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Sample records for pre-clinical pharmacology iftekhar

  1. [Pharmacological properties of vortioxetine and its pre-clinical consequences].

    PubMed

    David, D J; Tritschler, L; Guilloux, J-P; Gardier, A M; Sanchez, C; Gaillard, R

    2016-02-01

    Selective Serotonin Reuptake Inhibitors (SSRIs) are extensively used for the treatment of major depressive disorder (MDD). SSRIs are defined as indirect receptor agonists since the activation of postsynaptic receptors is a consequence of an increase in extracellular concentrations of serotonin (5-HT) mediated by the blockade of serotonin transporter. The activation of some serotoninergic receptors (5-HT1A, post-synaptic, 5-HT1B post-synaptic, 5-HT2B, and 5-HT4), but not all (5-HT1A, pre-synaptic, 5-HT1B pre-synaptic, 5-HT2A, 5-HT2C, 5-HT3, and probably 5-HT6), induces anxiolytic/antidepressive - like effects. Targetting specifically some of them could potentially improve the onset of action and/or efficacy and/or prevent MD relapse. Vortioxetine (Brintellix, 1- [2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a novel multi-target antidepressant drug approved by the Food and Drug Administration (FDA) and by European Medicines Agency. Its properties are markedly different from the extensively prescribed SSRIs. Compared to the SSRIs, vortioxetine is defined as a multimodal antidepressant drug since it is not only a serotonin reuptake inhibitor, but also a 5-HT1D, 5-HT3, 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist and 5-HT1A receptor agonist. This specific pharmacological profile enables vortioxetine to affect not only the serotoninergic and noradrenergic systems, but also the histaminergic, cholinergic, gamma-butyric acid (GABA) ergic and glutamatergic ones. Thus, vortioxetine not only induces antidepressant-like or anxiolytic-like activity but also improves cognitive parameters in several animal models. Indeed, vortioxetine was shown to improve working memory, episodic memory, cognitive flexibility and spatial memory in young adult rodents and also in old animal models. These specific effects of the vortioxetine are of interest considering that cognitive dysfunction is a common comorbidity to MDD. Altogether, even though this molecule still

  2. Pre-clinical pharmacology training in a student-centered veterinary curriculum.

    PubMed

    Buur, Jennifer L

    2009-01-01

    The appropriate use of therapeutics is important to both human and animal health. The field of pharmacology is rapidly progressing such that it is impossible to convey to students every possible piece of information they will need to know throughout their veterinary careers. Instead, it is more important to train students for lifelong and self-directed learning so that they will be able to adapt to the ever-changing pharmaceutical landscape. Western University of Health Sciences College of Veterinary Medicine teaches pharmacology using a student-centered and problem-based curriculum designed to teach students not only the basics of pharmacology and clinical pharmacology, but also the personal skills needed to continue to learn beyond their formal education. The aim of this manuscript is to document the pharmacology curriculum during phase I of the veterinary curriculum. Review of the graduating class of 2010's exposure to pharmacology learning issues reveals broad-based coverage of major functional and mechanistic drug classes as well as peripheral topics, including pharmacokinetics, legal and ethical issues, and dosing regimen calculations. Previous classes have scored well on external examinations leading to a belief that this pharmacology curriculum provides adequate training for graduate veterinarians.

  3. Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences

    PubMed Central

    Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J.; Granero, Luis; Polache, Ana; Zornoza, Teodoro

    2017-01-01

    Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism. PMID:28326026

  4. Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences.

    PubMed

    Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J; Granero, Luis; Polache, Ana; Zornoza, Teodoro

    2017-01-01

    Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism.

  5. The Use of Pharmacological-challenge fMRI in Pre-clinical Research: Application to the 5-HT System

    PubMed Central

    Klomp, Anne; Tremoleda, Jordi L.; Schrantee, Anouk; Gsell, Willy; Reneman, Liesbeth

    2012-01-01

    Pharmacological MRI (phMRI) is a new and promising method to study the effects of substances on brain function that can ultimately be used to unravel underlying neurobiological mechanisms behind drug action and neurotransmitter-related disorders, such as depression and ADHD. Like most of the imaging methods (PET, SPECT, CT) it represents a progress in the investigation of brain disorders and the related function of neurotransmitter pathways in a non-invasive way with respect of the overall neuronal connectivity. Moreover it also provides the ideal tool for translation to clinical investigations. MRI, while still behind in molecular imaging strategies compared to PET and SPECT, has the great advantage to have a high spatial resolution and no need for the injection of a contrast-agent or radio-labeled molecules, thereby avoiding the repetitive exposure to ionizing radiations. Functional MRI (fMRI) is extensively used in research and clinical setting, where it is generally combined with a psycho-motor task. phMRI is an adaptation of fMRI enabling the investigation of a specific neurotransmitter system, such as serotonin (5-HT), under physiological or pathological conditions following activation via administration of a specific challenging drug. The aim of the method described here is to assess brain 5-HT function in free-breathing animals. By challenging the 5-HT system while simultaneously acquiring functional MR images over time, the response of the brain to this challenge can be visualized. Several studies in animals have already demonstrated that drug-induced increases in extracellular levels of e.g. 5-HT (releasing agents, selective re-uptake blockers, etc) evoke region-specific changes in blood oxygenation level dependent (BOLD) MRI signals (signal due to a change of the oxygenated/deoxygenated hemoglobin levels occurring during brain activation through an increase of the blood supply to supply the oxygen and glucose to the demanding neurons) providing an index

  6. [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.

  7. Pre-clinical Models for Oral and Periodontal Reconstructive Therapies

    PubMed Central

    Pellegrini, G.; Seol, Y.J.; Gruber, R.; Giannobile, W.V.

    2009-01-01

    The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Pre-clinical testing has contributed to the recent approval of NMF such as GEM 21S® and INFUSE® bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable pre-clinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use. PMID:19887682

  8. Binge eating in pre-clinical models.

    PubMed

    Rospond, Bartłomiej; Szpigiel, Joanna; Sadakierska-Chudy, Anna; Filip, Małgorzata

    2015-06-01

    Obesity is a globally widespread disease. Approximately 35% of world population has the problem of inappropriate body weight due to sedentary lifestyle, excessive food consumption and the lack of physical activity. In the course of many years, several pharmacological anti-obesity drugs have been discovered. Most of them, however, possess severe side effects. Recent findings suggest that disturbed functioning of the reward system can be involved in the development of obesity. The data coming from clinical and animal studies provide new evidence that links excessive food consumption with compulsive behavior that can lead to binge eating disease occurrence. In this review we discuss most commonly used animal models of binge eating such as restriction/refeeding, limited access and stress schedule model, and related to them neurobiological findings as well. We also present new, anti-obesity drugs, which are characterized by central mechanism of action. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Pre-clinical studies with the GABAergic compounds vigabatrin and tiagabine.

    PubMed

    Sills, Graeme J

    2003-03-01

    In the last decade, nine new antiepileptic drugs have reached the global marketplace. These new agents can be categorised according to their principal mechanisms of action. Vigabatrin and tiagabine are the only new compounds with selective effects on inhibitory neurotransmission. The principal inhibitory neurotransmitter in mammalian brain is gamma-aminobutyric acid (GABA). Both vigabatrin and tiagabine exert their pharmacological effects by reducing the inactivation of GABA. Vigabatrin attenuates the metabolism of GABA by inhibiting the enzyme GABA-transaminase, whereas tiagabine blocks the uptake of GABA from the synaptic cleft by an action on the GAT-1 transporter. These mechanistic differences are borne out in a range of experimental seizure models in which vigabatrin and tiagabine have very different anticonvulsant profiles. Pre-clinical neurotoxicity and pharmacokinetic profiles also differ. Long-term vigabatrin treatment is associated with intramyelinic oedema in white matter tracts of several brain regions and further studies have revealed an accumulation of vigabatrin in the retina. In contrast, it seems that tiagabine does not precipitate any significant neurotoxicity and does not appear to accumulate in the retina. The results of these pre-clinical investigations suggest that vigabatrin and tiagabine are pharmacologically distinct compounds with different anticonvulsant, neurotoxicity and pharmacokinetic profiles. It is possible that they will ultimately prove to have different clinical efficacies and spectra of activity.

  10. Screening for pre-clinical disability in different residential settings.

    PubMed

    Gibson, Kate; Day, Lesley; Hill, Keith D; Jolley, Damien; Newstead, Stuart; Cicuttini, Flavia; Segal, Leonie; Flicker, Leon

    2010-08-03

    Preventing disability and offering effective interventions to older people during early decline in function is most likely to be effective if those most at risk of progressive disablement are able to be identified. Similarly the ability to easily identify a group with similar functional profile from disparate sectors of the community is of significant benefit to researchers. This study aimed to (1) describe the use of a pre-clinical disability screening tool to select a functionally comparable group of older men and women with early functional limitation from different settings, and (2) explore factors associated with function and disability. Self-reported function and disability measured with the Late-Life Function and Disability Instrument along with a range of physical performance measurements were compared across residential settings and gender in a sample of 471 trial participants identified as pre-clinically disabled after being screened with the Fried pre-clinical disability tool. Factors that might lie on the pathway to progressive disablement were identified using multiple linear regression analysis. We found that a sample population, screened for pre-clinical disability, had a functional status and disability profile reflecting early functional limitation, regardless of residential setting or gender. Statistical models identified a range of factors associated with function and disability which explained a greater degree of the variation in function, than disability. We selected a group of people with a comparable function and disability profile, consistent with the pre-clinical stage of disability, from a sample of older Australian men and women from different residential settings using the Fried pre-clinical disability screening tool. The results suggest that the screening tool can be used with greater confidence for research, clinical and population health purposes. Further research is required to examine the validity of the tool. These findings offer

  11. Pre-clinical endodontics: a survey amongst German dental schools.

    PubMed

    Sonntag, D; Bärwald, R; Hülsmann, M; Stachniss, V

    2008-10-01

    To evaluate the state and level of pre-clinical endodontic education in German dental schools and to evaluate differences with regard to intensity and extent of teaching, time devoted to teaching pre-clinical endodontics, personnel resources in teaching and technical equipment. Twenty-eight questionnaires were e-mailed to those in charge of pre-clinical endodontic education in German dental schools. The extent of education, the student-teacher ratio, the teaching content as well as the application of teaching materials and technologies were asked. If, after 4 weeks, no response had been received, the questionnaire was sent out by e-mail again. In the absence of a reply, a phone call was made to the corresponding university to conduct the survey by phone. With feedback from 27 of 28 dental schools, the response rate was 96%. Pre-clinical endodontic education at German universities varied considerably. Theory classes ranged from 5 to 30 h (13.3 h mean), practical classes from 12.5 to 60 h (45.4 h mean). The student to staff ratio varied between 9 : 1 and 30 : 1 (16 : 1 mean). Forty-eight per cent of the universities had a specialist in endodontics or a teacher with a special interest. A dental microscope was available for pre-clinical teaching purposes in 38% of the universities. The majority (63%) of universities taught root canal preparation with rotary nickel titanium instruments. Pre-clinical endodontic education varied considerably between German universities because of differences in programme design, staff and course content.

  12. Quality Assurance in Biobanking for Pre-Clinical Research

    PubMed Central

    Simeon-Dubach, Daniel; Zeisberger, Steffen M.; Hoerstrup, Simon P.

    2016-01-01

    It is estimated that not less than USD 28 billion are spent each year in the USA alone on irreproducible pre-clinical research, which is not only a fundamental loss of investment and resources but also a strong inhibitor of efficiency for upstream processes regarding the translation towards clinical applications and therapies. The issues and cost of irreproducibility has mainly been published on pre-clinical research. In contrast to pre-clinical research, test material is often being transferred into humans in clinical research. To protect treated human subjects and guarantee a defined quality standard in the field of clinical research, the manufacturing and processing infrastructures have to strictly follow and adhere to certain (inter-)national quality standards. It is assumed and suggested by the authors that by an implementation of certain quality standards within the area of pre-clinical research, billions of USD might be saved and the translation phase of promising pre-clinical results towards clinical applications may substantially be improved. In this review, we discuss how an implementation of a quality assurance (QA) management system might positively improve sample quality and sustainability within pre-clinically focused biobank infrastructures. Biobanks are frequently positioned at the very beginning of the biomedical research value chain, and, since almost every research material has been stored in a biobank during the investigated life cycle, biobanking seems to be of substantial importance from this perspective. The role model of a QA-regulated biobank structure can be found in biobanks within the context of clinical research organizations such as in regenerative medicine clusters. PMID:27781023

  13. Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

    PubMed Central

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2015-01-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

  14. Collaborative learning in pre-clinical dental hygiene education.

    PubMed

    Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

    2013-04-01

    Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

  15. Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors.

    PubMed

    Basner-Tschakarjan, Etiena; Bijjiga, Enoch; Martino, Ashley T

    2014-01-01

    Transitioning to human trials from pre-clinical models resulted in the emergence of inhibitory AAV vector immune responses which has become a hurdle for sustained correction. Early animal studies did not predict the full range of host immunity to the AAV vector in human studies. While pre-existing antibody titers against AAV vectors has been a lingering concern, cytotoxic T-cell (CTL) responses against the input capsid can prevent long-term therapy in humans. These discoveries spawned more thorough profiling of immune response to rAAV in pre-clinical models, which have assessed both innate and adaptive immunity and explored methods for bypassing these responses. Many efforts toward measuring innate immunity have utilized Toll-like receptor deficient models and have focused on differential responses to viral capsid and genome. From adaptive studies, it is clear that humoral responses are relevant for initial vector transduction efficiency while cellular responses impact long-term outcomes of gene transfer. Measuring humoral responses to AAV vectors has utilized in vitro neutralizing antibody assays and transfer of seropositive serum to immunodeficient mice. Overcoming antibodies using CD20 inhibitors, plasmapheresis, altering route of delivery and using different capsids have been explored. CTL responses were measured using in vitro and in vivo models. In in vitro assays expansion of antigen-specific T-cells as well as cytotoxicity toward AAV transduced cells can be shown. Many groups have successfully mimicked antigen-specific T-cell proliferation, but actual transgene level reduction and parameters of cytotoxicity toward transduced target cells have only been shown in one model. The model utilized adoptive transfer of capsid-specific in vitro expanded T-cells isolated from immunized mice with LPS as an adjuvant. Finally, the development of immune tolerance to AAV vectors by enriching regulatory T-cells as well as modulating the response pharmacologically has also

  16. Pre-clinical Orthotopic Murine Model of Human Prostate Cancer.

    PubMed

    Shahryari, Varahram; Nip, Hannah; Saini, Sharanjot; Dar, Altaf A; Yamamura, Soichiro; Mitsui, Yozo; Colden, Melissa; Bucay, Nathan; Tabatabai, Laura Z; Greene, Kirsten; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir; Majid, Shahana

    2016-08-29

    To study the multifaceted biology of prostate cancer, pre-clinical in vivo models offer a range of options to uncover critical biological information about this disease. The human orthotopic prostate cancer xenograft mouse model provides a useful alternative approach for understanding the specific interactions between genetically and molecularly altered tumor cells, their organ microenvironment, and for evaluation of efficacy of therapeutic regimens. This is a well characterized model designed to study the molecular events of primary tumor development and it recapitulates the early events in the metastatic cascade prior to embolism and entry of tumor cells into the circulation. Thus it allows elucidation of molecular mechanisms underlying the initial phase of metastatic disease. In addition, this model can annotate drug targets of clinical relevance and is a valuable tool to study prostate cancer progression. In this manuscript we describe a detailed procedure to establish a human orthotopic prostate cancer xenograft mouse model.

  17. Mouse models for pre-clinical drug testing in leukemia.

    PubMed

    Bhatia, Sanil; Daschkey, Svenja; Lang, Franziska; Borkhardt, Arndt; Hauer, Julia

    2016-11-01

    The development of novel drugs which specifically target leukemic cells, with the overall aim to increase complete remission and to reduce toxicity and morbidity, is the most important prerequisite for modern leukemia treatment. In this regard, the current transition rate of potential novel drugs from bench to bedside is remarkably low. Although many novel drugs show promising data in vitro and in vivo, testing of these medications in clinical phase I trials is often sobering with intolerable toxic side effects leading to failure in FDA approval. Areas covered: In this review, the authors discuss the development of murine model generation in the context of targeted therapy development for the treatment of childhood leukemia, aiming to decrease the attrition rate of progressively complex targeted therapies ranging from small molecules to cell therapy. As more complex therapeutic approaches develop, more complex murine models are needed, to recapitulate closely the human phenotype. Expert opinion: Combining xenograft models for efficacy testing and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics and will contribute to the clinical approval of novel compounds. Finally, this approach is likely to increase clinical approval of novel compounds.

  18. HDL and Atherosclerosis Regression: Evidence from Pre-clinical and Clinical Studies

    PubMed Central

    Feig, Jonathan E.; Hewing, Bernd; Smith, Jonathan D.; Hazen, Stanley L.; Fisher, Edward A.

    2014-01-01

    High density lipoprotein particles (HDL) transport, among other molecules, cholesterol (HDL-C). In epidemiologic studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease (CVD). It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, a number of recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased CVD risk, giving rise to a controversy over whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. On balance, the evidence from pre-clinical and (limited) clinical studies show that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. While more research will be needed on basic mechanisms and to establish that these changes translate clinically to reduced CVD events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent, but emphasizes the important distinction between HDL function and plasma levels of HDL-C. PMID:24385513

  19. Clinical and Pre-Clinical Evidence for Functional Interactions of Cannabidiol and Δ(9)-Tetrahydrocannabinol.

    PubMed

    Boggs, Douglas L; Nguyen, Jacques D; Morgenson, Daralyn; Taffe, Michael A; Ranganathan, Mohini

    2017-09-06

    The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.209.

  20. Measuring cognitive outcomes in a pre-clinical bioethics course.

    PubMed

    Fernandes, Ashley K; Borges, Nicole; Rodabaugh, Heather

    2012-05-01

    Medical schools universally accept the idea that bioethics courses are essential components of education, but few studies which measure outcomes (i.e., knowledge or retention) have demonstrated their educational value in the literature. The goal of this study was to examine whether core concepts of a pre-clinical bioethics course were learned and retained. Over the course of 2 years, a pre-test comprising 25 multiple-choice questions was administered to two classes (2008-2010) of first-year medical students prior to the start of a 15-week ethics course, and an identical post-test was administered at the end of the course. A total of 189 students participated. Paired t tests showed a significant difference between pre-test scores and post-test scores. The pre-test average score was 69.8 %, and the post-test average was 82.6 %, an increase of 12.9 % after the ethics course. The pre- and post-test results also suggested a shift in difficulty level of the questions, with students finding identical questions easier after the intervention. Given the increase in post-test scores after the 15-week intervention, the study suggests that core concepts in medical ethics were learned and retained. These results demonstrate that an introductory bioethics course can improve short-term outcomes in knowledge and comprehension, and should provide impetus to educators to demonstrate improved educational outcomes in ethics at higher levels of B.S. Bloom's Taxonomy of Learning.

  1. The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic.

    PubMed

    Makvandi, Mehran; Lieberman, Brian P; LeGeyt, Ben; Hou, Catherine; Mankoff, David A; Mach, Robert H; Pryma, Daniel A

    2016-01-01

    The sigma-2 receptor is a protein with a Heme binding region and is capable of receptor-mediated endocytosis. It is overexpressed in many cancers making it a potential vector for therapeutic drug delivery. Our objective was to introduce an alpha-emitting radionuclide, astatine-211, into a selective sigma-2 ligand moiety to provide cytotoxic capabilities without adversely altering the pharmacological characteristics. In this study we investigated the in vitro/in vivo tumor targeting and estimated dosimetry of alpha-emitting sigma-2 ligand, 5-(astato-(211)At)-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide ((211)At-MM3), in a pre-clinical human breast cancer model. Astatine-211 was produced in a cyclotron and isolated by dry distillation. Radiosynthesis of (211)At-MM3 was performed using a tin precursor through radioastatodestannylation. In vitro sigma-2 binding experiments using (211)At-MM3 were carried out in live EMT6 and MDA-MB-231 breast cancer cells and liver homogenate tissue. In vivo biodistribution experiments were performed using EMT6 mouse breast cancer cells in BALB/c female mice. Approximately 370 kBq of (211)At-MM3 was administered intravenously and at time points of 5 min, 1, 2, 4, 8, and 24 h organs/tissue were harvested. Estimated human dosimetry was extrapolated from biodistribution data using OLINDA/EXM (VU e-Innovations). Astatine-211 was successfully produced and isolated in quantities suitable for in vitro and small animal in vivo experiments. Radiosynthesis of (211)At-MM3 was reproducible with high radiochemical purity. Astatine-211-MM3 exhibited picomolar affinity to the sigma-2 receptor in contrast to the iodinated analog that had nanomolar affinity. Prolonged tumor targeting was measured through biodistribution studies with a maximal tumor to muscle ratio of 9.02 at 4h. Estimated human dosimetry revealed doses of up to 370 MBq in an adult female patient were below organ radiation limits with the potential to

  2. Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

    PubMed

    Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

    2013-03-01

    Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted

  3. Myocardial collagen deposition and inflammatory cell infiltration in cats with pre-clinical hypertrophic cardiomyopathy.

