammatory, antiatherogenic, hypoglycemic, hepatoprotective and central activities are covered, focusing on the review of recent literature. The production of mushrooms or mushroom compounds is discussed briefly. PMID:16136207

Gas chromatograph-mass spectrometer (GC/MS) system for quantitative analysis of reactive chemical compounds

DOEpatents

Grindstaff, Quirinus G.

1992-01-01

Described is a new gas chromatograph-mass spectrometer (GC/MS) system and method for quantitative analysis of reactive chemical compounds. All components of such a GC/MS system external to the oven of the gas chromatograph are programmably temperature controlled to operate at a volatilization temperature specific to the compound(s) sought to be separated and measured.

The Concise Guide to Pharmacology 2013/14: Enzymes

PubMed Central

Alexander, Stephen PH; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Spedding, Michael; Peters, John A; Harmar, Anthony J

2013-01-01

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Enzymes are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates. PMID:24528243

Phytochemistry, pharmacology, and clinical trials of Morus alba.

PubMed

Chan, Eric Wei-Chiang; Lye, Phui-Yan; Wong, Siu-Kuin

2016-01-01

The present review is aimed at providing a comprehensive summary on the botany, utility, phytochemistry, pharmacology, and clinical trials of Morus alba (mulberry or sang shu). The mulberry foliage has remained the primary food for silkworms for centuries. Its leaves have also been used as animal feed for livestock and its fruits have been made into a variety of food products. With flavonoids as major constituents, mulberry leaves possess various biological activities, including antioxidant, antimicrobial, skin-whitening, cytotoxic, anti-diabetic, glucosidase inhibition, anti-hyperlipidemic, anti-atherosclerotic, anti-obesity, cardioprotective, and cognitive enhancement activities. Rich in anthocyanins and alkaloids, mulberry fruits have pharmacological properties, such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-obesity, and hepatoprotective activities. The root bark of mulberry, containing flavonoids, alkaloids and stilbenoids, has antimicrobial, skin-whitening, cytotoxic, anti-inflammatory, and anti-hyperlipidemic properties. Other pharmacological properties of M. alba include anti-platelet, anxiolytic, anti-asthmatic, anthelmintic, antidepressant, cardioprotective, and immunomodulatory activities. Clinical trials on the efficiency of M. alba extracts in reducing blood glucose and cholesterol levels and enhancing cognitive ability have been conducted. The phytochemistry and pharmacology of the different parts of the mulberry tree confer its traditional and current uses as fodder, food, cosmetics, and medicine. Overall, M. alba is a multi-functional plant with promising medicinal properties. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

The Concise Guide to Pharmacology 2013/14: Transporters

PubMed Central

Alexander, Stephen PH; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Spedding, Michael; Peters, John A; Harmar, Anthony J

2013-01-01

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Transporters are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates. PMID:24528242

Clinical Pharmacology and Therapeutics—past, present and future

PubMed Central

Reid, John L.

1997-01-01

Aims To obtain information about the speciality of clinical pharmacology and therapeutics in the United Kingdom. Methods A survey of the views of 26 individuals in academic posts in clinical pharmacology and therapeutics was carried out by postal questionnaire. Response rate was 100%. Results Of 25 assessable responses of 25 centres, there were 35 academic staff of professorial status (median 2, range 0–5) and 61 staff of reader/senior lecturer status (median 2, range 0–5) but only 20 clinical staff in training grades in 19 institutions. All had extensive clinical commitments. Two-thirds of respondents considered that the speciality was stable locally and nationally. However, recruitment of trainees was poor with only 8% of responders having several good applicants for each post and 90% reported that recruitment had deteriorated in the last 5–10 years. Likely good future careers for clinical pharmacologists in training were considered by 75–80% of respondents to likely lie in the pharmaceutical industry or regulatory authorities. Greater flexibility is required to facilitate training in clinical pharmacology and therapeutics. Conclusions Clincal pharmacology and therapeutics in the United Kingdom has a strong academic base but a sub-optimal age structure. Recent experience in recruitment into training posts was disappointing. This may reflect wider problems of recruitment into academic medicine in this country. PMID:9241105

Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology.

PubMed

Zhao, Zheng; Martin, Che; Fan, Raymond; Bourne, Philip E; Xie, Lei

2016-02-18

The recent outbreak of Ebola has been cited as the largest in history. Despite this global health crisis, few drugs are available to efficiently treat Ebola infections. Drug repurposing provides a potentially efficient solution to accelerating the development of therapeutic approaches in response to Ebola outbreak. To identify such candidates, we use an integrated structural systems pharmacology pipeline which combines proteome-scale ligand binding site comparison, protein-ligand docking, and Molecular Dynamics (MD) simulation. One thousand seven hundred and sixty-six FDA-approved drugs and 259 experimental drugs were screened to identify those with the potential to inhibit the replication and virulence of Ebola, and to determine the binding modes with their respective targets. Initial screening has identified a number of promising hits. Notably, Indinavir; an HIV protease inhibitor, may be effective in reducing the virulence of Ebola. Additionally, an antifungal (Sinefungin) and several anti-viral drugs (e.g. Maraviroc, Abacavir, Telbivudine, and Cidofovir) may inhibit Ebola RNA-directed RNA polymerase through targeting the MTase domain. Identification of safe drug candidates is a crucial first step toward the determination of timely and effective therapeutic approaches to address and mitigate the impact of the Ebola global crisis and future outbreaks of pathogenic diseases. Further in vitro and in vivo testing to evaluate the anti-Ebola activity of these drugs is warranted.

Pharmacological modulation of spreading depolarizations.