    PubMed

    Khor, K H; Campbell, F E; Owen, H; Shiels, I A; Mills, P C

    2015-02-01

    The histological features of feline hypertrophic cardiomyopathy (HCM) have been well documented, but there are no reports describing the histological features in mild pre-clinical disease, since cats are rarely screened for the disease in the early stages before clinical signs are apparent. Histological changes at the early stage of the disease in pre-clinical cats could contribute to an improved understanding of disease aetiology or progression. The aim of this study was to evaluate the histological features of HCM in the left ventricular (LV) myocardium of cats diagnosed with pre-clinical HCM. Clinically healthy cats with normal (n = 11) and pre-clinical HCM (n = 6) were identified on the basis of echocardiography; LV free wall dimensions (LVFWd) and/or interventricular septal wall (IVSd) dimensions during diastole of 6-7 mm were defined as HCM, while equivalent dimensions <5.5 mm were defined as normal. LV myocardial sections were assessed and collagen content and inflammatory cell infiltrates were quantified objectively. Multifocal areas of inflammatory cell infiltration, predominantly lymphocytes, were observed frequently in the left myocardium of cats with pre-clinical HCM. Tissue from cats with pre-clinical HCM also had a higher number of neutrophils and a greater collagen content than the myocardium of normal cats. The myocardium variably demonstrated other features characteristic of HCM, including arteriolar mural hypertrophy and interstitial fibrosis and, to a lesser extent, myocardial fibre disarray and cardiomyocyte hypertrophy. These results suggest that an inflammatory process could contribute to increased collagen content and the myocardial fibrosis known to be associated with HCM. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  4. Relationships between admissions requirements and pre-clinical and clinical performance in a distributed veterinary curriculum.

    PubMed

    Fuentealba, Carmen; Hecker, Kent G; Nelson, Phil D; Tegzes, John H; Waldhalm, Stephen J

    2011-01-01

    The purpose of this study was twofold: first, to assess the relationships between knowledge-based admission requirements and pre-clinical and clinical performance in a distributed model of veterinary education that uses problem-based learning as the main instruction method in the first two years of the curriculum; second, to compare pre-clinical and clinical performance with performance on the Program for the Assessment of Veterinary Education Equivalence (PAVE) exam. Admissions data including overall GPA, prerequisite GPA, Graduate Record Examination (GRE) score on the Analytical, Analytical Writing, Quantitative, and Verbal sections), veterinary school performance data (GPA for pre-clinical and clinical years), and performance PAVE (taken at the end of second year) were analyzed for two classes (N = 155, 85.8% women and 14.2% men). Overall GPA, prerequisite GPA, and GRE Quantitative and Analytical scores were the best predictors for pre-clinical (years 1 and 2) performance (R = 0.49, 23.5% of the variance), GRE Analytical score was the best predictor for year 3 (pre-clinical and clinical) performance (R = 0.25, 6.3% of the variance), GRE Quantitative score was the best predictor for PAVE performance (R = 0.27, 7.5% of the variance), and GRE Analytical score was the best predictor for clinical performance (year 4; R = 0.21, 4.4% of the variance). PAVE scores correlated with GRE Quantitative scores (r = 0.27, p <.01) and veterinary school performance, with higher correlations in the pre-clinical years (rs = 0.67-0.36, p < .01), providing evidence of convergent validity for the PAVE exam.

  5. Problem-Solving in the Pre-Clinical Curriculum: The Uses of Computer Simulations.

    ERIC Educational Resources Information Center

    Michael, Joel A.; Rovick, Allen A.

    1986-01-01

    Promotes the use of computer-based simulations in the pre-clinical medical curriculum as a means of providing students with opportunities for problem solving. Describes simple simulations of skeletal muscle loads, complex simulations of major organ systems and comprehensive simulation models of the entire human body. (TW)

  6. VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

    ERIC Educational Resources Information Center

    Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

    2016-01-01

    Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

  7. Implementing an assessment-based communication skills training in pre-clinical phase: an IMU experience.

    PubMed

    Lukman, H; Beevi, Z; Mohamadou, G; Yeap, R

    2006-06-01

    This article describes the communication skills programme of the International Medical University, which adopts an integrated medical curriculum. The programme, implemented in February 2005, is based on a systematic framework aimed at teaching students basic interpersonal communication skills progressively and continuously throughout the pre-clinical phase.

  8. Problem-Solving in the Pre-Clinical Curriculum: The Uses of Computer Simulations.

    ERIC Educational Resources Information Center

    Michael, Joel A.; Rovick, Allen A.

    1986-01-01

    Promotes the use of computer-based simulations in the pre-clinical medical curriculum as a means of providing students with opportunities for problem solving. Describes simple simulations of skeletal muscle loads, complex simulations of major organ systems and comprehensive simulation models of the entire human body. (TW)

  9. VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

    ERIC Educational Resources Information Center

    Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

    2016-01-01

    Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

  10. Evaluation of quantitative accuracy in CZT-based pre-clinical SPECT for various isotopes

    NASA Astrophysics Data System (ADS)

    Park, S.-J.; Yu, A. R.; Kim, Y.-s.; Kang, W.-S.; Jin, S. S.; Kim, J.-S.; Son, T. J.; Kim, H.-J.

    2015-05-01

    In vivo pre-clinical single-photon emission computed tomography (SPECT) is a valuable tool for functional small animal imaging, but several physical factors, such as scatter radiation, limit the quantitative accuracy of conventional scintillation crystal-based SPECT. Semiconductor detectors such as CZT overcome these deficiencies through superior energy resolution. To our knowledge, little scientific information exists regarding the accuracy of quantitative analysis in CZT-based pre-clinical SPECT systems for different isotopes. The aim of this study was to assess the quantitative accuracy of CZT-based pre-clinical SPECT for four isotopes: 201Tl, 99mTc, 123I, and 111In. The quantitative accuracy of the CZT-based Triumph X-SPECT (Gamma-Medica Ideas, Northridge, CA, U.S.A.) was compared with that of a conventional SPECT using GATE simulation. Quantitative errors due to the attenuation and scatter effects were evaluated for all four isotopes with energy windows of 5%, 10%, and 20%. A spherical source containing the isotope was placed at the center of the air-or-water-filled mouse-sized cylinder phantom. The CZT-based pre-clinical SPECT was more accurate than the conventional SPECT. For example, in the conventional SPECT with an energy window of 10%, scatter effects degraded quantitative accuracy by up to 11.52%, 5.10%, 2.88%, and 1.84% for 201Tl, 99mTc, 123I, and 111In, respectively. However, with the CZT-based pre-clinical SPECT, the degradations were only 9.67%, 5.45%, 2.36%, and 1.24% for 201Tl, 99mTc, 123I, and 111In, respectively. As the energy window was increased, the quantitative errors increased in both SPECT systems. Additionally, the isotopes with lower energy of photon emissions had greater quantitative error. Our results demonstrated that the CZT-based pre-clinical SPECT had lower overall quantitative errors due to reduced scatter and high detection efficiency. Furthermore, the results of this systematic assessment quantifying the accuracy of these SPECT

  11. Novel target for high-risk neuroblastoma identified in pre-clinical research | Center for Cancer Research

    Cancer.gov

    Pre-clinical research by investigators at the Center for Cancer Research and their colleagues have identified a number of novel epigenetic targets for high-risk neuroblastoma and validated a promising new targeted inhibitor in pre-clinical models.  Read more...

  12. Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration.

    PubMed

    Trachtenberg, Jordan E; Vo, Tiffany N; Mikos, Antonios G

    2015-03-01

    Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth.

  13. Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

    PubMed Central

    Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.

    2011-01-01

    Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-clinical studies. Mdx mice ambulated shorter distances than normal controls, a disparity accentuated after mild exercise. An asymmetric pathophysiology in mdx mice was unmasked with exercise, and peak measurements of serum creatine kinase and myoglobinuria were identified. Our data highlights the necessity to consider asymmetric pathology and timing of biomarkers when testing potential therapies for muscular dystrophy. PMID:22154712

  14. Pre-clinical research in small animals using radiotherapy technology--a bidirectional translational approach.

    PubMed

    Tillner, Falk; Thute, Prasad; Bütof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang

    2014-12-01

    For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

  15. Students' perceptions of pre-clinical endodontic training with artificial teeth compared to extracted human teeth.

    PubMed

    Al-Sudani, D I; Basudan, S O

    2016-08-06

    Artificial teeth have several advantages in pre-clinical endodontics training. This study aimed to compare artificial resin teeth with extracted human teeth, from a student's perspective, during a pre-clinical undergraduate endodontic course for three consecutive academic years (2011-2014). At the end of the course, students completed a questionnaire that included questions about their perceptions of the difficulty of artificial teeth vs. natural teeth and ranked the perceived advantages of artificial teeth. Participants expressed that all procedures, except obturation, were more difficult to perform on artificial teeth than on natural teeth, a result that was due to the hardness of the resin. They ranked the fairness and availability as the best advantages. Artificial teeth have multiple advantages but cannot replace natural teeth. The physical characteristics through the manufacturing material of artificial teeth should be enhanced to increase wider use and acceptance. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration

    PubMed Central

    Trachtenberg, Jordan E.; Vo, Tiffany N.; Mikos, Antonios G.

    2014-01-01

    Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth. PMID:25319726

  17. Tendinopathies and platelet-rich plasma (PRP): from pre-clinical experiments to therapeutic use

    PubMed Central

    Kaux, Jean-François; Drion, Pierre; Croisier, Jean-Louis; Crielaard, Jean-Michel

    2015-01-01

    Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon’s healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed. PMID:26195890

  18. The Flipped Classroom for pre-clinical dental skills teaching - a reflective commentary.

    PubMed

    Crothers, A J; Bagg, J; McKenzie, R

    2017-05-12

    A Flipped Classroom method for teaching of adult practical pre-clinical dental skills was introduced to the BDS curriculum in Glasgow during the 2015/2016 academic session. This report provides a commentary of the first year of employing this method - from the identification of the need to optimise teaching resources, through the planning, implementation and development of the method, with an early indication of performance.

  19. Healthspan Pharmacology

    PubMed Central

    2015-01-01

    Abstract The main goal of this paper is to present the case for shifting the focus of research on aging and anti-aging from lifespan pharmacology to what I like to call healthspan pharmacology, in which the desired outcome is the extension of healthy years of life rather than lifespan alone. Lifespan could be influenced by both genetic and epigenetic factors, but a long lifespan may not be a good indicator of an optimal healthspan. Without improving healthspan, prolonging longevity would have enormous negative socioeconomic outcomes for humans. Therefore, the goal of aging and anti-aging research should be to add healthy years to life and not merely to increase the chronological age. This article summarizes and compares two categories of pharmacologically induced lifespan extension studies in animal model systems from the last two decades—those reporting the effects of pharmacological interventions on lifespan extension alone versus others that include their effects on both lifespan and healthspan in the analysis. The conclusion is that the extrapolation of pharmacological results from animal studies to humans is likely to be more relevant when both lifespan and healthspan extension properties of pharmacological intervention are taken into account. PMID:26444965

  20. Healthspan Pharmacology.

    PubMed

    Jafari, Mahtab

    2015-12-01

    The main goal of this paper is to present the case for shifting the focus of research on aging and anti-aging from lifespan pharmacology to what I like to call healthspan pharmacology, in which the desired outcome is the extension of healthy years of life rather than lifespan alone. Lifespan could be influenced by both genetic and epigenetic factors, but a long lifespan may not be a good indicator of an optimal healthspan. Without improving healthspan, prolonging longevity would have enormous negative socioeconomic outcomes for humans. Therefore, the goal of aging and anti-aging research should be to add healthy years to life and not merely to increase the chronological age. This article summarizes and compares two categories of pharmacologically induced lifespan extension studies in animal model systems from the last two decades-those reporting the effects of pharmacological interventions on lifespan extension alone versus others that include their effects on both lifespan and healthspan in the analysis. The conclusion is that the extrapolation of pharmacological results from animal studies to humans is likely to be more relevant when both lifespan and healthspan extension properties of pharmacological intervention are taken into account.

  1. 'Net Generation' medical students: technological experiences of pre-clinical and clinical students.

    PubMed

    Kennedy, Gregor; Gray, Kathleen; Tse, Justin

    2008-02-01

    While institutions have been keen to integrate information and communication technologies into medical education, little is known about the technological experiences of the current cohort of so-called 'Net Generation' students. This study investigated the technological experiences of medical students and determined whether there were differences between pre-clinical and clinical students. In 2006, 207 pre-clinical and 161 clinical students studying medicine at a major Australian university were surveyed. The questionnaire asked students about their access to, use of and skills with an array of technologies and technology-based tools. The results show that access to mobile phones, memory sticks, desktop computers, and broadband Internet connections was high while technologies such as PDAs were used in very low numbers. A factor analysis of students' use of 39 technology-based tools revealed nine clear activity types, including the 'standard' use of computers and mobile-phones, and the use of the Internet as a pastime activity, for podcasting and for accessing services. A comparison of pre-clinical and clinical students revealed a number of significant differences in terms of the frequency and skill with which these students use distinct technology-based tools. The findings inform current technology-based teaching and learning activities and shed light on potential areas of educational technology development.

  2. Pre-Clinical Medical Students' Exposure to and Attitudes Toward Pharmaceutical Industry Marketing.

    PubMed

    Fein, Eric H; Vermillion, Michelle L; Uijtdehaage, Sebastian H J

    2007-12-01

    Background - Recent studies have examined the exposures and attitudes of physicians and third- and fourth-year medical students toward pharmaceutical industry marketing, but fewer studies have addressed these topics among pre-clinical medical students. Thus, the purpose of this study was to assess pre-clinical students' level of exposure to the pharmaceutical industry and their attitudes toward marketing. Method - First and second-year medical students at UCLA completed a 40-item survey based on previous studies. Results - Over three quarters of pre-clinical students (78.5% or 226 of 288) responded to the survey. Exposure to pharmaceutical industry marketing started very early in medical school. Most second-year students (77%) had received gifts including drug samples after three semesters. Most felt that this would not affect their future prescribing behavior. Conclusions - These findings and findings from related studies, coupled with the students' desire to learn more about the issue, suggest that an early educational intervention addressing this topic may be warranted in American medical schools.

  3. Dissociating emotional and cognitive empathy in pre-clinical and clinical Huntington's disease.

    PubMed

    Maurage, Pierre; Lahaye, Magali; Grynberg, Delphine; Jeanjean, Anne; Guettat, Lamia; Verellen-Dumoulin, Christine; Halkin, Stéphane; Heeren, Alexandre; Billieux, Joël; Constant, Eric

    2016-03-30

    Huntington's disease (HD) is centrally characterized by motor, neurocognitive and psychiatric symptoms, but impaired emotional decoding abilities have also been reported. However, more complex affective abilities are still to be explored, and particularly empathy, which is essential for social relations and is impaired in various psychiatric conditions. This study evaluates empathic abilities and social skills in pre-clinical and clinical HD, and explores the distinction between two empathy sub-components (emotional-cognitive). Thirty-six HD patients (17 pre-clinical) and 36 matched controls filled in the Empathy Quotient Scale, while controlling for psychopathological comorbidities. At the clinical stage of HD, no global empathy impairment was observed but rather a specific deficit for the cognitive sub-component, while emotional empathy was preserved. A deficit was also observed for social skills. Pre-clinical HD was not associated with any empathy deficit. Emotional deficits in clinical HD are thus not limited to basic emotion decoding but extend towards complex interpersonal abilities. The dissociation between impaired cognitive and preserved emotional empathy in clinical HD reinforces the proposal that empathy subtypes are sustained by distinct processes. Finally, these results underline the extent of distinct affective and social impairments in HD and the need to grasp them in clinical contexts. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Is Your System Calibrated? MRI Gradient System Calibration for Pre-Clinical, High-Resolution Imaging

    PubMed Central

    O’Callaghan, James; Wells, Jack; Richardson, Simon; Holmes, Holly; Yu, Yichao; Walker-Samuel, Simon

    2014-01-01

    High-field, pre-clinical MRI systems are widely used to characterise tissue structure and volume in small animals, using high resolution imaging. Both applications rely heavily on the consistent, accurate calibration of imaging gradients, yet such calibrations are typically only performed during maintenance sessions by equipment manufacturers, and potentially with acceptance limits that are inadequate for phenotyping. To overcome this difficulty, we present a protocol for gradient calibration quality assurance testing, based on a 3D-printed, open source, structural phantom that can be customised to the dimensions of individual scanners and RF coils. In trials on a 9.4 T system, the gradient scaling errors were reduced by an order of magnitude, and displacements of greater than 100 µm, caused by gradient non-linearity, were corrected using a post-processing technique. The step-by-step protocol can be integrated into routine pre-clinical MRI quality assurance to measure and correct for these errors. We suggest that this type of quality assurance is essential for robust pre-clinical MRI experiments that rely on accurate imaging gradients, including small animal phenotyping and diffusion MR. PMID:24804737

  5. Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase?

    PubMed

    Salem, Raneem O; Al-Mously, Najwa; AlFadil, Sara; Baalash, Amal

    2016-01-01

    Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). Pre-clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress.

  6. Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models.

    PubMed

    Lobo, D S S; Aleksandrova, L; Knight, J; Casey, D M; el-Guebaly, N; Nobrega, J N; Kennedy, J L

    2015-08-01

    Neurobiological research supports the characterization of disordered gambling (DG) as a behavioral addiction. Recently, an animal model of gambling behavior was developed (rat gambling task, rGT), expanding the available tools to investigate DG neurobiology. We investigated whether rGT performance and associated risk gene expression in the rat's brain could provide cross-translational understanding of the neuromolecular mechanisms of addiction in DG. We genotyped tagSNPs (single-nucleotide polymorphisms) in 38 addiction-related genes in 400 DG and 345 non-DG subjects. Genes with P<0.1 in the human association analyses were selected to be investigated in the animal arm to determine whether their mRNA expression in rats was associated with the rat's performance on the rGT. In humans, DG was significantly associated with tagSNPs in DRD3 (rs167771) and CAMK2D (rs3815072). Our results suggest that age and gender might moderate the association between CAMK2D and DG. Moderation effects could not be investigated due to sample power. In the animal arm, only the association between rGT performance and Drd3 expression remained significant after Bonferroni correction for 59 brain regions. As male rats were used, gender effects could not be investigated. Our results corroborate previous findings reporting the involvement of DRD3 receptor in addictions. To our knowledge, the use of human genetics, pre-clinical models and gene expression as a cross-translation paradigm has not previously been attempted in the field of addictions. The cross-validation of human findings in animal models is crucial for improving the translation of basic research into clinical treatments, which could accelerate neurobiological and pharmacological investigations in addictions.

  7. Spatial resolution properties of digital autoradiography systems for pre-clinical alpha particle imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Tanguay, Jesse; Benard, Francois; Celler, Anna; Ruth, Thomas; Schaffer, Paul

    2017-03-01

    Attaching alpha-emitting radionuclides to cancer-targeting agents increases the anti-tumor effects of targeted cancer therapies. The success of alpha therapy for treating bone metastases has increased interest in using targeted alpha therapy (TAT) to treat a broad spectrum of metastatic cancers. Estimating radiation doses to targeted tumors, including small (<250 μm) clusters of cancer cells, and to non-targeted tissues is critical in the pre-clinical development of TATs. However, accurate quantification of heterogeneous distributions of alpha-emitters in small metastases is not possible with existing pre-clinical in-vivo imaging systems. Ex-vivo digital autoradiography using a scintillator in combination with an image intensifier and a charged coupled device (CCD) has gained interest for pre-clinical ex-vivo alpha particle imaging. We present a simulation-based analysis of the fundamental spatial resolution limits of digital autoradiography systems. Spatial resolution was quantified in terms of the modulation transfer function (MTF) and Wagner's equivalent aperture. We modeled systems operating in either particle-counting (PC) or energy-integrating (EI) mode using a cascaded systems approach that accounts for: 1) the stopping power of alpha particles; 2) the distance alpha particles travel within the scintillator; 3) optical blur, and; 4) binning in detector elements. We applied our analysis to imaging of astatine-211 using an LYSO scintillator with thickness ranging from 10 μm to 20 μm. Our analysis demonstrates that when these systems are operated in particle-counting mode with a centroid-calculation algorithm, the effective apertures of 35 μm can be achieved, which suggests that digital autoradiography may enable quantifying the uptake of alpha emitters in tumors consisting of a few cancer cells. Future work will investigate the image noise and energy-resolution properties of digital autoradiography systems.

  8. Pre-clinical cognitive phenotypes for Alzheimer's disease: a latent profile approach

    PubMed Central

    Hayden, Kathleen M.; Kuchibhatla, Maragatha; Romero, Heather R.; Plassman, Brenda L.; Burke, James R.; Browndyke, Jeffrey N.; Welsh-Bohmer, Kathleen A.

    2013-01-01

    Background Cognitive profiles for pre-clinical Alzheimer's disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. Objective(s) The aim of this work is to evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. Methods The National Alzheimer's Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 NIA funded Alzheimer's Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (n=3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Results Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post-hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Conclusions Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; however comparable results can be achieved with very sensitive tests and contrast scores. PMID:24080384

  9. Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

    PubMed Central

    Xiong, Jianghui; Liu, Juan; Rayner, Simon; Tian, Ze; Li, Yinghui; Chen, Shanguang

    2010-01-01

    The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies. PMID:21085674

  10. [Methotrexate pharmacology].

    PubMed

    Lagarce, L; Zenut, M; Lainé-Cessac, P

    2015-03-01

    Methotrexate is a folic acid analog, which is a thymidylate synthetase and dihydrofolate reductase inhibitor. It is used in oncology, dermatology and rheumatology and off labelling in the treatment of ectopic pregnancies. This paper is a review of methotrexate pharmacology with focus on data concerning ectopic pregnancies.