PubMed

Sánchez-Porras, Renán; Zheng, Zelong; Sakowitz, Oliver W

2015-01-01

Spreading depolarization (SD) is a wave of almost complete depolarization of the neuronal and glial cells. Nowadays there is sufficient evidence demonstrating its pathophysiological effect in migraine with aura, transient global amnesia, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. In these cases, occurrence of SD has been associated with functional neuronal damage, neuronal necrosis, neurological degeneration, and poor clinical outcome. Animal models show that SD can be modulated by drugs that interfere with its initiation and propagation. There are many pharmacological targets that may help to suppress SD occurrence, such as Na⁺, K⁺, Cl⁻, and Ca²⁺ channels; Na⁺/K⁺ -ATPase; gap junctions; and ligand-based receptors, for example, adrenergic, serotonin, sigma-1, calcitonin gene-related peptide, GABAA, and glutamate receptors. In this regard, N-methyl-d-aspartate (NMDA) receptor blockers, in particular, ketamine, have shown promising results. Therefore, theoretically pharmacologic modulation of SD could help diminish its pathological effects.

Pharmacological potential of cerium oxidenanoparticles

NASA Astrophysics Data System (ADS)

Celardo, Ivana; Pedersen, Jens Z.; Traversa, Enrico; Ghibelli, Lina

2011-04-01

Nanotechnology promises a revolution in pharmacology to improve or create ex novo therapies. Cerium oxidenanoparticles (nanoceria), well-known as catalysts, possess an astonishing pharmacological potential due to their antioxidant properties, deriving from a fraction of Ce3+ ions present in CeO2. These defects, compensated by oxygen vacancies, are enriched at the surface and therefore in nanosized particles. Reactions involving redox cycles between the Ce3+ and Ce4+oxidation states allow nanoceria to react catalytically with superoxide and hydrogen peroxide, mimicking the behavior of two key antioxidant enzymes, superoxide dismutase and catalase, potentially abating all noxious intracellularreactive oxygen species (ROS) via a self-regenerating mechanism. Hence nanoceria, apparently well tolerated by the organism, might fight chronic inflammation and the pathologies associated with oxidative stress, which include cancer and neurodegeneration. Here we review the biological effects of nanoceria as they emerge from in vitro and in vivo studies, considering biocompatibility and the peculiar antioxidant mechanisms.

Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer☆

PubMed Central

Moser, Justin C.; Rawal, Malvika; Wagner, Brett A.; Du, Juan; Cullen, Joseph J.; Buettner, Garry R.

2013-01-01

Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors. PMID:24396727

Molecular Pharmacology of δ-Opioid Receptors

PubMed Central

Gendron, Louis; Cahill, Catherine M.; von Zastrow, Mark; Schiller, Peter W.

2016-01-01

Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs’ capacity to engage a multiplicity of canonical and noncanonical G protein–dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management. PMID:27343248

A high throughput geocomputing system for remote sensing quantitative retrieval and a case study

NASA Astrophysics Data System (ADS)

Xue, Yong; Chen, Ziqiang; Xu, Hui; Ai, Jianwen; Jiang, Shuzheng; Li, Yingjie; Wang, Ying; Guang, Jie; Mei, Linlu; Jiao, Xijuan; He, Xingwei; Hou, Tingting

2011-12-01

The quality and accuracy of remote sensing instruments have been improved significantly, however, rapid processing of large-scale remote sensing data becomes the bottleneck for remote sensing quantitative retrieval applications. The remote sensing quantitative retrieval is a data-intensive computation application, which is one of the research issues of high throughput computation. The remote sensing quantitative retrieval Grid workflow is a high-level core component of remote sensing Grid, which is used to support the modeling, reconstruction and implementation of large-scale complex applications of remote sensing science. In this paper, we intend to study middleware components of the remote sensing Grid - the dynamic Grid workflow based on the remote sensing quantitative retrieval application on Grid platform. We designed a novel architecture for the remote sensing Grid workflow. According to this architecture, we constructed the Remote Sensing Information Service Grid Node (RSSN) with Condor. We developed a graphic user interface (GUI) tools to compose remote sensing processing Grid workflows, and took the aerosol optical depth (AOD) retrieval as an example. The case study showed that significant improvement in the system performance could be achieved with this implementation. The results also give a perspective on the potential of applying Grid workflow practices to remote sensing quantitative retrieval problems using commodity class PCs.

Fraxinus: A Plant with Versatile Pharmacological and Biological Activities.

PubMed

Sarfraz, Iqra; Rasul, Azhar; Jabeen, Farhat; Younis, Tahira; Zahoor, Muhammad Kashif; Arshad, Muhammad; Ali, Muhammad

2017-01-01

Fraxinus , a member of the Oleaceae family, commonly known as ash tree is found in northeast Asia, north America, east and western France, China, northern areas of Pakistan, India, and Afghanistan. Chemical constituents of Fraxinus plant include various secoiridoids, phenylethanoids, flavonoids, coumarins, and lignans; therefore, it is considered as a plant with versatile biological and pharmacological activities. Its tremendous range of pharmacotherapeutic properties has been well documented including anticancer, anti-inflammatory, antioxidant, antimicrobial, and neuroprotective. In addition, its bioactive phytochemicals and secondary metabolites can be effectively used in cosmetic industry and as a competent antiaging agent. Fraxinus presents pharmacological effectiveness by targeting the novel targets in several pathological conditions, which provide a spacious therapeutic time window. Our aim is to update the scientific research community with recent endeavors with specifically highlighting the mechanism of action in different diseases. This potentially efficacious pharmacological drug candidate should be used for new drug discovery in future. This review suggests that this plant has extremely important medicinal utilization but further supporting studies and scientific experimentations are mandatory to determine its specific intracellular targets and site of action to completely figure out its pharmacological applications.