  11. Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

    NASA Astrophysics Data System (ADS)

    Bass, Christopher Paul

    Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of

  12. Pre-Clinical Rheumatoid Arthritis: Identification, Evaluation and Future Directions for Investigation

    PubMed Central

    Deane, Kevin D.; Norris, Jill M.; Holers, V. Michael

    2010-01-01

    Synopsis Rheumatoid arthritis (RA) likely develops in several phases, beginning with genetic risk, followed by asymptomatic autoimmunity, then finally, clinically-apparent disease. Investigating the phases of disease that exist prior to the onset of symptoms - i.e. the pre-clinical period of RA – will lead to understanding of the important relationships between genetic and environmental factors that may lead to disease, as well as allow for the development of predictive models for disease, and ultimately preventive strategies for RA. PMID:20510231

  13. Pre-clinical drug tests in the mdx mouse as a model of dystrophinopathies: an overview.

    PubMed

    De Luca, Annamaria

    2012-05-01

    Duchenne muscular dystrophy is a lethal X-linked muscle disease affecting 1/3500 live male birth. It results from defects in the subsarcolemmal protein dystrophin, a component of the dystrophin-glycoprotein complex (DGC) which links the intracellular cytoskeleton to the extracellular matrix. The absence of dystrophin leads to muscle membrane fragility, muscle necrosis and gradual replacement of skeletal muscle by fat and connective tissue, through a complex and still unclear cascade of interconnecting events. No cure is currently available, with glucocorticoids being the sole drugs in clinical use in spite of their remarkable side effects. A great effort is devoted at performing pre-clinical tests on the mdx mouse, the mostly used homologous animal model for DMD, with the final aim to identify drugs safer than steroids and able to target the pathogenic mechanisms so to delay pathology progression. This review updates the efforts on this topic, focusing on the open issues about the animal model and highlighting the classes of pharmaceuticals that are more promising as disease-modifiers, while awaiting for more corrective therapies. Although caution is necessary in data transfer from mdx model to DMD patients, the implementation of standard operating procedures and the growing understanding of the pathology may allow a more accurate evaluation of therapeutics, alone or in combination, in pre-clinical settings. A continuous cross-talk with clinicians and patients associations are also crucial points for proper translation of data from mouse to bedside.

  14. A blended learning approach to teaching pre-clinical complete denture prosthodontics.

    PubMed

    Faraone, K L; Garrett, P H; Romberg, E

    2013-02-01

    The current study tested the hypothesis that a blended learning curriculum would develop competency in both pre-clinical laboratory and didactic learning with less direct supervision than in a traditional curriculum, and be positively accepted by both the students and the faculty. With the ability to efficiently deliver course material electronically came the ability to blend the traditional delivery of course material with an asynchronous approach involving online lecture presentations and online laboratory demonstrations. The class was divided into two groups with bench space available to accommodate self-paced learning. All audio-visual and written support materials for both didactic and laboratory procedures were provided to the students at the beginning of the semester on a DVD. These materials included online access through the Blackboard Learning System™. Students' performance and satisfaction in the course as well as the supporting faculty response to the course were very favourable to the new blended curriculum. Making use of the technologically advanced environment, the blended curriculum fostered student-focused learning to develop the didactic and laboratory skills necessary for competency in a pre-clinical setting. © 2012 John Wiley & Sons A/S.

  15. Voxel-level reproducibility assessment of modality independent elastography in a pre-clinical murine model

    NASA Astrophysics Data System (ADS)

    Flint, Katelyn M.; Weis, Jared A.; Yankeelov, Thomas E.; Miga, Michael I.

    2015-03-01

    Changes in tissue mechanical properties, measured non-invasively by elastography methods, have been shown to be an important diagnostic tool, particularly for cancer. Tissue elasticity information, tracked over the course of therapy, may be an important prognostic indicator of tumor response to treatment. While many elastography techniques exist, this work reports on the use of a novel form of elastography that uses image texture to reconstruct elastic property distributions in tissue (i.e., a modality independent elastography (MIE) method) within the context of a pre-clinical breast cancer system.1,2 The elasticity results have previously shown good correlation with independent mechanical testing.1 Furthermore, MIE has been successfully utilized to localize and characterize lesions in both phantom experiments and simulation experiments with clinical data.2,3 However, the reproducibility of this method has not been characterized in previous work. The goal of this study is to evaluate voxel-level reproducibility of MIE in a pre-clinical model of breast cancer. Bland-Altman analysis of co-registered repeat MIE scans in this preliminary study showed a reproducibility index of 24.7% (scaled to a percent of maximum stiffness) at the voxel level. As opposed to many reports in the magnetic resonance elastography (MRE) literature that speak to reproducibility measures of the bulk organ, these results establish MIE reproducibility at the voxel level; i.e., the reproducibility of locally-defined mechanical property measurements throughout the tumor volume.

  16. Assessment of clinical reasoning: A Script Concordance test designed for pre-clinical medical students.

    PubMed

    Humbert, Aloysius J; Johnson, Mary T; Miech, Edward; Friedberg, Fred; Grackin, Janice A; Seidman, Peggy A

    2011-01-01

    The Script Concordance test (SCT) measures clinical reasoning in the context of uncertainty by comparing the responses of examinees and expert clinicians. It uses the level of agreement with a panel of experts to assign credit for the examinee's answers. This study describes the development and validation of a SCT for pre-clinical medical students. Faculty from two US medical schools developed SCT items in the domains of anatomy, biochemistry, physiology, and histology. Scoring procedures utilized data from a panel of 30 expert physicians. Validation focused on internal reliability and the ability of the SCT to distinguish between different cohorts. The SCT was administered to an aggregate of 411 second-year and 70 fourth-year students from both schools. Internal consistency for the 75 test items was satisfactory (Cronbach's alpha = 0.73). The SCT successfully differentiated second- from fourth-year students and both student groups from the expert panel in a one-way analysis of variance (F(2,508) = 120.4; p < 0.0001). Mean scores for students from the two schools were not significantly different (p = 0.20). This SCT successfully differentiated pre-clinical medical students from fourth-year medical students and both cohorts of medical students from expert clinicians across different institutions and geographic areas. The SCT shows promise as an easy-to-administer measure of "problem-solving" performance in competency evaluation even in the beginning years of medical education.

  17. Pre-Clinical Studies of Epigenetic Therapies Targeting Histone Modifiers in Lung Cancer

    PubMed Central

    Huffman, Kenneth; Martinez, Elisabeth D.

    2013-01-01

    Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases. PMID:24058902

  18. Guidelines for reporting pre-clinical in vitro studies on dental materials.

    PubMed

    Faggion, Clovis Mariano

    2012-12-01

    In vitro pre-clinical research is an important aspect of the development of new dental materials and techniques, because it can provide essential information for further testing of therapeutic approaches in clinical trials. These pre-clinical experiments should therefore be reported with the same rigor as studies involving humans. The objectives of this paper were twofold: (a) to search and assess existing guidelines for reporting in vitro studies in dentistry, and (b) to present a methodology for reporting these studies, based on the CONSORT checklist for reporting randomized clinical trials. After a comprehensive search in PubMed database, no guidelines for reporting in vitro studies in dentistry were found. The proposed methodology is presented and the rationale for the choice of fourteen guidelines for producing the different sections of such papers is described in detail. The assessment of a sample of in vitro studies using the proposed guidelines showed that the standards of reporting should be improved. Good standards of reporting of studies are necessary for improvement of efficiency in dental research. The guidelines presented are the first standards for reporting in vitro studies in dentistry. As with the original CONSORT document, the modified checklist is evolving. It should, therefore, be further tested by researchers and the results of these assessments should be used for further improvement of this tool.

  19. Pre-clinical Experience with a Multi-Chordal Patch for Mitral Valve Repair.

    PubMed

    Chawla, Surendra K; Shi, Weiwei; McIver, Bryant V; Vinten-Johansen, Jakob; Frater, Robert W M; Padala, Muralidhar

    2016-04-01

    Surgical repair of flail mitral valve leaflets with neochordoplasty has good outcomes, but implementing it in anterior and bi-leaflet leaflet repair is challenging. Placing and sizing individual neochordae is time consuming and error prone, with persistent localized flail if performed incorrectly. In this study, we report our pre-clinical experience with a novel multi-chordal patch for mitral valve repair. The device was designed based on human cadaver hearts, and laser cut from expanded polytetrafluoroethylene. The prototypes were tested in: (stage 1) ex vivo hearts with leaflet flail (N = 6), (stage 2) acute swine induced with flail (N = 6), and (stage 3) two chronic swine survived to 23 and 120 days (N = 2). A2 and P2 prolapse were successfully repaired with coaptation length restored to 8.1 ± 2.2mm after posterior repair and to 10.2 ± 1.3mm after anterior repair in ex vivo hearts. In vivo, trace regurgitation was seen after repair with excellent patch durability, healing, and endothelialization at euthanasia. A new device for easier mitral repair is reported, with good early pre-clinical outcomes.

  20. Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.

    PubMed

    Iglesias, Ainhoa; García-Nimo, Laura; Cocho de Juan, José A; Moreno, José C

    2014-03-01

    DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review.

  1. A generalizable pre-clinical research approach for orphan disease therapy

    PubMed Central

    2012-01-01

    With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease. PMID:22704758

  2. Pre-clinical medical student experience in a pediatric pulmonary clinic.

    PubMed

    Saba, Thomas G; Hershenson, Marc B; Arteta, Manuel; Ramirez, Ixsy A; Mullan, Patricia B; Owens, Sonal T

    2015-01-01

    Objective Our objective was to evaluate the educational value of introducing pre-clinical medical students to pediatric patients and their families in a subspecialty clinic setting. Methods First- and second-year medical students at the University of Michigan seeking clinical experience outside of the classroom attended an outpatient pediatric pulmonary clinic. Evaluation of the experience consisted of pre- and post-clinic student surveys and post-clinic parent surveys with statements employing a four-point Likert scale as well as open-ended questions. Results Twenty-eight first-year students, 6 second-year students, and 33 parents participated in the study. Post-clinic statement scores significantly increased for statements addressing empathic attitudes, confidence communicating with children and families, comfort in the clinical environment, and social awareness. Scores did not change for statements addressing motivation, a sense of team membership, or confidence with career goals. Students achieved their goals of gaining experience interacting with patients, learning about pulmonary diseases, and observing clinic workflow. Parents felt that they contributed to student education and were not inconvenienced. Conclusions Students identified several educational benefits of exposure to a single pediatric pulmonary clinic. Patients and families were not inconvenienced by the participation of a student. Additional studies are warranted to further investigate the value of this model of pre-clinical medical student exposure to subspecialty pediatrics.

  3. Pre-clinical medical student experience in a pediatric pulmonary clinic

    PubMed Central

    Saba, Thomas G.; Hershenson, Marc B.; Arteta, Manuel; Ramirez, Ixsy A.; Mullan, Patricia B.; Owens, Sonal T.

    2015-01-01

    Objective Our objective was to evaluate the educational value of introducing pre-clinical medical students to pediatric patients and their families in a subspecialty clinic setting. Methods First- and second-year medical students at the University of Michigan seeking clinical experience outside of the classroom attended an outpatient pediatric pulmonary clinic. Evaluation of the experience consisted of pre- and post-clinic student surveys and post-clinic parent surveys with statements employing a four-point Likert scale as well as open-ended questions. Results Twenty-eight first-year students, 6 second-year students, and 33 parents participated in the study. Post-clinic statement scores significantly increased for statements addressing empathic attitudes, confidence communicating with children and families, comfort in the clinical environment, and social awareness. Scores did not change for statements addressing motivation, a sense of team membership, or confidence with career goals. Students achieved their goals of gaining experience interacting with patients, learning about pulmonary diseases, and observing clinic workflow. Parents felt that they contributed to student education and were not inconvenienced. Conclusions Students identified several educational benefits of exposure to a single pediatric pulmonary clinic. Patients and families were not inconvenienced by the participation of a student. Additional studies are warranted to further investigate the value of this model of pre-clinical medical student exposure to subspecialty pediatrics. PMID:26547081

  4. Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models.

    PubMed

    Labrijn, Aran F; Meesters, Joyce I; Bunce, Matthew; Armstrong, Anthony A; Somani, Sandeep; Nesspor, Tom C; Chiu, Mark L; Altintaş, Işil; Verploegen, Sandra; Schuurman, Janine; Parren, Paul W H I

    2017-05-30

    Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab-arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual-targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre-clinical evaluation in immuno-competent rodents.

  5. Pre-clinical functional Magnetic Resonance Imaging Part I: The kidney.

    PubMed

    Zöllner, Frank G; Kalayciyan, Raffi; Chacón-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R

    2014-12-01

    The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging. Copyright © 2014. Published by Elsevier GmbH.

  6. Pre-clinical medical student experience in a pediatric pulmonary clinic.

    PubMed

    Saba, Thomas G; Hershenson, Marc B; Arteta, Manuel; Ramirez, Ixsy A; Mullan, Patricia B; Owens, Sonal T

    2015-01-01

    Our objective was to evaluate the educational value of introducing pre-clinical medical students to pediatric patients and their families in a subspecialty clinic setting. First- and second-year medical students at the University of Michigan seeking clinical experience outside of the classroom attended an outpatient pediatric pulmonary clinic. Evaluation of the experience consisted of pre- and post-clinic student surveys and post-clinic parent surveys with statements employing a four-point Likert scale as well as open-ended questions. Twenty-eight first-year students, 6 second-year students, and 33 parents participated in the study. Post-clinic statement scores significantly increased for statements addressing empathic attitudes, confidence communicating with children and families, comfort in the clinical environment, and social awareness. Scores did not change for statements addressing motivation, a sense of team membership, or confidence with career goals. Students achieved their goals of gaining experience interacting with patients, learning about pulmonary diseases, and observing clinic workflow. Parents felt that they contributed to student education and were not inconvenienced. Students identified several educational benefits of exposure to a single pediatric pulmonary clinic. Patients and families were not inconvenienced by the participation of a student. Additional studies are warranted to further investigate the value of this model of pre-clinical medical student exposure to subspecialty pediatrics.

  7. Pharmacologic vitreolysis.

    PubMed

    Rhéaume, Marc-André; Vavvas, Demetrios

    2010-01-01

    It is now well recognized that vitreous plays an important role in the pathogenesis of various retinal disorders. In many instances it can be addressed with pars plana vitrectomy, although this approach, like any surgery, has its limitations. The search for alternatives or adjunct to surgery has led to the development of pharmacologic vitreolysis. The use of intravitreal agents to alter the vitreous in order to reduce or eliminate its role in disease seems promising. The purpose of this article is to summarize the present knowledge on pharmacologic vitreolysis. A review of the different agents used and of ongoing trials will be presented. Also, current understanding of vitreous structure and its interaction with the retina will be discussed.

  8. Pre-clinical validation of a novel alpha-7 nicotinic receptor radiotracer, [(3)H]AZ11637326: target localization, biodistribution and ligand occupancy in the rat brain.

    PubMed

    Maier, Donna L; Hill, Geraldine; Ding, Min; Tuke, David; Einstein, Emily; Gurley, David; Gordon, John C; Bock, Mary J; Smith, Jeff S; Bialecki, Russell; Eisman, Mark; Elmore, Charles S; Werkheiser, Jennifer L

    2011-01-01

    The alpha-7 neuronal nicotinic receptor is a novel pharmacological target for psychiatric and cognitive disorders. Selective radiotracer tools for pre-clinical receptor occupancy can facilitate the interpretation of the biological actions of small molecules at a target receptor. We discovered a high affinity nicotinic alpha-7 subtype-selective ligand, AZ11637326, with physical-chemical and pharmacokinetic properties suitable for an in vivo radioligand tool. [(3)H]AZ11637326 synthesis by tritiodehalogenation of the corresponding tribromide precursor yielded a high specific activity radiotracer with high affinity alpha-7 receptor binding in the rat hippocampus determined by autoradiography (Kd = 0.2 nM). When [(3)H]AZ11637326 was administered to rats by intravenous bolus, rapid uptake was measured in the brain followed by a 3-4 fold greater specific binding in regions containing the alpha-7 receptor (frontal cortex, hippocampus, hypothalamus and midbrain) when compared to non-target regions (striatum and cerebellum). Systemic administration of the high affinity alpha-7 receptor antagonist, methyllycaconitine (MLA), or pretreatment with alpha-7 selective agonists (AR-R17779, PyrQTC, DBCO-4-POM, and DBCO-3-POM) significantly blocked the alpha-7 specific binding of [(3)H]AZ11637326 in the rat brain. The rank order of ligand ED(50) values for in vivo alpha-7 receptor occupancy in rat hippocampus was: DBCO-4-POM > DBCO-3-POM ∼ MLA > PyrQTC > AR-R17779. The occupancy affinity shift was consistent with in vitro binding affinity in autoradiography. Our studies established the optimal conditions for [(3)H]AZ11637326 in vivo specific binding in the rat brain and support the use of [(3)H]AZ11637326 as a pre-clinical tool for assessment of novel alpha-7 compounds in drug discovery.

  9. Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

    PubMed Central

    2014-01-01

    Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical

  10. Disease Animal Models of TDP-43 Proteinopathy and Their Pre-Clinical Applications

    PubMed Central

    Liu, Yu-Chih; Chiang, Po-Min; Tsai, Kuen-Jer

    2013-01-01

    Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it’s exact role in the pathogenesis and the effective treatments remains unknown. To address this question and to determine a potential treatment for FTLD/ALS, the disease animal models of TDP-43 proteinopathy have been established. TDP-43 proteinopathy is the histologic feature of FTLD/ALS and is associated with disease progression. Studies on the disease animal models with TDP-43 proteinopathy and their pre-clinical applications are reviewed and summarized. Through these disease animal models, parts of TDP-43 functions in physiological and pathological conditions will be better understood and possible treatments for FTLD/ALS with TDP-43 proteinopathy may be identified for possible clinical applications in the future. PMID:24113586

  11. Pre-clinical and clinical development of the first placental malaria vaccine.

    PubMed

    Pehrson, Caroline; Salanti, Ali; Theander, Thor G; Nielsen, Morten A

    2017-06-01

    Malaria during pregnancy is a massive health problem in endemic areas. Placental malaria infections caused by Plasmodium falciparum are responsible for up to one million babies being born with a low birth weight every year. Significant efforts have been invested into preventing the condition. Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical vaccine development. However, all papers from these searches were not systematically included. Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy will contribute to endpoint measurements, further it may require extensive follow-up to establish protection. Future second generation vaccines may overcome the inherent challenges in making an effective placental malaria vaccine.

  12. Carbon nanotube based X-ray sources: Applications in pre-clinical and medical imaging

    NASA Astrophysics Data System (ADS)

    Lee, Yueh Z.; Burk, Laurel; Wang, Ko-Han; Cao, Guohua; Lu, Jianping; Zhou, Otto

    2011-08-01

    Field emission offers an alternate method of electron production for Bremsstrahlung based X-ray tubes. Carbon nanotubes (CNTs) serve as very effective field emitters, allowing them to serve as electron sources for X-ray sources, with specific advantages over traditional thermionic tubes. CNT derived X-ray sources can create X-ray pulses of any duration and frequency, gate the X-ray pulse to any source and allow the placement of many sources in close proximity.We have constructed a number of micro-CT systems based on CNT X-ray sources for applications in small animal imaging, specifically focused on the imaging of the heart and lungs. This paper offers a review of the pre-clinical applications of the CNT based micro-CT that we have developed. We also discuss some of the current and potential clinical applications of the CNT X-ray sources.

  13. The FDA Perspective on Pre-Clinical Testing for High Intensity Focused Ultrasound Devices

    NASA Astrophysics Data System (ADS)

    Harris, Gerald R.

    2006-05-01

    In the U. S., the pre-market review of high intensity focused ultrasound (HIFU) devices is carried out under the authority of the 1976 Medical Device Amendments to the Food, Drug, and Cosmetic Act. Different regulatory mechanisms may apply depending on the complexity of the HIFU device and the indications for use, but in all cases pre-clinical testing is required. This testing typically includes ultrasound field characterization, thermal modeling and measurement, and may include demonstrating the accuracy of targeting and monitoring, if applicable. Because there are no guidance documents or standards for these tests at present, the U.S. Food and Drug Administration (FDA) welcomes working with interested parties to develop acceptable procedures that can be incorporated into the regulatory review process.

  14. HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

    PubMed Central

    Larochelle, Andre; Dunbar, Cynthia E.

    2013-01-01

    The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

  15. Photobiomodulation (PBM) with 20 W at 640 nm: pre-clinical results and propagation model

    NASA Astrophysics Data System (ADS)

    Gendron, Denis J.; Ménage, Alexander R.

    2017-02-01

    A novel treatment modality for photobiomodulation (PBM) is introduced called High Intensity Physio Light (HIPL) Therapy with a light source at 640 nm wavelength, 20 nm bandwidth, and up to 20 W in large 10 cm flat beam. This report exemplifies the efficacy performance of this method with three pre-clinical cases: (i) ankle: sport injury, (ii) foot: bone fractures, and (iii) shoulder: musculoskeletal disorder (MSD). In all cases, the patients systematically experienced a significant pain reduction (by 2 / 10 - 4 / 10) on a visual pain scale. In case (ii) and (iii), a steady improvement and complete recovery of the patient was respectfully obtained. This report describes the experimental treatment condition for each case, and introduces an intensity-dependant propagation model to explain our observation.

  16. Pre-clinical considerations in the assessment of immunogenicity for protein therapeutics.

    PubMed

    Baker, Matthew P; Carr, Francis J

    2010-10-01

    Protein therapeutics offer distinct advantages over other classes of drugs largely due to the high level of target specificity and generally low toxicity. Problems have, however, been encountered with some protein therapeutics inducing undesirable immune responses in patients. This immunogenicity can produce pleiotropic effects including the development of a high affinity B cell-mediated humoral response that is often directed against the therapeutic. Opinions are divided as to the principal causes of clinical immunogenicity and, as a result, this area has been the subject of much research. One thing that has emerged as a result of this intense activity is the development of pre-clinical models that can provide a level of prediction of the immunogenic potential of novel protein therapeutics before administration in man.

  17. T CELLS THERAPIES FOR HIV: PRE-CLINICAL SUCCESSES AND CURRENT CLINICAL STRATEGIES

    PubMed Central

    Patel, Shabnum; Jones, R. Brad; Nixon, Doug F.; Bollard, Catherine M.

    2016-01-01

    While antiretroviral therapy (ART) has been successful in controlling HIV infection, it does not provide a permanent cure solution, requires lifelong treatment, and HIV+ individuals are left with social dysmorphias such as stigma [1, 2]. The recent application of T cells to treat cancer and viral reactivations post-transplant offers a potential strategy to control HIV infection. It is known that naturally occurring HIV-specific T cells can inhibit HIV initially, but this response is not sustained in the majority of people living with HIV (PLWH). Genetically modifying T cells to target HIV, resist infection, and persist in the immunosuppressive environment found in chronically infected HIV+ individuals might provide a therapeutic solution for HIV. This review focuses on successful pre-clinical studies and current clinical strategies using T cell therapy to control HIV infection and mediate a functional cure solution. PMID:27265874

  18. [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.

  19. CFTR pharmacology.

    PubMed

    Zegarra-Moran, Olga; Galietta, Luis J V

    2017-01-01

    CFTR protein is an ion channel regulated by cAMP-dependent phosphorylation and expressed in many types of epithelial cells. CFTR-mediated chloride and bicarbonate secretion play an important role in the respiratory and gastrointestinal systems. Pharmacological modulators of CFTR represent promising drugs for a variety of diseases. In particular, correctors and potentiators may restore the activity of CFTR in cystic fibrosis patients. Potentiators are also potentially useful to improve mucociliary clearance in patients with chronic obstructive pulmonary disease. On the other hand, CFTR inhibitors may be useful to block fluid and electrolyte loss in secretory diarrhea and slow down the progression of polycystic kidney disease.

  20. A novel pre-clinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity

    PubMed Central

    Cheng, Hui; Kari, Gabor; Dicker, Adam P; Rodeck, Ulrich; Koch, Walter J; Force, Thomas

    2011-01-01

    Rationale 1) Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. 2) Sorafenib is a KI of concern since it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of ERKs and signal cardiomyocyte survival in the setting of stress. Objectives 1) Explore the potential use of zebrafish as a pre-clinical model to predict cardiotoxicity. 2) Determine whether sorafenib has associated cardiotoxicity and, if so, define the mechanisms. Methods and Results We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1 which restores ERK activity even in the presence of sorafenib. While growth factor-induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish. Conclusions 1) Zebrafish may be a valuable pre-clinical tool to predict cardiotoxicity. 2) The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act via a here-to-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs. PMID:21998323

  1. The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches

    PubMed Central

    O'Brien, Emma R.; Howarth, Clare; Sibson, Nicola R.

    2013-01-01

    Brain metastasis is a significant clinical problem, yet the mechanisms governing tumor cell extravasation across the blood-brain barrier (BBB) and CNS colonization are unclear. Astrocytes are increasingly implicated in the pathogenesis of brain metastasis but in vitro work suggests both tumoricidal and tumor-promoting roles for astrocyte-derived molecules. Also, the involvement of astrogliosis in primary brain tumor progression is under much investigation. However, translation of in vitro findings into in vivo and clinical settings has not been realized. Increasingly sophisticated resources, such as transgenic models and imaging technologies aimed at astrocyte-specific markers, will enable better characterization of astrocyte function in CNS tumors. Techniques such as bioluminescence and in vivo fluorescent cell labeling have potential for understanding the real-time responses of astrocytes to tumor burden. Transgenic models targeting signaling pathways involved in the astrocytic response also hold great promise, allowing translation of in vitro mechanistic findings into pre-clinical models. The challenging nature of in vivo CNS work has slowed progress in this area. Nonetheless, there has been a surge of interest in generating pre-clinical models, yielding insights into cell extravasation across the BBB, as well as immune cell recruitment to the parenchyma. While the function of astrocytes in the tumor microenvironment is still unknown, the relationship between astrogliosis and tumor growth is evident. Here, we review the role of astrogliosis in both primary and secondary brain tumors and outline the potential for the use of novel imaging modalities in research and clinical settings. These imaging approaches have the potential to enhance our understanding of the local host response to tumor progression in the brain, as well as providing new, more sensitive diagnostic imaging methods. PMID:23596394

  2. Evidence-based medicine in pre-clinical years: a study of early introduction and usefulness

    PubMed Central

    ACHARYA, YOGESH; RAGHAVENDRA RAO, M.V.; ARJA, SATEESH

    2017-01-01

    Introduction: Evidence Based Medicine (EBM) has established itself as a strong predictor of future medical practice by medical students. The purpose of this study was to determine the effectiveness of EBM in pre-clinical years and reflect on self-assessment skill of 4th semester medical students regarding the understanding of EBM and its various determinants. Methods: All of the 4th semester (MD4) medical students at the Avalon University of Medical School, Curacao who had completed their EBM curriculum were asked to voluntarily participate in a cross sectional student survey containing qualitative and quantitative questionnaires in a 10-point scale. The students’ responses were analyzed statistically and the results reported. Results: Twenty-three students participated in the survey. 91% of them reported that EBM had helped them to better understand research process and 95% believed that EBM was necessary to develop clinical skills in the future. 78% of the students agreed that they were provided with enough resources for effective implementation of EBM in the university. All participants (100%) self reported that they could appraise the research articles effectively (mean score 8.26, S.D-1.45). Conclusions: EBM is an integrative and comprehensive way to successfully adopt concepts of acquired medical knowledge for effective medical practice. Early introduction of EBM in preclinical years proved favorable in students and better equipped them with the ability to critically apprehend and appraise new research and innovations in medicine for optimal learning experience. There is a definitive need for scientific and systematic design of the curriculum for early introduction of EBM in pre-clinical years, best suited for the students. The principles should be directed towards further research for the effective implementation of EBM to enhance clinical skills. PMID:28761882

  3. Functional and structural MRI biomarkers to detect pre-clinical neurodegeneration.

    PubMed

    Abdulkadir, Ahmed; Ronneberger, Olaf; Wolf, Robert Christian; Pfleiderer, Bettina; Saft, Carsten; Klöppel, Stefan

    2013-02-01

    The availability of an accurate genetic test to identify Huntington's Disease (HD) in the pre-symptomatic stage makes HD an important model to develop biomarkers for other neurodegenerative diseases, such as pre-clinical Alzheimer's Disease. We reasoned that functional changes, measured by functional MRI (fMRI), would precede gray matter changes and that performing a task specifically affected by the disease would carry the clearest signature. Separate cohorts of HD gene mutations carriers and controls performed four different fMRI tasks, probing functions either primarly affected by the disease (i.e. motor control), higher cognitive functions (i.e. working memory and irritability), or basic sensory functions (i.e. auditory system). With the aim to compare fMRI and structural MRI biomarkers, all subjects underwent an additional high-resolution T1-weighted MRI. Best classification performance was achived from fMRI-based activations with motor sequence tapping and task-induced irritation. Classification performance based on gray matter probability maps was also significantly above chance and similar to that of fMRI. Both were sufficiently informative to separate gene mutation carriers that were on average 17 years before predicted disease onset from controls with up to 80% accuracy. Further analyses showed that classification accuracy was best in regions of interest with low within-group heterogeneity in relation to disease specific changes. Our study indicates that structural and some functional markers can accurately detect pre-clinical neurodegeneration. However, the lower variability and easier processing of the strucutral MRI data make latter the more useful tool for disease detection in a clinical setting.

  4. Trans Apical Mitral Implantation (TAMI) of the Tiara ™ Bio-prosthesis: Pre-Clinical Results

    PubMed Central

    Banai, Shmuel; Verheye, Stefan; Cheung, Anson; Schwartz, Marc; Marko, Alexei; Lane, Randy; Jolicoeur, E. Marc; Garceau, Patrick; Biner, Simon; Tanguay, Jean-Francois; Edelman, Elazer R.; White, Christopher J.

    2015-01-01

    Objectives To describe the pre-clinical evaluation of Trans-Apical Mitral Implantation (TAMI) of the Tiara in preparation for first-in-man implantation. Background The Tiara™ is a trans-catheter self-expanding mitral bio-prosthesis, specifically designed for the complex anatomical configuration of the mitral apparatus. Methods Tiara valves were implanted in an acute porcine model, in a chronic ovine model, and in human cadavers. Results Acute and chronic evaluation demonstrated excellent function and alignment of the valves, with no left ventricular outflow tract (LVOT) obstruction, coronary artery obstruction, or transvalvular gradients. Chronic evaluation of 7 sheep demonstrated clinically stable animals. A mild degree of prosthetic valve regurgitation was seen in 2 of the 7 sheep. Mild to moderate degree of paravalvular leak, which was attributed to this animal model, was observed in 6 of these animals. Cardioscopy and macroscopic evaluation demonstrated stable and secure positioning of the Tiara with no evidence of injury to the ventricular or atrial walls. Pericardial leaflets were free and mobile without calcifications. Implantation of the Tiara valves in human cadaver hearts demonstrated, upon visual inspection, proper anatomic alignment and seating of the valve both at the atrial and at the ventricular aspects of the native mitral apparatus. Conclusions In preparation for the first-in-man trans-catheter mitral valve implantation we report the successful pre-clinical evaluation of the Tiara trans-catheter self-expanding mitral bioprosthetic valve. In porcine and ovine models without mitral regurgitation, trans-apical mitral implantation of the Tiara valve is technically feasible, safe, and results in a stable and well-functioning mitral bioprosthesis. PMID:24556094

  5. Gastrointestinal Pharmacology.

    PubMed

    Saps, Miguel; Miranda, Adrian

    2017-01-01

    There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial. A small study found that cyproheptadine was beneficial in the treatment of FAPDs in children. There are conflicting data regarding amitriptyline. While one small study found a significant benefit in quality of life compared with placebo, a large multicenter study found no benefit compared with placebo. The antidepressant, citalopram, failed to meet the primary outcomes in intention-to-treat and per-protocol analysis. Rifaximin has been shown to be efficacious in the treatment of adults with IBS. Those findings differ from studies in children where no benefit was found compared to placebo. To date, there are no placebo-controlled trials published on the use of linaclotide or lubiprostone in children. Alpha 2 delta ligands such as gabapentin and pregabalin are sometimes used in the care of this group of children, but no clinical trials are available in children with FAPDs. Similarly, novel drugs that have been approved for the care of irritable bowel with diarrhea in adults such as eluxadoline have yet to be studied in children. Little data support the use of most medications commonly used to treat FAPDs in children. More randomized, placebo-controlled studies are needed to assess the efficacy of pharmacological interventions in the treatment of FAPDs in children.

  6. KDI: a wireless power-efficient modular platform for pre-clinical evaluation of implantable neural recording designs.

    PubMed

    Foerster, M; Burdin, F; Seignon, F; Lambert, A; Vasquez, C; Charvet, G

    2014-01-01

    This paper presents a power-efficient modular wireless platform which has been designed for prototyping and pre-clinical evaluations of neural recording implants. This Kit for Designing Implants (KDI) is separated in function specific modules of 34×34mm which can be assembled as needed. Five modules have been designed and optimized for ultra-low power consumption and a protective casing has been designed for pre-clinical trials. Two different wireless modules have been compared and the KDI performances have been evaluated in terms of modularity, wireless throughput and power consumption.

  7. Observations of veterinary medicine students' approaches to study in pre-clinical years.

    PubMed

    Ryan, Marion T; Irwin, Jane A; Bannon, Finian J; Mulholland, Clive W; Baird, Alan W

    2004-01-01

    This study has two purposes. The first is to explore an instrument of evaluation of the approaches to study (deep, strategic, and surface) adopted by students in the pre-clinical years of their veterinary degree program. The second is to examine relationships between these approaches and a broad range of further factors deemed relevant to the veterinary medicine context. We envisage that a greater knowledge of how these students learn will aid curriculum reform in a way that will enrich the learning experience of veterinary students. A questionnaire consisting of the 52-question Approaches to Study Inventory (ASI) and an additional 49 questions relating mainly to teaching, assessment, and study skills was distributed to 215 veterinary medicine (MVB) students in their pre-clinical years of study. Factor analysis was used to ensure that the ASI section of the questionnaire maintained previously reported structure. The internal reliability of the approaches measured was tested using Cronbach alpha analysis. The approaches were described as frequency distributions. Associations between the parameters (deep, strategic, and surface) and 49 additional context-specific factors were investigated using loglinear analysis. (1) Factor analysis revealed that the integrity and structure of the instrument in this context was generally comparable to previous studies. (2) The impact of a high workload was evident in the surface approach, with fear of failure becoming a strong motivating factor and syllabus boundness a widely used strategy. (3) Associations made between the approaches and 49 context-specific factors showed strong associations between both workload and lack of prior knowledge with the surface approach. (4) Grades were associated positively with both the deep and strategic approaches but negatively with the surface approach. (5) A range of learning and study skills were associated positively with the deep and strategic approaches and negatively with the surface

  8. Learning style preferences: A study of pre-clinical medical students in Barbados

    PubMed Central

    OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

    2017-01-01

    Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist

  9. Learning style preferences: A study of pre-clinical medical students in Barbados.

    PubMed

    Ojeh, Nkemcho; Sobers-Grannum, Natasha; Gaur, Uma; Udupa, Alaya; Majumder, Md Anwarul Azim

    2017-10-01

    Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students' learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching

  10. Evaluation of incidence rates in pre-clinical studies using a Williams-type procedure.

    PubMed

    Hothorn, Ludwig A; Sill, Martin; Schaarschmidt, Frank

    2010-01-01

    The analysis of dose-response relationships is a common problem in pre-clinical studies. For example, proportions such as mortality rates and histopathological findings are of particular interest in repeated toxicity studies. Commonly applied designs consist of an untreated control group and several, possibly unequally spaced, dosage groups. The Williams test can be formulated as a multiple contrast test and is a powerful option to evaluate such data. In this paper, we consider simultaneous inference for Williams-type multiple contrasts when the response variable is binomial and sample sizes are only moderate. Approximate simultaneous confidence limits can be constructed using the quantiles of a multivariate normal distribution taking the correlation into account. Alternatively, multiplicity-adjusted p-values can be calculated as well. A simulation study shows that a simple correction based on adding pseudo observations leads to acceptable performance for moderate sample sizes, such as 40 per group. In addition, the calculation of adjusted p-values and approximate power is presented. Finally, the proposed methods are applied to example data from two toxicological studies; the methods are available in an R-package.

  11. A dual-use imaging system for pre-clinical small animal radiation research.

    PubMed

    Meng Li; Xingchi He; Eslami, Sohrab; Ken Kang-Hsin Wang; Bin Zhang; Wong, John; Iordachita, Iulian

    2015-01-01

    The current cone beam computed tomography (CBCT) system on the small animal radiation research platform (SARRP) is less effective in localizing soft-tissue targets. On the contrary, molecular optical imaging techniques, such as bioluminescence tomography (BLT) and fluorescence tomography (FT), can provide high contrast soft tissue images to complement CBCT and offer functional information. In this study, we present a dual-use optical imaging system that enables BLT/FT for both on-board and stand-alone applications. The system consists of a mobile cart and an imaging unit. Multi-projection optical images can be acquired in a range of -90°~90° angles. An optical fiber driven by an X-Y-Z Cartesian stage serves as an excitation light source specifically for FT. Our results show that the accuracy and reproducibility of the system meets the requirements set by the pre-clinical workflow (<;0.1 mm and 0.5 degree error). Preliminary experiments demonstrate the feasibility of bioluminescent imaging in a tissue-simulating phantom with a luminescent source embedded. In a considerable light-tight environment, we can achieve average background optical intensity significantly lower than the luminescent signal (<; 5%).

  12. Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Alsup, Jason W.; Lai, Yurong; Hu, Yiding; Heyde, Bruce R.; Tung, David

    2009-03-01

    Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT), intranasal (IN), or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD) was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN) dosing, and was able to achieve dose dependent lung deposition.

  13. Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

    PubMed

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Borçoi, Aline R; Fernandes, Helaine A; Procópio-Souza, Roberta; Hollais, André W; Santos, Renan; Ribeiro, Luciana T C; Corrêa, Jussara M R M; Talhati, Fernanda; Saito, Luis P; Aramini, Tatiana C F; Kameda, Sonia R; Bittencourt, Lia R A; Tufik, Sergio; Frussa-Filho, Roberto

    2011-10-01

    Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.

  14. Design, calibration and pre-clinical testing of an instrumented tibial tray.

    PubMed

    Heinlein, Bernd; Graichen, Friedmar; Bender, Alwina; Rohlmann, Antonius; Bergmann, Georg

    2007-01-01

    An instrumented tibial tray was developed that enables the measurement of six load components in a total knee arthroplasty (TKA). The design is fully compatible with a commonly available knee arthroplasty product since it uses the original tibial insert and femoral component. Two plates with hollow stems made from titanium alloy are separated by a small gap. Six semiconductor strain gages are used for measuring the load-dependent deformation of the inner hollow stem. A 9-channel telemetry unit with a radio-frequency transmitter is encapsulated hermetically in the cavity of the prosthesis. The telemetry is powered inductively and strain gage signals are transmitted via a small antenna at the tip of the implant. The mean sampling rate is 125Hz. The calibration of the prosthesis resulted in an accuracy better than 2% mean measuring error. Fatigue testing of the implant was performed up to 10 million loading cycles and showed no failure. The pending in vivo application will give further insight into the kinetics of TKA. The measured values will enhance the quality of future pre-clinical testing, numerical modeling in knee biomechanics and the patients' physiotherapy and rehabilitation.

  15. Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

    PubMed Central

    Tse, Gary; Liu, Tong; Li, Ka H. C.; Laxton, Victoria; Chan, Yin W. F.; Keung, Wendy; Li, Ronald A.; Yan, Bryan P.

    2016-01-01

    Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers. PMID:27803673

  16. Perceptions about mental illness among pre-clinical medical students in Trinidad & Tobago.

    PubMed

    Hutchinson, G; Neehall, J E; Simeon, D T; Littlewood, R

    1999-06-01

    Perceptions about mental illness among medical practitioners are likely to determine their capacity to recognise, treat appropriately and refer patients who have mental health problems. It is therefore important that training of medical students in psychiatry is undertaken with knowledge of their attitudes to mental health disorders. We determined the perceptions of 108 pre-clinical medical students (69 males, 39 females; mean age 22 years) toward mental illness in Trinidad & Tobago by analysing their responses to a questionnaire based on a case vignette of a young man with a paranoid psychotic illness. 88% felt that medical treatment in hospital was the best means of treating the illness and 86% suggested that discharge should be conditional on regular visits to a doctor. 89% however opposed the patient's marrying into their families and 85% to his teaching their children. This was associated significantly with having a personal relationship with someone having a mental illness (p < 0.03). Surprisingly, 25% believed that mental illness could be caused by supernatural forces, particularly females who were almost twice as likely as males to express this belief.

  17. Translational research for Parkinson׳s disease: The value of pre-clinical primate models.

    PubMed

    Aron Badin, Romina; Vadori, Marta; Cozzi, Emanuele; Hantraye, Philippe

    2015-07-15

    Animal models have been highly questioned for their ability to predict the efficacy of different therapeutic strategies for neurodegenerative diseases. The increasing number of phase I/II clinical trials that fail to proceed to further stages of drug development has discredited the pertinence of such investigations. However, critical analysis of the data has often revealed errors and partially explained the lack of efficacy, opening the way to a refinement in designing pre-clinical studies. In parallel, many promising methods of drug delivery to the brain such as gene therapy or cell therapy have considerably advanced thanks to the clinical failures in the past 10 years. As methodological advances appear and knowledge becomes available, scientists will be faced with the choice of how to test new strategies or re-test old ones. With the hardening of social views and legislation regarding animal experimentation, there is increasing pressure to find alternative methods of assessment that predict efficacy (such as computational based models), or to perform efficacy trials directly in patients and only safety assays in animals. In this review we will focus on Parkinson׳s disease and on the impact of a body of data issued from NHP studies. We will attempt to critically examine the advantages and limitations of various approaches from the perspective of the animal model used to address specific questions.

  18. An Integrated X-Ray/Optical Tomography System for Pre-clinical Radiation Research

    PubMed Central

    Eslami, S.; Yang, Y.; Wong, J.; Patterson, M. S.; Iordachita, I.

    2013-01-01

    The current Small Animal Radiation Research Platform (SARRP) is poor for localizing small soft tissue targets for irradiation or tumor models growing in a soft tissue environment. Therefore, an imaging method complementary to x-ray CT is required to localize the soft tissue target’s Center of Mass (CoM) to within 1 mm. In this paper, we report the development of an integrated x-ray/bioluminescence imaging/tomography (BLI/BLT) system to provide a pre-clinical, high resolution irradiation system. This system can be used to study radiation effects in small animals under the conebeam computed tomography (CBCT) imaging guidance by adding the bioluminescence imaging (BLI) system as a standalone system which can also be docked onto the SARRP. The proposed system integrates two robotic rotating stages and an x-ray source rated at maximum 130 kVp and having a small variable focal spot. A high performance and low noise CCD camera mounted in a light-tight housing along with an optical filter assembly is used for multi-wavelength BL tomography. A three-mirror arrangement is implemented to eliminate the need of rotating the CCD camera for acquiring multiple views. The mirror system is attached to a motorized stage to capture images in angles between 0–90° (for the standalone system). Camera and CBCT calibration are accomplished. PMID:25745539

  19. Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations.

    PubMed

    Prata, Joana; Santos, Susana G; Almeida, Maria Inês; Coelho, Rui; Barbosa, Mário A

    2017-09-04

    In recent years, evidence supporting a link between inflammation and neuropsychiatric disorders has been mounting. Autism spectrum disorders (ASD) and schizophrenia share some clinical similarities which we hypothesize might reflect the same biological basis, namely, in terms of inflammation. However, the diagnosis of ASD and schizophrenia relies solely on clinical symptoms, and to date, there is no clinically useful biomarker to diagnose or monitor the course of such illnesses.The focus of this review is the central role that inflammation plays in ASD and schizophrenia. It spans from pre-clinical animal models to clinical research and excludes in vitro studies. Four major areas are covered: (1) microglia, the inflammatory brain resident myeloid cells, (2) biomarkers, including circulating cytokines, oxidative stress markers, and microRNA players, known to influence cellular processes at brain and immune levels, (3) effect of anti-psychotics on biomarkers and other predictors of response, and (4) impact of gender on response to immune activation, biomarkers, and response to anti-psychotic treatments.

  20. Extending the theoretical framework for curriculum integration in pre-clinical medical education.

    PubMed

    Vergel, John; Stentoft, Diana; Montoya, Juny

    2017-08-01

    Curriculum integration is widely discussed in medical education but remains ill defined. Although there is plenty of information on logistical aspects of curriculum integration, little attention has been paid to the contextual issues that emerge from its practice and may complicate students' knowledge integration. Therefore, we aimed to uncover how curriculum integration is manifested through context. We collected data from the official curriculum and interviewed ten participants (including curriculum designers, facilitators, and students) in the bachelor's medical program at Aalborg University. We observed various learning activities focused on pre-clinical education. Inspired by grounded theory, we analyzed the information we gathered. The following theoretical constructs emerged after the inductive analysis: 1) curriculum integration complexity is embedded in the institutional learning perspectives; 2) curriculum integration is used to harmonize conflicting learning perspectives in curriculum practice; 3) curriculum integration creates tensions that self-organize its structure; and 4) curriculum integration becomes visible in collaborative learning spaces. These constructs provide a framework for analyzing curriculum integration in the context in which it is meant to appear, which may assist educationalists to gain a more specific understanding of the term. This may enable effective curriculum integration since contextual issues are addressed in addition to the goals specified in the official curriculum.

  1. Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

    PubMed Central

    Brown, Scott A.; Surman, Sherri L.; Sealy, Robert; Jones, Bart G.; Slobod, Karen S.; Branum, Kristen; Lockey, Timothy D.; Howlett, Nanna; Freiden, Pamela; Flynn, Patricia; Hurwitz, Julia L.

    2010-01-01

    Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans. PMID:20407589

  2. Systems Pharmacology

    PubMed Central

    Boran, Aislyn D. W.; Iyengar, Ravi

    2011-01-01

    We examine how physiology and pathophysiology are studied from a systems perspective, using high-throughput experiments and computational analysis of regulatory networks. We describe the integration of these analyses with pharmacology, which leads to new understanding of drug action and enables drug discovery for complex diseases. Network studies of drug-target relationships can serve as an indication on the general trends in the approved drugs and the drug-discovery progress. There is a growing number of targeted therapies approved and in the pipeline, which meets a new set of problems with efficacy and adverse effects. The pitfalls of these mechanistically based drugs are described, along with how a systems view of drug action is increasingly important to uncover intricate signaling mechanisms that play an important part in drug action, resistance mechanisms, and off-target effects. Computational methodologies enable the classification of drugs according to their structures and to which proteins they bind. Recent studies have combined the structural analyses with analysis of regulatory networks to make predictions about the therapeutic effects of drugs for complex diseases and possible off-target effects. PMID:20687178

  3. Vets and Videos: Student Learning from Context-Based Assessment in a Pre-Clinical Science Course

    ERIC Educational Resources Information Center

    Seddon, Jennifer

    2008-01-01

    To increase the perceived relevance of pre-clinical science courses to undergraduates, a context-based assessment item was introduced to a genetics course that occurs early within a five-year veterinary science programme. The aim was to make a direct link between genetic concepts and the future clinical profession of the students. In the…

  4. Time-resolved diffuse optical tomography for non-invasive flap viability assessment: pre-clinical tests on rats

    NASA Astrophysics Data System (ADS)

    Di Sieno, L.; Bettega, G.; Berger, M.; Hamou, C.; Aribert, M.; Dalla Mora, A.; Puszka, A.; Grateau, H.; Contini, D.; Hervé, L.; Coll, J.-L.; Dinten, J.-M.; Pifferi, A.; Planat-Chrétien, A.

    2015-07-01

    We present a new setup for time-resolved diffuse optical tomography based on multiple source-detector acquisitions analysed by means of the Mellin-Laplace transform. The proposed setup has been used to perform pre-clinical measurements on rats in order to show its suitability for non-invasive assessment of flap viability.

  5. Vets and Videos: Student Learning from Context-Based Assessment in a Pre-Clinical Science Course

    ERIC Educational Resources Information Center

    Seddon, Jennifer

    2008-01-01

    To increase the perceived relevance of pre-clinical science courses to undergraduates, a context-based assessment item was introduced to a genetics course that occurs early within a five-year veterinary science programme. The aim was to make a direct link between genetic concepts and the future clinical profession of the students. In the…

  6. Use of primary cultures of human bronchial epithelial cells isolated from cystic fibrosis patients for the pre-clinical testing of CFTR modulators.

    PubMed

    Neuberger, Timothy; Burton, Bill; Clark, Heather; Van Goor, Fredrick

    2011-01-01

    The use of human bronchial epithelial (HBE) cell cultures derived from the bronchi of CF patients offers the opportunity to study the effects of CFTR correctors and potentiators on CFTR function and epithelial cell biology in the native pathological environment. Cultured HBE cells derived from CF patients exhibit many of the morphological and functional characteristics believed to be associated with CF airway disease in vivo, including abnormal ion and fluid transport leading to dehydration of the airway surface and the loss of cilia beating. In addition, they can be generated in sufficient quantities to support routine lab testing of compound potency and efficacy and retain reproducible levels of CFTR function over time. Here we describe the development and validation of the CF HBE pharmacology model and its use to characterize, optimize, and select clinical candidates. It is expected that the pre-clinical testing of CFTR potentiators and correctors using epithelial cell cultures derived from CF patients will help to increase their likelihood of clinical efficacy.

  7. Image quality assessment of a pre-clinical flat-panel volumetric micro-CT scanner

    NASA Astrophysics Data System (ADS)

    Du, Louise Y.; Lee, Ting-Yim; Holdsworth, David W.

    2006-03-01

    Small animal imaging has recently become an area of increased interest because more human diseases can be modeled in transgenic and knockout rodents. Current micro-CT systems are capable of achieving spatial resolution on the order of 10 μm, giving highly detailed anatomical information. However, the speed of data acquisition of these systems is relatively slow, when compared with clinical CT systems. Dynamic CT perfusion imaging has proven to be a powerful tool clinically in detecting and diagnosing cancer, stroke, pulmonary and ischemic heart diseases. In order to perform this technique in mice and rats, quantitative CT images must be acquired at a rate of at least 1 Hz. Recently, a research pre-clinical CT scanner (eXplore Ultra, GE Healthcare) has been designed specifically for dynamic perfusion imaging in small animals. Using an amorphous silicon flat-panel detector and a clinical slip-ring gantry, this system is capable of acquiring volumetric image data at a rate of 1 Hz, with in-plane resolution of 150 μm, while covering the entire thoracic region of a mouse or whole organs of a rat. The purpose of this study was to evaluate the principal imaging performance of the micro-CT system, in terms of spatial resolution, image uniformity, linearity, dose and voxel noise for the feasibility of imaging mice and rats. Our investigations show that 3D images can be obtained with a limiting spatial resolution of 2.7 line pairs per mm and noise of 42 HU, using an acquisition interval of 8 seconds at an entrance dose of 6.4 cGy.

  8. Patient-derived xenograft models of colorectal cancer in pre-clinical research: a systematic review

    PubMed Central

    Brown, Kai M.; Xue, Aiqun; Mittal, Anubhav; Samra, Jaswinder S.; Smith, Ross; Hugh, Thomas J.

    2016-01-01

    AIMS We sought to objectively assess the internal and external validity of patient-derived xenograft (PDX) models as a platform in pre-clinical research into colorectal cancer (CRC). Metastatic disease is the most common cause of death from CRC, and despite significant research, the results of current combination chemotherapy and targeted therapies have been underwhelming for most of this patient group. One of the key factors limiting the success of translational CRC research is the biologically inaccurate models in which new therapies are developed. METHODS We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist and SYRCLE (Systematic Review Centre for Laboratory animal Experimentation) guidelines to search Ovid MEDLINE and Embase databases up to July 2015 to identify studies involving PDX models of CRC where the model had been validated across multiple parameters. Data was extracted including host mouse strain, engraftment rate, site of engraftment, donor tumour source and development of metastases in the model. RESULTS Thirteen articles satisfied the inclusion criteria. There was significant heterogeneity amongst the included studies, but overall the median engraftment rate was high (70%) and PDX models faithfully recapitulated the characteristics of their patient tumours on the microscopic, genetic and functional levels. CONCLUSIONS PDX models of CRC have a reasonable internal validity and a high external validity. Developments in xenografting technology are broadening the applications of the PDX platform. However, the included studies could be improved by standardising reporting standards and closed following the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines. PMID:27517155

  9. Ethnic and social disparities in different types of examinations in undergraduate pre-clinical training.

    PubMed

    Stegers-Jager, K M; Brommet, F N; Themmen, A P N

    2016-12-01

    Medical schools are increasingly faced with a more diverse student population. Generally, ethnic minority students are reported to underperform compared with those from the ethnic majority. However, there are inconsistencies in findings in different types of examinations. Additionally, little is known about the performance of first-generation university students and about performance differences across ethnic minority groups. This study aimed to investigate underperformance across ethnic minority groups and by first-generation university students in different types of written tests and clinical skills examinations during pre-clinical training. A longitudinal prospective cohort study of progress on a 3-year Dutch Bachelor of Medicine course was conducted. Participants included 2432 students who entered the course over a consecutive 6-year period (2008-2013). Compared with Dutch students, the three non-Western ethnic minority groups (Turkish/Moroccan/African, Surinamese/Antillean and Asian) underperformed in the clinical problem solving tests, the language test and the OSCEs. Findings on the theoretical end-of-block tests and writing skills tests, and results for Western minority students were less consistent. Age, gender, pre-university grade point average and additional socio-demographic variables (including first-generation university student, first language, and medical doctor parent) could explain the ethnicity-related differences in theoretical examinations, but not in language, clinical and writing skills examinations. First-generation university students only underperformed in the language test. Apparently, underperformance differs both across ethnic subgroups and between different types of written and clinical examinations. Medical schools should ensure their assessment strategies create a level playing field for all students and explore reasons for underperformance in the clinical and writing skills examinations.

  10. Myeloid-Derived Suppressor Cells in Multiple Myeloma: Pre-Clinical Research and Translational Opportunities

    PubMed Central

    Botta, Cirino; Gullà, Annamaria; Correale, Pierpaolo; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2014-01-01

    Immunosuppressive cells have been reported to play an important role in tumor-progression mainly because of their capability to promote immune-escape, angiogenesis, and metastasis. Among them, myeloid-derived suppressor cells (MDSCs) have been recently identified as immature myeloid cells, induced by tumor-associated inflammation, able to impair both innate and adaptive immunity. While murine MDSCs are usually identified by the expression of CD11b and Gr1, human MDSCs represent a more heterogeneous population characterized by the expression of CD33 and CD11b, low or no HLA-DR, and variable CD14 and CD15. In particular, the last two may alternatively identify monocyte-like or granulocyte-like MDSC subsets with different immunosuppressive properties. Recently, a substantial increase of MDSCs has been found in peripheral blood and bone marrow (BM) of multiple myeloma (MM) patients with a role in disease progression and/or drug resistance. Pre-clinical models recapitulating the complexity of the MM-related BM microenvironment (BMM) are major tools for the study of the interactions between MM cells and cells of the BMM (including MDSCs) and for the development of new agents targeting MM-associated immune-suppressive cells. This review will focus on current strategies for human MDSCs generation and investigation of their immunosuppressive function in vitro and in vivo, taking into account the relevant relationship occurring within the MM–BMM. We will then provide trends in MDSC-associated research and suggest potential application for the treatment of MM. PMID:25538892

  11. Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.

    PubMed

    Forte, Amalia; Rinaldi, Barbara; Berrino, Liberato; Rossi, Francesco; Galderisi, Umberto; Cipollaro, Marilena

    2014-12-01

    Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

  12. Anti-RANKL therapy for bone tumours: Basic, pre-clinical and clinical evidences

    PubMed Central

    Heymann, Dominique

    2012-01-01

    Bone remodelling is related to coordinated phases of bone resorption and bone apposition allowing the maintenance of bone integrity, the phosphocalcic homoeostasis all along the life and consequently the bone adaptation to mechanical constraints or/and to endocrine fluctuations. Unfortunately, bone is a frequent site of tumour development originated from bone cell lineages (primary bone tumours: bone sarcomas) or from nonosseous origins (bone metastases: carcinomas). These tumour cells disrupt the balance between osteoblast and osteoclast activities resulting in a disturbed bone remodelling weakening the bone tissue, in a strongly altered bone microenvironment and consequently facilitating the tumour growth. At the early stage of tumour development, osteoclast differentiation and recruitment of mature osteoclasts are strongly activated resulting in a strong bone matrix degradation and release of numerous growth factors initially stored into this organic/calcified matrix. In turn these soluble factors stimulate the proliferation of tumour cells and exacerbate their migration and their ability to initiate metastases. Because Receptor Activator of NFκB Ligand (RANKL) is absolutely required for in vivo osteoclastogenesis, its role in the bone tumour growth has been immediately pointed out and has consequently allowed the development of new targeted therapies of these malignant diseases. The present review summarises the role of RANKL in the bone tumour microenvironment, the most recent pre-clinical and clinical evidences of its targeting in bone metastases and bone sarcomas. The following sections position RANKL targeted therapy among the other anti-resorptive therapies available and underline the future directions which are currently under investigations. PMID:26909248

  13. A metabonomic approach for mechanistic exploration of pre-clinical toxicology.

    PubMed

    Coen, Muireann

    2010-12-30

    Metabonomics involves the application of advanced analytical tools to profile the diverse metabolic complement of a given biofluid or tissue. Subsequent statistical modelling of the complex multivariate spectral profiles enables discrimination between phenotypes of interest and identifies panels of discriminatory metabolites that represent candidate biomarkers. This review article presents an overview of recent developments in the field of metabonomics with a focus on application to pre-clinical toxicology studies. Recent research investigations carried out as part of the international COMET 2 consortium project on the hepatotoxic action of the aminosugar, galactosamine (galN) are presented. The application of advanced, high-field NMR spectroscopy is demonstrated, together with complementary application of a targeted mass spectrometry platform coupled with ultra-performance liquid chromatography. Much novel mechanistic information has been gleaned on both the mechanism of galN hepatotoxicity in multiple biofluids and tissues, and on the protection afforded by co-administration of glycine and uridine. The simultaneous identification of both the metabolic fate of galN and its associated endogenous consequences in spectral profiles is demonstrated. Furthermore, metabonomic assessment of inter-animal variability in response to galN presents enhanced mechanistic insight on variable response phentoypes and is relevant to understanding wider aspects of individual variability in drug response. This exemplar highlights the analytical and statistical tools commonly applied in metabonomic studies and notably, the approach is applicable to the study of any toxin/drug or intervention of interest. The metabonomic approach holds considerable promise and potential to significantly advance our understanding of the mechanistic bases for adverse drug reactions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. VARK learning preferences and mobile anatomy software application use in pre-clinical chiropractic students.

    PubMed

    Meyer, Amanda J; Stomski, Norman J; Innes, Stanley I; Armson, Anthony J

    2016-05-06

    Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists between preferred learning styles as determined by the validated VARK(©) questionnaire and use of mobile anatomy apps. The majority of the students who completed the VARK questionnaire were multimodal learners with kinesthetic and visual preferences. Sixty-seven percent (73/109) of students owned one or more mobile anatomy apps which were used by 57 students. Most of these students owned one to five apps and spent less than 30 minutes per week using them. Six of the top eight mobile anatomy apps owned and recommended by the students were developed by 3D4Medical. Visual learning preferences were not associated with time spent using mobile anatomy apps (OR = 0.40, 95% CI 0.12-1.40). Similarly, kinesthetic learning preferences (OR = 1.88, 95% CI 0.18-20.2), quadmodal preferences (OR = 0.71, 95% CI 0.06-9.25), or gender (OR = 1.51, 95% CI 0.48-4.81) did not affect the time students' spent using mobile anatomy apps. Learning preferences do not appear to influence students' time spent using mobile anatomy apps. Anat Sci Educ 9: 247-254. © 2015 American Association of Anatomists. © 2015 American Association of Anatomists.

  15. Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir.

    PubMed

    Murphy, Diarmaid J; Desjardins, Delphine; Dereuddre-Bosquet, Nathalie; Brochard, Patricia; Perrot, Ludivine; Pruvost, Alain; Le Grand, Roger; Lagatie, Ole; Vanhooren, Leen; Feyaerts, Maxim; van Roey, Jens; Malcolm, R Karl

    2014-09-01

    Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the pre-clinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir. Macaque rings containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir or 100 mg dapivirine+300 mg darunavir were manufactured and characterized by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28 day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values were calculated. Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present and the release medium. In macaques, serum concentrations of both microbicides were maintained between 10(1) and 10(2) pg/mL. Vaginal fluid levels ranged between 10(3) and 10(4) ng/g and between 10(4) and 10(5) ng/g for dapivirine and darunavir, respectively. Both dapivirine and darunavir showed very similar concentrations in each tissue type; the range of drug tissue concentrations followed the general rank order: vagina (1.8 × 10(3)-3.8 × 10(3) ng/g)  > cervix (9.4 × 10(1)-3.9 × 10(2) ng/g)  > uterus (0-108 ng/g)  > rectum (0-40 ng/g). Measured IC50 values were >2 ng/mL for both compounds. Based on these results, and in light of recent clinical progress of the 25 mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate. © The Author 2014. Published by Oxford University Press on behalf of the British Society for

  16. Pre-Clinical Evaluation of a Novel Nanoemulsion-Based Hepatitis B Mucosal Vaccine

    PubMed Central

    Nigavekar, Shraddha S.; Janczak, Katarzyna W.; Knowlton, Jessica; Scott, Alison J.; Mank, Nicholas; Cao, Zhengyi; Rathinavelu, Sivaprakash; Beer, Michael R.; Wilkinson, J. Erby; Blanco, Luz P.; Landers, Jeffrey J.; Baker, James R.

    2008-01-01

    Background Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg) in a novel nanoemulsion (NE) adjuvant (HBsAg-NE) could be effective with fewer administrations. Methodology and Principal Findings Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/−17 nm) associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached ≥106 titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu). Normalization showed that HBsAg-NE vaccination correlates with a protective immunity equivalent or greater than 1000 IU/ml. Th1 polarized immune response was indicated by IFN-γ and TNF-α cytokine production and elevated levels of IgG2 subclass of HBsAg-specific antibodies. The vaccine retains full immunogenicity for a year at 4°C, 6 months at 25°C and 6 weeks at 40°C. Comprehensive pre-clinical toxicology evaluation demonstrated that HBsAg-NE vaccine is safe and well tolerated in multiple animal models. Conclusions Our results suggest that needle-free nasal immunization with HBsAg-NE could be a safe and effective hepatitis B vaccine, or provide an alternative booster administration for the parenteral hepatitis B vaccines. This vaccine induces a Th1 associated cellular immunity and also may provide therapeutic benefit to patients with chronic hepatitis B infection who lack cellular immune responses to adequately control viral replication. Long

  17. Can revisiting pre-clinical coursework at the end of medical school enhance learning for near-peer teachers?

    PubMed

    Rana, Jasmine

    2016-11-01

    Many medical schools have integrated early clinical skills courses to ease the "pre-clinical" to "clinical" transition for medical students. However, it may also be beneficial for medical students to revisit the pre-clinical basic sciences after their core clerkship rotations to foster a deeper understanding of causal pathways of disease that often take a backseat to clinical management principles during the clerkship experience. To this point, the author reflects on the learning benefits she experienced at the end of medical school when she served as a near-peer teacher in an integrated, organ-based physiology and pathophysiology course for first-year medical students. "Teaching to learn" as a senior medical student may be a way to consolidate and foster deeper understanding of medical knowledge in the post-clerkship period of medical school.

  18. Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe.

    PubMed

    Field, J; Stone, S; Orsini, C; Hussain, A; Vital, S; Crothers, A; Walmsley, D

    2017-06-21

    Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan-European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills. A request to complete an online questionnaire, in English, was sent electronically to skills leads at all Association of Dental Education in Europe member schools. The questionnaire collected information in relation to institution and country, regulatory requirements to demonstrate safety, details of specific pre-clinical skills courses, learning materials and teaching staff. Forty-eight institutions, from 25 European countries responded. Seven countries (n=7, 28%) reported no requirement to demonstrate student operative safety prior to patient treatment. Several core and operative clinical skills are common to the majority of institutions. The most commonly taught core skills related directly to the clinical environment such as cross-infection control and hand washing. The least common were skills that indirectly related to patient care, such as communication skills and working as a team. There are clear differences within European pre-clinical dental education, and greater efforts are needed to demonstrate that all European students are fit to practice before they start treating patients. Learning outcomes, teaching activities and assessment activities of pre-clinical skills should be shared collaboratively to further standardise curricula. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models

    PubMed Central

    Olaciregui, Nagore G.; Barton, Kelly L.; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J.; Tsoli, Maria; Ziegler, David S.; Carcaboso, Angel M.; Becher, Oren J.

    2017-01-01

    Background Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. Methods A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. Results In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Conclusion Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation. PMID

  20. High-Resolution Mutational Profiling Suggests the Genetic Validity of Glioblastoma Patient-Derived Pre-Clinical Models

    PubMed Central

    Yost, Shawn E.; Pastorino, Sandra; Rozenzhak, Sophie; Smith, Erin N.; Chao, Ying S.; Jiang, Pengfei; Kesari, Santosh; Frazer, Kelly A.; Harismendy, Olivier

    2013-01-01

    Recent advances in the ability to efficiently characterize tumor genomes is enabling targeted drug development, which requires rigorous biomarker-based patient selection to increase effectiveness. Consequently, representative DNA biomarkers become equally important in pre-clinical studies. However, it is still unclear how well these markers are maintained between the primary tumor and the patient-derived tumor models. Here, we report the comprehensive identification of somatic coding mutations and copy number aberrations in four glioblastoma (GBM) primary tumors and their matched pre-clinical models: serum-free neurospheres, adherent cell cultures, and mouse xenografts. We developed innovative methods to improve the data quality and allow a strict comparison of matched tumor samples. Our analysis identifies known GBM mutations altering PTEN and TP53 genes, and new actionable mutations such as the loss of PIK3R1, and reveals clear patient-to-patient differences. In contrast, for each patient, we do not observe any significant remodeling of the mutational profile between primary to model tumors and the few discrepancies can be attributed to stochastic errors or differences in sample purity. Similarly, we observe ∼96% primary-to-model concordance in copy number calls in the high-cellularity samples. In contrast to previous reports based on gene expression profiles, we do not observe significant differences at the DNA level between in vitro compared to in vivo models. This study suggests, at a remarkable resolution, the genome-wide conservation of a patient’s tumor genetics in various pre-clinical models, and therefore supports their use for the development and testing of personalized targeted therapies. PMID:23441165

  1. Growth/differentiation factor-5: a candidate therapeutic agent for periodontal regeneration? A review of pre-clinical data.

    PubMed

    Moore, Yolanda R; Dickinson, Douglas P; Wikesjö, Ulf M E

    2010-03-01

    Therapeutic concepts involving the application of matrix, growth and differentiation factors have been advocated in support of periodontal wound healing/regeneration. Growth/differentiation factor-5 (GDF-5), a member of the bone morphogenetic protein family, represents one such factor. The purpose of this review is to provide a background of the therapeutic effects of GDF-5 expressed in various musculoskeletal settings using small and large animal platforms. A comprehensive literature search was conducted to identify all reports in the English language evaluating GDF-5 using the PubMed and Google search engines, and a manual search of the reference lists from the electronically retrieved reports. Two reviewers independently screened the titles and abstracts from a total of 69 reports, 22 of which were identified as pre-clinical (in vivo) evaluations of GDF-5. The full-length article of the 22 pre-clinical reports was then reviewed. Various applications including cranial and craniofacial bone formation, spine fusion, long bone fracture healing, cartilage, and tendon/ligament repair using a variety of small and large animal platforms evaluating GDF-5 as a therapeutic agent were identified. A majority of studies, using biomechanical, radiographic, and histological analysis, demonstrated significant dose-dependent effects of GDF-5. These include increased/enhanced local bone formation, fracture healing/repair, and cartilage and tendon/ligament formation. GDF-5 frequently was shown to accelerate wound maturation. Several studies demonstrated GDF-5 to be a realistic alternative to autograft bone. Studies using pre-clinical models and human histology suggest GDF-5 may also increase/enhance periodontal wound healing/regeneration. GDF-5 appears a promising therapeutic agent for periodontal wound healing/regeneration as GDF-5 supports/accelerates bone and tendon/ligament formation in several musculoskeletal settings including periodontal tissues.

  2. Obesity and use of compensatory strategies to perform common daily activities in pre-clinically disabled older adults.

    PubMed

    Naugle, Kelly M; Higgins, Torrance J; Manini, Todd M

    2012-01-01

    To examine the association between the use of compensatory strategies to successfully complete common daily activities-an indicator of pre-clinical disability-and body mass in pre-clinically disabled older adults. Cross-sectional observational study. Two hundred and fifty-nine pre-clinically disabled older adults defined as having changed the frequency or manner of performing daily tasks without reporting any difficulty. The use of compensatory strategies were objectively evaluated using the Modification (MOD) scale-a reliable and valid scale for assessing the manner in which common daily activities were completed. Height and weight were measured to classify participants into the following body mass index (BMI) categories: (1) normal: 18.5-24.9 kg/m(2), (2) overweight: 25.0-29.9 kg/m(2), (3) obese class I: 30.0-34.9 kg/m(2), and (4) obese class II: 35.0-39.9 kg/m(2). Compared to other BMI categories, individuals with class II obesity demonstrated a significantly higher probability of using ≥1 compensatory strategies when rising from a chair (30 cm height), kneel to stand, stair ascent, stair descent, and supine to stand tasks. When summarized over all tasks, individuals with class II obesity were 18 times more likely to use extensive compensatory strategies (≥6 on MOD scale) compared to normal weight older adults. Similar trends at a lesser magnitude were found in obese and overweight compared to normal weight older adults. Obesity is associated with extensive use of compensatory strategies when performing common daily tasks prior to the onset of perceived difficulty, thus placing them at higher risk of disability compared to their peers with lower body mass. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. Growth/differentiation factor-5: pre-clinical and clinical evaluations of periodontal regeneration and alveolar augmentation--review.

    PubMed

    Lee, Jaebum; Wikesjö, Ulf M E

    2014-08-01

    Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

    PubMed Central

    Johnstone, Daniel; Milward, Elizabeth A.; Berretta, Regina; Moscato, Pablo

    2012-01-01

    Background Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of

  5. Pre-Clinical Study of a Novel Recombinant Botulinum Neurotoxin Derivative Engineered for Improved Safety

    PubMed Central

    Vazquez-Cintron, Edwin; Tenezaca, Luis; Angeles, Christopher; Syngkon, Aurelia; Liublinska, Victoria; Ichtchenko, Konstantin; Band, Philip

    2016-01-01

    Cyto-012 is a recombinant derivative of Botulinum neurotoxin Type A (BoNT/A). It primarily differs from wild type (wt) BoNT/A1 in that it incorporates two amino acid substitutions in the catalytic domain of the light chain (LC) metalloprotease (E224 > A and Y366 > A), designed to provide a safer clinical profile. Cyto-012 is specifically internalized into rat cortical and hippocampal neurons, and cleaves Synaptosomal-Associated Protein 25 (SNAP-25), the substrate of wt BoNT/A, but exhibits slower cleavage kinetics and therefore requires a higher absolute dose to exhibit pharmacologic activity. The pharmacodynamics of Cyto-012 and wt BoNT/A have similar onset and duration of action using the Digital Abduction Assay (DAS). Intramuscular LD50 values for Cyto-012 and wt BoNT/A respectively, were 0.63 ug (95% CI = 0.61, 0.66) and 6.22 pg (95% CI = 5.42, 7.02). ED50 values for Cyto-012 and wt BoNT/A were respectively, 0.030 ug (95% CI = 0.026, 0.034) and 0.592 pg (95% CI = 0.488, 0.696). The safety margin (intramuscular LD50/ED50 ratio) for Cyto-012 was found to be improved 2-fold relative to wt BoNT/A (p < 0.001). The DAS response to Cyto-012 was diminished when a second injection was administered 32 days after the first. These data suggest that the safety margin of BoNT/A can be improved by modulating their activity towards SNAP-25. PMID:27484492

  6. Pre-Clinical Study of a Novel Recombinant Botulinum Neurotoxin Derivative Engineered for Improved Safety.

    PubMed

    Vazquez-Cintron, Edwin; Tenezaca, Luis; Angeles, Christopher; Syngkon, Aurelia; Liublinska, Victoria; Ichtchenko, Konstantin; Band, Philip

    2016-08-03

    Cyto-012 is a recombinant derivative of Botulinum neurotoxin Type A (BoNT/A). It primarily differs from wild type (wt) BoNT/A1 in that it incorporates two amino acid substitutions in the catalytic domain of the light chain (LC) metalloprotease (E224 > A and Y366 > A), designed to provide a safer clinical profile. Cyto-012 is specifically internalized into rat cortical and hippocampal neurons, and cleaves Synaptosomal-Associated Protein 25 (SNAP-25), the substrate of wt BoNT/A, but exhibits slower cleavage kinetics and therefore requires a higher absolute dose to exhibit pharmacologic activity. The pharmacodynamics of Cyto-012 and wt BoNT/A have similar onset and duration of action using the Digital Abduction Assay (DAS). Intramuscular LD50 values for Cyto-012 and wt BoNT/A respectively, were 0.63 ug (95% CI = 0.61, 0.66) and 6.22 pg (95% CI = 5.42, 7.02). ED50 values for Cyto-012 and wt BoNT/A were respectively, 0.030 ug (95% CI = 0.026, 0.034) and 0.592 pg (95% CI = 0.488, 0.696). The safety margin (intramuscular LD50/ED50 ratio) for Cyto-012 was found to be improved 2-fold relative to wt BoNT/A (p < 0.001). The DAS response to Cyto-012 was diminished when a second injection was administered 32 days after the first. These data suggest that the safety margin of BoNT/A can be improved by modulating their activity towards SNAP-25.

  7. Validation and reproducibility assessment of modality independent elastography in a pre-clinical model of breast cancer

    NASA Astrophysics Data System (ADS)

    Weis, Jared A.; Kim, Dong K.; Yankeelov, Thomas E.; Miga, Michael I.

    2014-03-01

    Clinical observations have long suggested that cancer progression is accompanied by extracellular matrix remodeling and concomitant increases in mechanical stiffness. Due to the strong association of mechanics and tumor progression, there has been considerable interest in incorporating methodologies to diagnose cancer through the use of mechanical stiffness imaging biomarkers, resulting in commercially available US and MR elastography products. Extension of this approach towards monitoring longitudinal changes in mechanical properties along a course of cancer therapy may provide means for assessing early response to therapy; therefore a systematic study of the elasticity biomarker in characterizing cancer for therapeutic monitoring is needed. The elastography method we employ, modality independent elastography (MIE), can be described as a model-based inverse image-analysis method that reconstructs elasticity images using two acquired image volumes in a pre/post state of compression. In this work, we present preliminary data towards validation and reproducibility assessment of our elasticity biomarker in a pre-clinical model of breast cancer. The goal of this study is to determine the accuracy and reproducibility of MIE and therefore the magnitude of changes required to determine statistical differences during therapy. Our preliminary results suggest that the MIE method can accurately and robustly assess mechanical properties in a pre-clinical system and provide considerable enthusiasm for the extension of this technique towards monitoring therapy-induced changes to breast cancer tissue architecture.

  8. [Application of role-play simulation in pre-clinical practice of the fourth grade students in department of endodontics].

    PubMed

    Zhu, Lin-lin; Qiu, Li-hong; Qu, Liu; Xue, Ming; Yan, Lu

    2014-10-01

    To apply role- play simulation in pre-clinical practice of the fourth grade students in department of endodontics. Thirty-two students were randomly divided into 2 groups, there were 16 students in each group. Students in one group were taught with role-play simulation while the other group with lecture-based learning method. The teaching effect was measured with examination and questionnaire survey. The data was analyzed by using SPSS 17.0 software package. There were no significant differences in basic knowledge, case analysis and oral examination between 2 groups (P>0.05), but there was significant difference in history taking and medical records writing, practical examination and total scores between 2 groups (P<0.05). The role-play simulation was generally approved by both teachers and students in experimental group. The abilities of the fourth grade students can be developed by role-play simulation in different aspects. Role-play simulation can be applied in pre-clinical practice of the fourth grade students in department of endodontics.

  9. The influence of the cage environment on rodent physiology and behavior: Implications for reproducibility of pre-clinical rodent research.

    PubMed

    Toth, Linda A

    2015-08-01

    The reproducibility of pre-clinical research is an important concern that is now being voiced by constituencies that include the National Institutes of Health, the pharmaceutical industry, Congress, the public and the scientific community. An important facet of performing and publishing well-controlled reproducible pre-clinical research is to stabilize and more completely define the environment of the animal subjects. Scientists who use rodents in research generally recognize the importance of maintaining a stable animal environment. However, despite a theoretical and general awareness of these issues, many may lack a true appreciation of how significantly even seemingly minor variations in the environment can affect research outcomes. The purpose of this article is to help investigators gain a more comprehensive and substantiated understanding of the potentially significant impact of even seemingly minor environmental changes on the animals and the data. An important caveat to this article is that the examples presented were selected from a very large literature, admittedly in order to illustrate certain points. The goal of this article is not to provide an overview of the entire literature on how the environment affects rodents but rather to make preclinical scientists more aware of how these factors can potentially influence the experimental data and contribute to poor reproducibility of research. Copyright © 2015. Published by Elsevier Inc.

  10. Pre-clinical safety assessment of Ad[I/PPT-E1A], a novel oncolytic adenovirus for prostate cancer.

    PubMed

    Schenk, Ellen; Essand, Magnus; Kraaij, Robert; Adamson, Rachel; Maitland, Norman; Bangma, Chris H

    2014-02-18

    Prostate cancer is the most common malignancy in the Western world. Patients can only be cured when the tumour has not metastasised outside the prostate. However, treatment with curative intent fails in a significant number of men, often resulting in untreatable progressive disease with a fatal outcome. Oncolytic adenovirus therapy may be a promising adjuvant treatment to reduce local failure or the outgrowth of micrometastatic disease. Within the European gene therapy consortium GIANT, we have developed a novel prostate-specific oncolytic adenovirus: Ad[I/PPT-E1A] that specifically kills prostate cells via prostate-specific replication. This paper describes the clinical development of Ad[I/PPT-E1A] with particular reference to the pre-clinical safety assessment of this novel virus. The pre-clinical safety assessment involved an efficacy study in a human orthotopic xenograft mouse model, a specificity study in human primary cells and a toxicity study in normal mice. These studies confirmed that Ad[I/PPT-E1A] efficiently kills prostate tumour cells in vivo, is not harmful to other organs and is well-tolerated in mice after systemic delivery. The safety, as well as the immunological effects of Ad[I/PPT-E1A] as a local adjuvant therapy will now be studied in a phase I dose-escalating trial in patients with localised prostate cancer who are scheduled for curative radical prostatectomy and can be used as an updated paradigm for similar therapeutic viruses.

  11. Integration of internet-based genetic databases into the medical school pre-clinical and clinical curriculum.

    PubMed

    Waggoner, Darrel J; Martin, Christa Lese

    2006-06-01

    Over the past several years, the field of medical genetics has continued to expand and is now impacting a broad range of medical care, mainly due to rapid advances in genetic technology and information generated by the Human Genome Project. Physicians from multiple disciplines will need to become familiar with genetic principles, and the availability of genetic databases on the internet is a valuable resource for medical students and physicians. To integrate these tools into medical student training, the University of Chicago Pritzker School of Medicine set out to develop multiple, interactive, case-based, educational sessions in the pre-clinical and clinical curriculum, designed to reinforce basic principles taught in the pre-clinical genetics class and demonstrate the usefulness of genetic information accessible via the internet in the clinical setting. Two interactive sessions and a self-assessment exercise were developed. The sessions took place in a computer classroom where each student had access to the internet and could work independently. The sessions used case-based scenarios to help students become familiar with internet based resources and demonstrate how genetic information can affect medical care. The sessions were well received by the student participants with 99% agreeing that the material was useful and important to clinical medicine. In a follow-up questionnaire 1/3 of the students reported using the databases presented during class in a clinical setting.

  12. 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.

  13. Principles of safety pharmacology.

    PubMed

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

    2008-08-01

    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.).

  14. Effects of Brief Psychoeducational Program on Stigma in Malaysian Pre-clinical Medical Students: A Randomized Controlled Trial.

    PubMed

    Fernandez, Aaron; Tan, Kit-Aun; Knaak, Stephanie; Chew, Boon How; Ghazali, Sazlina Shariff

    2016-12-01

    If presented with serious mental illness (SMI), individuals' low help-seeking behaviors and poor adherence to treatment are associated with negative stereotypes and attitudes of healthcare providers. In this study, we examined the effects of a brief psychoeducational program on reducing stigma in pre-clinical medical students. One hundred and two pre-clinical medical students (20-23 years old) were randomly assigned to face-to-face contact + educational lecture (n = 51) condition or video-based contact + educational lecture (n = 51) condition. Measures of pre-clinical medical students' mental illness-related stigma using the Opening Minds Stigma Scale for Health Care Providers (OMS-HC) were administered at pre-, post-treatment, and 1-month follow-up. A 2 (condition: face-to-face contact + educational lecture, video-based contact + educational lecture) by 3 (time: pre-treatment, post-treatment, and 1-month follow-up) mixed model MANOVA was conducted on the Attitudes, Disclosure and Help-Seeking, and Social Distance OMS-HC subscales. Participants' scores on all subscales changed significantly across time, regardless of conditions. To determine how participants' scores changed significantly over time on each subscale, Bonferroni follow-up comparisons were performed to access pairwise differences for the main effect of time. Specifically, pairwise comparisons produced a significant reduction in Social Distance subscale between pre-treatment and post-treatment and between pre-treatment and 1-month follow-up, and a significant increase between post-treatment and 1-month follow-up, regardless of conditions. With respect to the Attitudes and Disclosure and Help-Seeking subscales, pairwise comparisons produced a significant reduction in scores between pre-treatment and post-treatment and a significant increase between post-treatment and 1-month follow-up. Our findings provide additional evidence that educational lecture on mental illness, coupled

  15. Scientific evidence for therapeutic effects of Chinese prescription Kangen-karyu from pre-clinical animal experiments.

    PubMed

    Yokozawa, Takako; Park, Chan Hum; Matsumoto, Kinzo

    2017-01-26

    Chinese prescription Kangen-karyu, comprised of six crude drugs, has received much attention due to its numerous biological activities. The present study reports therapeutic evidence for Kangen-karyu from pre-clinical animal experiments related to human diseases. Kangen-karyu showed beneficial effects on type 1 diabetes and related complications through the suppression of protein expression related to advanced glycation endproducts and oxidative stress. Kangen-karyu reduced oxidative stress via the regulation of dyslipidemia, and also exerted a renoprotective effect mainly through its antioxidant properties during the development of diabetic nephropathy in type 2 diabetes. In addition, Kangen-karyu showed neuroprotective effects by attenuating the spatial memory impairment and neuronal death induced by diabetes. Kangen-karyu counteracted oxidative stress and ameliorated tissue damage possibly associated with aging. These findings provide scientific evidence to explain the efficacy of Kangen-karyu based on its underlying therapeutic effects.

  16. The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds.

    PubMed

    Morphy, Richard

    2006-05-18

    The target families of greatest interest in drug discovery can be differentiated on the basis of the physicochemical properties of their pre-clinical ligands. The ligands for peptidergic targets, such as peptide GPCRs and integrin receptors, possess significantly higher median property values than those for aminergic targets, such as monoamine transporters and GPCRs. The ligands for peptide GPCRs were found to be less efficient, in terms of their binding energy per unit of molecular weight or lipophilicity, than ligands for monoamine GPCRs. The changes in the property values during the optimization process were found to vary only slightly across the target families, with the main determinant of the drug-likeness of the optimized compounds being the profile of the starting compounds. Agonists for monoamine GPCRs, opioid receptors and ion channels were typically smaller and less lipophilic than the antagonists, but there was no difference between the agonists and the antagonists for peptide GPCRs and nuclear receptors.

  17. Quantitative spectrally resolved intraoperative fluorescence imaging for neurosurgical guidance in brain tumor surgery: pre-clinical and clinical results

    NASA Astrophysics Data System (ADS)

    Valdés, Pablo A.; Jacobs, Valerie L.; Leblond, Frederic; Wilson, Brian C.; Paulsen, Keith D.; Roberts, David W.

    2014-03-01

    Fluorescence-guidance is a useful adjunct to maximize brain tumor resection but current commercial systems are limited by subjective assessment of fluorescence, low sensitivity and non-spectrally-resolved detection. We present a quantitative, spectrally-resolved system integrated onto a commercial neurosurgical microscope that performs spectrallyresolved detection and corrects for effects of tissue optical absorption and scattering on the detected fluorescence signal to image the true fluorophore concentration. Pre-clinical studies in rodent glioma models using multiple fluorophores (PpIX, fluorescein) and clinical studies demonstrate improved residual tumor tissue detection. This quantitative, spectrally-resolved technique opens the door to simultaneous image-guided surgery of multiple fluorophores in the visible and near infrared.

  18. Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

    PubMed Central

    Schütte, Moritz; Risch, Thomas; Abdavi-Azar, Nilofar; Boehnke, Karsten; Schumacher, Dirk; Keil, Marlen; Yildiriman, Reha; Jandrasits, Christine; Borodina, Tatiana; Amstislavskiy, Vyacheslav; Worth, Catherine L.; Schweiger, Caroline; Liebs, Sandra; Lange, Martin; Warnatz, Hans- Jörg; Butcher, Lee M.; Barrett, James E.; Sultan, Marc; Wierling, Christoph; Golob-Schwarzl, Nicole; Lax, Sigurd; Uranitsch, Stefan; Becker, Michael; Welte, Yvonne; Regan, Joseph Lewis; Silvestrov, Maxine; Kehler, Inge; Fusi, Alberto; Kessler, Thomas; Herwig, Ralf; Landegren, Ulf; Wienke, Dirk; Nilsson, Mats; Velasco, Juan A.; Garin-Chesa, Pilar; Reinhard, Christoph; Beck, Stephan; Schäfer, Reinhold; Regenbrecht, Christian R. A.; Henderson, David; Lange, Bodo; Haybaeck, Johannes; Keilholz, Ulrich; Hoffmann, Jens; Lehrach, Hans; Yaspo, Marie-Laure

    2017-01-01

    Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab. PMID:28186126

  19. Two years later: journals are not yet enforcing the ARRIVE guidelines on reporting standards for pre-clinical animal studies.

    PubMed

    Baker, David; Lidster, Katie; Sottomayor, Ana; Amor, Sandra

    2014-01-01

    There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented.

  20. Development of Veterinary Anesthesia Simulations for Pre-Clinical Training: Design, Implementation, and Evaluation Based on Student Perspectives.

    PubMed

    Jones, Jana L; Rinehart, Jim; Spiegel, Jacqueline Jordan; Englar, Ryane E; Sidaway, Brian K; Rowles, Joie

    2017-09-29

    Anesthesia simulations have been used in pre-clinical medical training for decades to help learners gain confidence and expertise in an operating room environment without danger to a live patient. The authors describe a veterinary anesthesia simulation environment (VASE) with anesthesia scenarios developed to provide a re-creation of a veterinarian's task environment while performing anesthesia. The VASE uses advanced computer technology with simulator inputs provided from standard monitoring equipment in common use during veterinary anesthesia and a commercial canine training mannequin that allows intubation, ventilation, and venous access. The simulation outputs are determined by a script that outlines routine anesthesia scenarios and describes the consequences of students' hands-on actions and interventions during preestablished anesthetic tasks and critical incidents. Patients' monitored physiologic parameters may be changed according to predetermined learner events and students' interventions to provide immediate learner feedback and clinical realism. A total of 96 students from the pre-clinical anesthesia course participated in the simulations and the pre- and post-simulation surveys evaluating students' perspectives. Results of the surveys and comparisons of overall categorical cumulative responses in the pre- and post-simulation surveys indicated improvement in learners' perceived preparedness and confidence as a result of the simulated anesthesia experience, with significant improvement in the strongly agree, moderately agree, and agree categories (p<.05 at a 95% CI). These results suggest that anesthesia simulations in the VASE may complement traditional teaching methods through experiential learning and may help foster classroom-to-clinic transference of knowledge and skills without harm to an animal.

  1. Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery.

    PubMed

    Ruggeri, Bruce A; Camp, Faye; Miknyoczki, Sheila

    2014-01-01

    Preclinical models of human cancers are indispensable in the drug discovery and development process for new cancer drugs, small molecules and biologics. They are however imperfect facsimiles of human cancers given the genetic and epigenetic heterogeneity of the latter and the multiplicity of dysregulated survival and growth-regulatory pathways that characterize this spectrum of diseases. This review discusses pre-clinical tumor models - traditional ectopic xenografts, orthotopic xenografts, genetically engineered tumor models, primary human tumorgrafts, and various multi-stage carcinogen-induced tumor models - their advantages, limitations, physiological and pathological relevance. Collectively, these animal models represent a portfolio of test systems that should be utilized at specific stages in the drug discovery process in a pragmatic and hierarchical manner of increasing complexity, physiological relevance, and clinical predictability of the human response. Additionally, evaluating the efficacy of novel therapeutic agents emerging from drug discovery programs in a variety of pre-clinical models can better mimic the heterogeneity of human cancers and also aid in establishing dose levels, dose regimens and drug combinations for use in clinical trials. Nonetheless, despite the sophistication and physiological relevance of these human cancer models (e.g., genetically engineered tumor models and primary human tumografts), the ultimate proof of concept for efficacy and safety of novel oncology therapeutics lies in humans. The judicious interpretation and extrapolation of data derived from these models to humans, and a correspondingly greater emphasis placed on translational medical research in early stage clinical trials, are essential to improve on the current clinical attrition rates for novel oncology therapeutic agents.

  2. The relationship between learning preferences (styles and approaches) and learning outcomes among pre-clinical undergraduate medical students.

    PubMed

    Liew, Siaw-Cheok; Sidhu, Jagmohni; Barua, Ankur

    2015-03-11

    Learning styles and approaches of individual undergraduate medical students vary considerably and as a consequence, their learning needs also differ from one student to another. This study was conducted to identify different learning styles and approaches of pre-clinical, undergraduate medical students and also to determine the relationships of learning preferences with performances in the summative examinations. A cross-sectional study was conducted among randomly selected 419 pre-clinical, undergraduate medical students of the International Medical University (IMU) in Kuala Lumpur. The number of students from Year 2 was 217 while that from Year 3 was 202. The Visual, Auditory, Read/Write, Kinesthetic (VARK) and the Approaches and Study Skills Inventory for Students (ASSIST) questionnaires were used for data collection. This study revealed that 343 students (81.9%) had unimodal learning style, while the remaining 76 (18.1%) used a multimodal learning style. Among the unimodal learners, a majority (30.1%) were of Kinesthetic (K) type. Among the middle and high achievers in summative examinations, a majority had unimodal (Kinaesthetic) learning style (30.5%) and were also strategic/deep learners (79.4%). However, the learning styles and approaches did not contribute significantly towards the learning outcomes in summative examinations. A majority of the students in this study had Unimodal (Kinesthetic) learning style. The learning preferences (styles and approaches) did not contribute significantly to the learning outcomes. Future work to re-assess the viability of these learning preferences (styles and approaches) after the incorporation of teaching-learning instructions tailored specifically to the students will be beneficial to help medical teachers in facilitating students to become more capable learners.

  3. 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…

  4. 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.…

  5. Curriculum Guidelines for Pharmacology.

    ERIC Educational Resources Information Center

    Shaw, David H.; And Others

    1990-01-01

    Pharmacology embraces the physical and chemical properties of drugs; the preparation of pharmaceutical agents; the absorption, fate, and excretion of drugs; and the effects of drugs on living systems. These guidelines represent a consensus on what would constitute a minimally acceptable pharmacology course for predoctoral dental students. (MLW)

  6. Pharmacology Information System Ready

    ERIC Educational Resources Information Center

    Chemical and Engineering News, 1973

    1973-01-01

    Discusses the development and future of Prophet,'' a specialized information handling system for pharmacology research. It is designed to facilitate the acquisition and dissemination of knowledge about mechanisms of drug action, and it is hoped that it will aid in converting pharmacology research from an empirical to a predictive science. (JR)

  7. 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.…

  8. 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…

  9. Pediatric sleep pharmacology.

    PubMed

    Pelayo, Rafael; Yuen, Kin

    2012-10-01

    This article reviews common sleep disorders in children and pharmacologic options for them. Discussions of pediatric sleep pharmacology typically focus on treatment of insomnia. Although insomnia is a major concern in this population, other conditions of concern in children are presented, such as narcolepsy, parasomnias, restless legs syndrome, and sleep apnea.

  10. Pharmacology Information System Ready

    ERIC Educational Resources Information Center

    Chemical and Engineering News, 1973

    1973-01-01

    Discusses the development and future of Prophet,'' a specialized information handling system for pharmacology research. It is designed to facilitate the acquisition and dissemination of knowledge about mechanisms of drug action, and it is hoped that it will aid in converting pharmacology research from an empirical to a predictive science. (JR)

  11. Curriculum Guidelines for Pharmacology.

    ERIC Educational Resources Information Center

    Shaw, David H.; And Others

    1990-01-01

    Pharmacology embraces the physical and chemical properties of drugs; the preparation of pharmaceutical agents; the absorption, fate, and excretion of drugs; and the effects of drugs on living systems. These guidelines represent a consensus on what would constitute a minimally acceptable pharmacology course for predoctoral dental students. (MLW)

  12. Integrating pharmacology and clinical pharmacology in universities

    PubMed Central

    Buckingham, Julia C

    2012-01-01

    Continuing development of safe and effective new medicines is critically important for global health, social prosperity and the economy. The drug discovery–development pipeline depends critically on close partnerships between scientists and clinicians and on educational programmes that ensure that the pharmacological workforce, in its broadest sense, is fit for purpose. Here I consider factors that have influenced the development of basic and clinical pharmacology in UK universities over the past 40 years and discuss ways in which basic pharmacologists, clinical pharmacologists and scientists from different disciplines can work together effectively, while retaining their professional identities and fostering developments in their disciplines. Specifically, I propose the establishment of Institutes of Drug Discovery and Development, whose activities could include development and implementation of a translational pharmacology research strategy, drawing on the collective expertise of the membership and the university as whole; provision of a forum for regular seminars and symposia to promote the discipline, encourage collaboration and develop a cohesive community; provision of a research advisory service, covering, for example, data management, applications for ethics permission, clinical trials design, statistics and regulatory affairs; liaison with potential funders and leadership of major funding bids, including funding for doctoral training; provision of advice on intellectual property protection and the commercialization of research; liaison with corporate partners to facilitate collaboration, knowledge transfer and effective translation; and leadership of undergraduate and postgraduate education in basic and clinical pharmacology and related sciences for medical and science students, including continuing professional development and transferable skills. PMID:22360628

  13. Integrating pharmacology and clinical pharmacology in universities.

    PubMed

    Buckingham, Julia C

    2012-06-01

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

  14. Pharmacology of Periodontal Disease.

    DTIC Science & Technology

    2014-09-26

    k 7RD-A157 116 PHARMRCOLOGY’ OF PERIODONTAL DISEASE(U) UNIVERSITY OF i/ I HEALTH SCIENCES/CHICAGO MEDICAL SCHOOL DEPT OF I PHARMACOLOGY S F HOFF 24...Region Bethesda, MD 20814-5044 • .RE: Annual Letter Report , ONR Contract #N00014-84-K-0562 "Pharmacology of Periodontal Disease" Dear Capt. Hancock...Annual Letter Report ONR Contract #N00014-84-K-0562 1,! t "Pharmacology of Periodontal Disease" f Steven F. Hoff, Ph.D. (Principal Investigator) A

  15. Pharmacology of Iron Transport

    PubMed Central

    Byrne, Shaina L.; Krishnamurthy, Divya; Wessling-Resnick, Marianne

    2013-01-01

    Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors. PMID:23020294

  16. Pharmacology of iron transport.

    PubMed

    Byrne, Shaina L; Krishnamurthy, Divya; Wessling-Resnick, Marianne

    2013-01-01

    Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors.

  17. Geriatric veterinary pharmacology.

    PubMed

    Kukanich, Butch

    2012-07-01

    Geriatric dogs and cats are an important group of patients in veterinary medicine. Healthy geriatric patients have similar physiology and presumably pharmacology as healthy adult animals. Geriatric patients with subclinical organ dysfunction are overtly healthy but have some organ dysfunction that may alter the clinical pharmacology of some drugs. Geriatric patients with an overt disease are expected to have altered drug pharmacology for some drugs based on the underlying disease. Diseases including cardiovascular, renal, hepatic, osteoarthritis, neurologic, and neoplastic are expected in the geriatric population and discussed, including the effects of the underlying disease and potential drug-drug interactions.

  18. Advancing pharmacometrics and systems pharmacology.

    PubMed

    Waldman, S A; Terzic, A

    2012-11-01

    Pharmacometrics and systems pharmacology are emerging as principal quantitative sciences within drug development and experimental therapeutics. In recognition of the importance of pharmacometrics and systems pharmacology to the discipline of clinical pharmacology, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), in collaboration with Nature Publishing Group and Clinical Pharmacology & Therapeutics, has established CPT: Pharmacometrics & Systems Pharmacology to inform the field and shape the discipline.

  19. Advancing Pharmacometrics and Systems Pharmacology

    PubMed Central

    Waldman, SA; Terzic, A

    2017-01-01

    Pharmacometrics and systems pharmacology are emerging as principal quantitative sciences within drug development and experimental therapeutics. In recognition of the importance of pharmacometrics and systems pharmacology to the discipline of clinical pharmacology, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), in collaboration with Nature Publishing Group and Clinical Pharmacology & Therapeutics, has established CPT: Pharmacometrics & Systems Pharmacology to inform the field and shape the discipline. PMID:23085873

  20. Evaluation of experimental and finite element models of synthetic and cadaveric femora for pre-clinical design-analysis.

    PubMed

    McNamara, B P; Cristofolini, L; Toni, A; Taylor, D

    1994-01-01

    The aim of this study was to determine the validity with which the finite element method could model synthetic bone and thereby determine the appropriateness of such femur analogues for application in pre-clinical tests. The performance of these synthetic femora was compared with cadaveric bone when employing the same geometric and material definition protocols. A four-point bend loading configuration was selected for this analysis. Four synthetic femurs and an embalmed cadaveric bone were tested experimentally to determine the structural bending stiffness (k) for the diaphysis of these bones. A finite element (FE) model was generated and an analysis performed for each bone type to estimate the Young's modulus (E) required to obtain a model stiffness equivalent to that obtained experimentally. The estimated material elastic modulus in the FE model for the synthetic femur was found to be very similar to available data for this bone analogue. The estimated cadaveric bone modulus however was found to differ significantly from documented values for cortical bone. A theoretical analysis demonstrated the great sensitivity of the estimated modulus value to the accuracy of the geometric definition. The very low variability found in the experimental test on the synthetic bones together with their more regular geometry and the possibility of achieving greater accuracy in geometric definition was shown to enable the production of a valid FE model of this bone for an isotropic homogeneous material description. Conversely, the greater irregularity of geometry, together with the less obvious differentiation between the cortical and cancellous bone in the cadaveric specimen makes accurate geometric description of this bone very difficult. This fact, together with the uncertainty concerning the quality of the cadaveric bone and its viscoelastic response during mechanical testing, makes reproduction of its behaviour in a FE model a much more demanding task. It is suggested that

  1. Pharmacology of epigenetics in brain disorders

    PubMed Central

    Narayan, Pritika; Dragunow, Mike

    2010-01-01

    Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome. PMID:20015091

  2. The pharmacology of psilocybin.

    PubMed

    Passie, Torsten; Seifert, Juergen; Schneider, Udo; Emrich, Hinderk M

    2002-10-01

    Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

  3. Pre-Clinical Lupus

    PubMed Central

    Bourn, Rebecka; James, Judith A.

    2015-01-01

    Purpose of review Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the pre-classification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention. Recent findings Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE can cause organ damage and mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension or renal, neurological, or peripheral vascular damage. The recently proposed SLICC SLE classification criteria could shift the period considered “preclinical SLE”. Murine studies suggest that the balance of T helper/T regulatory cells, peroxisome proliferator-activated receptor γ activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention. Summary Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE. PMID:26125103

  4. Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.

    PubMed

    Tosoni, Daniela; Pambianco, Sarah; Ekalle Soppo, Blanche; Zecchini, Silvia; Bertalot, Giovanni; Pruneri, Giancarlo; Viale, Giuseppe; Di Fiore, Pier Paolo; Pece, Salvatore

    2017-03-15

    The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.

  5. Quantification of skeletal blood flow and fluoride metabolism in rats using PET in a pre-clinical stress fracture model.

    PubMed

    Tomlinson, Ryan E; Silva, Matthew J; Shoghi, Kooresh I

    2012-06-01

    Blood flow is an important factor in bone production and repair, but its role in osteogenesis induced by mechanical loading is unknown. Here, we present techniques for evaluating blood flow and fluoride metabolism in a pre-clinical stress fracture model of osteogenesis in rats. Bone formation was induced by forelimb compression in adult rats. (15)O water and (18)F fluoride PET imaging were used to evaluate blood flow and fluoride kinetics 7 days after loading. (15)O water was modeled using a one-compartment, two-parameter model, while a two-compartment, three-parameter model was used to model (18)F fluoride. Input functions were created from the heart, and a stochastic search algorithm was implemented to provide initial parameter values in conjunction with a Levenberg-Marquardt optimization algorithm. Loaded limbs are shown to have a 26% increase in blood flow rate, 113% increase in fluoride flow rate, 133% increase in fluoride flux, and 13% increase in fluoride incorporation into bone as compared to non-loaded limbs (p < 0.05 for all results). The results shown here are consistent with previous studies, confirming this technique is suitable for evaluating the vascular response and mineral kinetics of osteogenic mechanical loading.

  6. A review of treatment planning for precision image-guided photon beam pre-clinical animal radiation studies.

    PubMed

    Verhaegen, Frank; van Hoof, Stefan; Granton, Patrick V; Trani, Daniela

    2014-12-01

    Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly. Copyright © 2014. Published by Elsevier GmbH.

  7. [Female with dentatorubral-pallidoluysian atrophy followed for 14 years from the pre-clinical stage: availability of gait analysis].

    PubMed

    Kurihara, Mana; Takahashi, Kayoko; Kohagizawa, Toshitaka; Yamauchi, Yuko; Ida, Hiroyuki

    2009-07-01

    We presented a 28-year-old female with dentatorubral-pallidoluysian atrophy (DRPLA) who had been followed from the pre-clinical stage. Her mother and elder brother were diagnosed as DRPLA at autopsy. Though the genetic diagnosis was not performed, we diagnosed this patient as DRPLA from her clinical course and family history. She first visited our hospital at age 14 with a symptoms of mental retardation. Generalized tonic-clonic type epilepsy developed at age 15, and valproate was prescribed from age 24. Gait disturbance and mental deterioration gradually progressed from age 15. We had performed gait analyses and brain MRI studies at regular intervals from age 14 to 27. She could walk even with gait disturbance until her early 20s. At one year after marked ataxia was recorded on gait analysis, she rapidly regressed and became unable to walk. Following this patient over a long period of time presented an opportunity to gather informative data regarding the progression of this disorder.

  8. Pre-clinical evaluation of a novel class of anti-cancer agents, the Pyrrolo-1, 5-benzoxazepines

    PubMed Central

    Greene, LM; Butini, S; Campiani, G; Williams, DC; Zisterer, DM

    2016-01-01

    Microtubules are currently ranked one of the most validated targets for chemotherapy; with clinical use of microtubule targeting agents (MTAs) extending beyond half a century. Recent research has focused on the development of novel MTAs to combat drug resistance and drug associated toxicities. Of particular interest are compounds structurally different to those currently used within the clinic. The pyrrolo-1, 5-benzoxazepines (PBOXs) are a structurally distinct novel group of anti-cancer agents, some of which target tubulin. Herein, we review the chemistry, mechanism of action, preclinical development of the PBOXs and comparisons with clinically relevant chemotherapeutics. The PBOXs induce a range of cellular responses including; cell cycle arrest, apoptosis, autophagy, anti-vascular and anti-angiogenic effects. The apoptotic potential of the PBOXs extends across a wide spectrum of cancer-derived cell lines, by targeting tubulin and multiple molecular pathways frequently deregulated in human cancers. Extensive experimental data suggest that combining the PBOXs with established chemotherapeutics or radiation is therapeutically advantageous. Pre-clinical highlights of the PBOXs include; cancer specificity and improved therapeutic efficacy as compared to some current first line therapeutics. PMID:27994676

  9. Anticancer properties of novel aminoacetonitrile derivative monepantel (ADD 1566) in pre-clinical models of human ovarian cancer.

    PubMed

    Bahrami, Farnaz; Morris, David L; Rufener, Lucien; Pourgholami, Mohammad H

    2014-01-01

    Monepantel (MPL) is a new anthelmintic agent approved for the treatment of nematode infections in farm animals. As a nematicide, it acts through a nematode-specific nicotinic receptor subtype which explains its exceptional safety in rodents and mammals. In the present study, we evaluated its potential as an anticancer agent. In vitro treatment of epithelial ovarian cancer cells with MPL resulted in reduced cell viability, inhibition of cell proliferation and suppression of colony formation. Proliferation of human ovarian surface epithelial cells and other non-malignant cells were however minimally affected. MPL-induced inhibition was found to be independent of the acetylcholine nicotinic receptor (nAChR) indicating that, its target in cancer cells is probably different from that in nematodes. Analysis of MPL treated cells by flow cytometry revealed G1 phase cell cycle arrest. Accordingly, MPL treated cells expressed reduced levels of cyclins D1 and A whereas cyclin E2 expression was enhanced. Consistent with a G1 phase arrest, cellular levels of cyclin dependent kinases (CDKs) 2 and 4 were lower, whereas expression of CDK inhibitor p27(kip) was increased. In cells expressing the wild-type p53, MPL treatment led to increased p53 expression. In line with these results, MPL suppressed cellular thymidine incorporation thus impairing DNA synthesis and inducing cleavage of poly (ADP-ribose) polymerase (PARP-1). Combined these pre-clinical findings reveal for the first time the anticancer potential of monepantel.

  10. Histological and morphometric lesions in the pre-clinical, developmental phase of insulin-induced laminitis in Standardbred horses.

    PubMed

    de Laat, Melody A; Patterson-Kane, Janet C; Pollitt, Christopher C; Sillence, Martin N; McGowan, Catherine M

    2013-03-01

    Lamellar pathology in experimentally-induced equine laminitis associated with euglycaemic hyperinsulinaemia is substantial by the acute, clinical phase (∼48h post-induction). However, lamellar pathology of the developmental, pre-clinical phase requires evaluation. The aim of this study was to analyse lamellar lesions both qualitatively and quantitatively, 6, 12 and 24h after the commencement of hyperinsulinaemia. Histological and histomorphometrical analyses of lamellar pathology at each time-point included assessment of lamellar length and width, epidermal cell proliferation and death, basement membrane (BM) pathology and leucocyte infiltration. Archived lamellar tissue from control horses and those with acute, insulin-induced laminitis (48h) was also assessed for cellular proliferative activity by counting the number of cells showing positive nuclear immuno labelling for TPX2. Decreased secondary epidermal lamellar (SEL) width and increased histomorphological evidence of SEL epidermal basal (and supra-basal) cell death occurred early in disease progression (6h). Increased cellular proliferation in SELs, infiltration of the dermis with small numbers of leucocytes and BM damage occurred later (24 and 48h). Some lesions, such as narrowing of the SELs, were progressive over this time period (6-48h). Cellular pathology preceded leucocyte infiltration and BM pathology, indicating that the latter changes may be secondary or downstream events in hyperinsulinaemic laminitis.

  11. Pre-clinical toxicokinetics and safety study of M2ES, a PEGylated recombinant human endostatin, in rhesus monkeys.

    PubMed

    Guo, Lifang; Geng, Xingchao; Chen, Yang; Qi, Feifei; Liu, Li; Miao, Yufa; Lin, Zhi; Yu, Min; Li, Zuogang; Fu, Yan; Li, Bo; Luo, Yongzhang

    2014-08-01

    PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30mg/kg body weight per day) for 3months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  12. A Novel Approach to Simulation-Based Education for Veterinary Medical Communication Training Over Eight Consecutive Pre-Clinical Quarters.

    PubMed

    Englar, Ryane E

    2017-01-01

    Experiential learning through the use of standardized patients (SPs) is the primary way by which human medical schools teach clinical communication. The profession of veterinary medicine has followed suit in response to new graduates' and their employers' concerns that veterinary interpersonal skills are weak and unsatisfactory. As a result, standardized clients (SCs) are increasingly relied upon as invaluable teaching tools within veterinary curricula to advance relationship-centered care in the context of a clinical scenario. However, there is little to no uniformity in the approach that various colleges of veterinary medicine take when designing simulation-based education (SBE). A further complication is that programs with pre-conceived curricula must now make room for training in clinical communication. Curricular time constraints challenge veterinary colleges to individually decide how best to utilize SCs in what time is available. Because it is a new program, Midwestern University College of Veterinary Medicine (MWU CVM) has had the flexibility and the freedom to prioritize an innovative approach to SBE. The author discusses the SBE that is currently underway at MWU CVM, which incorporates 27 standardized client encounters over eight consecutive pre-clinical quarters. Prior to entering clinical rotations, MWU CVM students are exposed to a variety of simulation formats, species, clients, settings, presenting complaints, and communication tasks. These represent key learning opportunities for students to practice clinical communication, develop self-awareness, and strategize their approach to future clinical experiences.

  13. Pre-clinical toxicity of a combination of berberine and 5-aminosalicylic acid in mice.

    PubMed

    Li, Yan-Hong; Zhang, Man; Fu, Hai-Bo; Xiao, Hai-Tao; Bian, Zhao-Xiang

    2016-11-01

    Our previous study demonstrated that a combination of alternative medicine berberine and conventional 5-aminosalicylic acid (5-ASA) showed promise to be a novel therapeutic strategy for ulcerative colitis (UC). This present study aims to sketch the pre-clinical toxicity profile of this combination (1:10 dose ratio) on mice. In acute toxicity test, the determined median lethal dose (LD50) was 278.7 mg/kg berberine plus 2787 mg/kg 5-ASA. The results from subacute toxicity test demonstrated that no toxic signs of clinical symptoms, no significant changes in hematological or biochemical parameters were detected in mice treated with 14 + 140, 28 + 280 or 56 + 560 mg/kg of berberine plus 5-ASA treatment. Histological examinations revealed that accompanied with an increase in spleen weight, frequently recorded enlargement and white pulp hyperplasia of spleen were detected in mice when exposed to three doses of combination treatments. Further in vitro assessment suggested that the spleen toxicity was originated from berberine by its inhibition in cell viability and cell proliferation of lymphocytes. The results of this study indicate that the combination of berberine and 5-ASA shows a slight toxic effect on spleen, suggesting that this combination should be used with caution for patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Establishment of a non-human primate Campylobacter disease model for the pre-clinical evaluation of Campylobacter vaccine formulations.

    PubMed

    Islam, Dilara; Lewis, Michael D; Srijan, Apichai; Bodhidatta, Ladaporn; Aksomboon, Ajchara; Gettayacamin, Montip; Baqar, Shahida; Scott, Daniel; Mason, Carl J

    2006-05-01

    Campylobacter jejuni is a common cause of enteritis worldwide. The mechanisms by which C. jejuni causes disease are unclear. Challenge studies in humans are currently considered unethical due to the possibility of severe complications, such as Guillain-Barré syndrome. Campylobacter infection in non-human primates closely mimics the disease and immune response, seen in humans. In this study, we attempted to determine the minimal dose of a pathogenic C. jejuni 81-176 strain required for clinical signs and symptoms of disease (> or = 80% attack rate) in Macaca mulatta monkeys using an escalating dosage (three doses for three monkey groups: 10(7), 10(9) and 10(11) cfu). Eighty percent of the monkeys challenged with highest dose (10(11) cfu) had mild disease, but the 80% attack rate (moderate diarrhea in 80% of the monkeys) was not achieved. However, 100% of monkeys showed IgA seroconversions (three-fold over pre-challenge titers). The elicited immune response was challenge dose-dependent. Campylobacter antigen specific fecal s-IgA responses were observed in all challenged groups but the response was not dose-dependent. Only IgM antibody secreting cells response was observed against Campylobacter antigens. The elicited immune response in three groups of rhesus monkeys was dose-dependent, indicating this monkey model can be used for pre-clinical evaluation of Campylobacter candidate vaccines, however these adult rhesus monkeys are less prone to Campylobacter infection.

  15. Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

    PubMed Central

    Kennelly, Helen; Mahon, Bernard P.; English, Karen

    2016-01-01

    Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emphysema the efficacy of human MSC therapy and optimal cell dose were investigated. Protective effects were examined in the lung through histological examination. Further in vivo experiments examined the reparative abilities of MSCs after tissue damage was established and the role played by soluble factors secreted by MSCs. The mechanism of MSC action was determined in using shRNA gene knockdown. Human MSC therapy and MSC conditioned media exerted significant cytoprotective effects when administered early at the onset of the disease. These protective effects were due to significant anti-inflammatory, anti-fibrotic and anti-apoptotic mechanisms, mediated in part through MSC production of hepatocyte growth factor (HGF). When MSC administration was delayed, significant protection of the lung architecture was observed but this was less extensive. MSC cell therapy was more effective than MSC conditioned medium in this emphysema model. PMID:27922052

  16. Comparative Analysis of Nursing Students' Perspectives toward Avatar Learning Modality: Gain Pre-Clinical Experience via Self-Paced Cognitive Tool

    ERIC Educational Resources Information Center

    Commendador, Kathleen; Chi, Robert

    2013-01-01

    This study was undertaken to better understand the nature of nursing students' perspectives toward simulative learning modality for gaining pre-clinical experience via self-paced cognitive tool--Avatar. Findings indicates that participants engaged in synchronous Avatar learning environment had higher levels of appreciation toward Avatar learning…

  17. Clinical research on new drugs (Phase I). Profile of scientific publications: data from the pre-clinical phase and bioethical aspects.

    PubMed

    Brick, Vanessa de Souza; Hossne, William Saad; Saad Hossne, Rogério

    2008-01-01

    To trace a profile of scientific publications, phase I, in order to know whether or not they show pre-clinical phase data, emphasizing bioethical aspects. Sixty-one scientific articles, published in 2007, involving research in human beings using new drugs, medicines and vaccines during phase I were analysed. A schedule for data collection was elaborated in which it would be possible to analyse and evaluate those articles. The schedule included items related to the pre-clinical phase associated to the clinical phase, and items related to the sample characteristics. Most of research works were carried out in USA. Taking into consideration that a large number of works have been dedicated to oncologic affections, most of them were carried out in voluntary ill individuals. Information on the pre-clinical phase, phase I, was very poor or absent. Even though some authors consider the phase I research as a promising one and also suggest some future studies on phase II, the reader is not able to consider the same way, as long as there is a shortage of information on the pre-clinical phase. The profile of scientific publications showed that data deserve some reflections and analysis to better evaluate the publications on phase I.

  18. Pharmacometrics of Pterostilbene: Pre-Clinical Pharmacokinetics and Metabolism, Anti-Cancer, Anti-Inflammatory, Anti-Oxidant, and Analgesic Activity

    USDA-ARS?s Scientific Manuscript database

    Purpose: To evaluate the pre-clinical pharmacokinetics and pharmacodynamics of pterostilbene. Methods: Rat liver microsomes were used to evaluate in vitro phase I and II metabolism. Right jugular vein cannulated male Sprague-Dawley rats were dosed intravenously with 20 mg/kg of pterostilbene and sam...

  19. Comparative Analysis of Nursing Students' Perspectives toward Avatar Learning Modality: Gain Pre-Clinical Experience via Self-Paced Cognitive Tool

    ERIC Educational Resources Information Center

    Commendador, Kathleen; Chi, Robert

    2013-01-01

    This study was undertaken to better understand the nature of nursing students' perspectives toward simulative learning modality for gaining pre-clinical experience via self-paced cognitive tool--Avatar. Findings indicates that participants engaged in synchronous Avatar learning environment had higher levels of appreciation toward Avatar learning…

  20. Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.

    PubMed

    Gump, Jacob M; Donson, Andrew M; Birks, Diane K; Amani, Vladimir M; Rao, Karun K; Griesinger, Andrea M; Kleinschmidt-DeMasters, B K; Johnston, James M; Anderson, Richard C E; Rosenfeld, Amy; Handler, Michael; Gore, Lia; Foreman, Nicholas; Hankinson, Todd C

    2015-05-21

    Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP. Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples. We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

  1. Pharmacological strategies for detoxification.

    PubMed

    Diaper, Alison M; Law, Fergus D; Melichar, Jan K

    2014-02-01

    Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2-adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti-glutamatergics and γ-aminobutyric acid (GABA)-ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination. © 2013 The British Pharmacological Society.

  2. The Pharmacology of Immunosuppression

    PubMed Central

    2009-01-01

    Objective To provide students with a comprehensive, integrated presentation on the pharmacology of immuosuppression. Design Course content on the pharmacology of immunosuppression relating to organ transplantation and treatment of autoimmune disorders was presented in integrated sequence modules that included content from pharmacology, medicinal chemistry, and therapeutics. Weekly recitation sessions and active-learning exercises were incorporated to allow students to apply the information they learned to integrated patient cases and stimulate involvement and critical thinking. Fundamental material related to the components and functions of the immune system was presented to students early in curriculum with courses such as biochemistry, pathophysiology, and immunology/microbiology. Assessment Comprehensive examinations, in-class quizzes, written case submissions, case discussions, review exercises, and group exercises were used to assess student learning. Conclusion Students at South University received a comprehensive and detailed understanding of all aspects relating to immunosuppressive therapy. This was accomplished by integrating instruction on immunosuppressive therapy from various disciplines. PMID:20221337

  3. Performance of two different digital evaluation systems used for assessing pre-clinical dental students' prosthodontic technical skills.

    PubMed

    Gratton, D G; Kwon, S R; Blanchette, D R; Aquilino, S A

    2016-07-29

    Proper integration of newly emerging digital assessment tools is a central issue in dental education in an effort to provide more accurate and objective feedback to students. The study examined how the outcomes of students' tooth preparation were correlated when evaluated using traditional faculty assessment and two types of digital assessment approaches. Specifically, incorporation of the Romexis Compare 2.0 (Compare) and Sirona prepCheck 1.1 (prepCheck) systems was evaluated. Additionally, satisfaction of students based on the type of software was evaluated through a survey. Students in a second-year pre-clinical prosthodontics course were allocated to either Compare (n = 42) or prepCheck (n = 37) systems. All students received conventional instruction and used their assigned digital system as an additional evaluation tool to aid in assessing their work. Examinations assessed crown preparations of the maxillary right central incisor (#8) and the mandibular left first molar (#19). All submissions were graded by faculty, Compare and prepCheck. Technical scores did not differ between student groups for any of the assessment approaches. Compare and prepCheck had modest, statistically significant correlations with faculty scores with a minimum correlation of 0.3944 (P = 0.0011) and strong, statistically significant correlations with each other with a minimum correlation of 0.8203 (P < 0.0001). A post-course student survey found that 55.26% of the students felt unfavourably about learning the digital evaluation protocols. A total of 62.31% felt favourably about the integration of these digital tools into the curriculum. Comparison of Compare and prepCheck showed no evidence of significant difference in students' prosthodontics technical performance and perception. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. A pre-clinical phantom comparison of tissue harmonic and brightness mode imaging for application in ultrasound guided prostate brachytherapy.

    PubMed

    Sandhu, G K; Dunscombe, P B; Khan, R F H

    2011-07-01

    The current practice of prostate brachytherapy utilizes the brightness (B) mode ultrasound imaging for volume definition and needle guidance. However, tissue harmonic (H) mode available with new scanners has shown the improved image quality. The aim of this study was to perform a pre-clinical phantom evaluation of harmonic imaging as an alternative to B mode in prostate brachytherapy. Performance characteristics viz. dead zone, depth of penetration, geometric accuracy, spatial resolution, tissue to clutter ratio (TCR) and signal to noise ratio (SNR), were compared between two modes using an in-house phantom. Images were acquired under the same settings except the gain; which is higher for the H mode than that of B mode. A qualitative comparison between two modes was also performed using commercial CIRS053 phantom. Dead zone, depth of penetration and geometric accuracy were respectively <1 mm, >8 cm and <1% for both modes. Relative TCR, SNR and the spatial resolution were improved in H mode compared with B mode. Images with CIRS053 phantom in H mode demonstrate sharper boundaries for prostate and urethra, freedom from background clutter, and better identification of the brachytherapy needles. This study indicates the superiority of H over B mode, in terms of spatial resolution, relative contrast, and overall image quality. Thus H mode has the potential benefit in prostate brachytherapy. This study provides the basis to move forward to investigate whether the superior image quality observed in the laboratory can be translated into a higher treatment quality for the patient. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

  5. PRE-CLINICAL EVALUATION OF EXTRACTS AND ESSENTIAL OILS FROM BETEL-LIKE SCENT PIPER SPECIES IDENTIFIED POTENTIAL CANCER TREATMENT.

    PubMed

    Sanubol, Arisa; Chaveerach, Arunrat; Tanee, Tawatchai; Sudmoon, Runglawan

    2017-01-01

    Nine Piper species with betel-like scents are sources of industrial and medicinal aromatic chemicals, but there is lack of information on cytotoxicity and genotoxicity for human safety, including how these plants impact human cervical cancer cell line. Plant leaves were extracted with hexane and hydro-distilled for essential oils. The extracts and oils were pre-clinically studied based on cyto - and genotoxicity using microculture tetrazolium (MTT) and comet assays. The crude extracts showed an IC50 in leukocytes and HeLa cells of 58.59-97.31 mg/ml and 34.91-101.79 mg/ml, the LD50 is higher than 5000 mg/kg. With lower values than the crude extracts, the essential oils showed an IC50 in leukocytes and HeLa cells of 0.023-0.059 μg/ml and 0.025-0.043 μg/ml the LD50 is less than 50 mg/kg. IC50 values showed that the essential oils were highly toxic than the crude extracts. At the level of human genetic materials, the crude extracts of two species, including P. betloides and P. crocatum, showed a significant toxicity (p < 0.05) in leukocytes. The other samples were non-toxic. The crude extracts of all samples showed significant genotoxicity in HeLa cells. The essential oils of all studied Piper species showed insignificant toxicity in leukocytes. For HeLa cells, the eight-studied species showed significant toxicity in HeLa cells, whereas only P. submultinerve showed insignificant toxicity. The crude extracts and essential oils should be tested as putative cervical cancer treatments due to less toxicity in human normal cells.

  6. Infusion-line pressure as a real-time monitor of convection-enhanced delivery in pre-clinical models.

    PubMed

    Lam, Miu Fei; Foo, Stacy W L; Thomas, Meghan G; Lind, Christopher R P

    2014-01-15

    Acute convection-enhanced delivery (CED) is a neurosurgical delivery technique that allows for precise and uniform distribution of an infusate to a brain structure. It remains experimental due to difficulties in ensuring successful delivery. Real-time monitoring is able to provide immediate feedback on cannula placement, infusate distribution, and if the infusion is proceeding as planned or is failing due to reflux or catheter obstruction. Pressure gradient is the driving force behind CED, with the infusion pressure being directly proportional to the flow-rate. The aim of this study was to assess the feasibility of using infusion-line pressure profiling to distinguish in real-time between succeeding and failing CED infusions. To do so we delivered cresyl violet dye at 0.5, 1.0 and 2.0 μl/min via CED in vitro using 0.6% agarose gel and in vivo to the rat striatum. Infusions that failed in agarose gel models could only be differentiated late during the procedures. In the rat in vivo model, the infusion-line profiles of obstructed infusions were not distinctive from those of successful infusions. Intraoperative magnetic resonance imaging (MRI) is used for real-time visualisation of cannula placement and infusate distribution. Particularly for animal pre-clinical work, it would be advantageous to supplement MRI with a cheap, accessible technique to monitor infusions and provide a real-time measure of infusion success or failure. Infusion-line pressure monitoring was of limited value in identifying successful CED with small volume infusions, whilst its utility for large volume infusion remains unknown. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  7. Monte Carlo simulation on pre-clinical irradiation: A heterogeneous phantom study on monoenergetic kilovoltage photon beams

    NASA Astrophysics Data System (ADS)

    Chow, James C. L.

    2012-10-01

    This study investigated radiation dose variations in pre-clinical irradiation due to the photon beam energy and presence of tissue heterogeneity. Based on the same mouse computed tomography image dataset, three phantoms namely, heterogeneous, homogeneous and bone homogeneous were used. These phantoms were generated by overriding the relative electron density of no voxel (heterogeneous), all voxel (homogeneous) and the bone voxel (bone homogeneous) to one. 360° photon arcs with beam energies of 50 - 1250 keV were used in mouse irradiations. Doses in the above phantoms were calculated using the EGSnrc-based DOSXYZnrc code through the DOSCTP. Monte Carlo simulations were carried out in parallel using multiple nodes in a high-performance computing cluster. It was found that the dose conformity increased with the increase of the photon beam energy from the keV to MeV range. For the heterogeneous mouse phantom, increasing the photon beam energy from 50 keV to 1250 keV increased seven times the dose deposited at the isocenter. For the bone dose enhancement, the mean dose was 2.7 times higher when the bone heterogeneity was not neglected using the 50 keV photon beams in the mouse irradiation. Bone dose enhancement affecting the mean dose was found in the photon beams with energy range of 50 - 200 keV and the dose enhancement decreased with an increase of the beam energy. Moreover, the MeV photon beam had a higher dose at the isocenter, and a better dose conformity compared to the keV beam.

  8. Towards a nanoscale mammographic contrast agent: development of a modular pre-clinical dual optical/x-ray agent

    NASA Astrophysics Data System (ADS)

    Hill, Melissa L.; Gorelikov, Ivan; Niroui, Farnaz; Levitin, Ronald B.; Mainprize, James G.; Yaffe, Martin J.; Rowlands, J. A.; Matsuura, Naomi

    2013-08-01

    Contrast-enhanced digital mammography (CEDM) can provide improved breast cancer detection and characterization compared to conventional mammography by imaging the effects of tumour angiogenesis. Current small-molecule contrast agents used for CEDM are limited by a short plasma half-life and rapid extravasation into tissue interstitial space. To address these limitations, nanoscale agents that can remain intravascular except at sites of tumour angiogenesis can be used. For CEDM, this agent must be both biocompatible and strongly attenuate mammographic energy x-rays. Nanoscale perfluorooctylbromide (PFOB) droplets have good x-ray attenuation and have been used in patients for other applications. However, the macroscopic scale of x-ray imaging (50-100 µm) is inadequate for direct verification that PFOB droplets localize at sites of breast tumour angiogenesis. For efficient pre-clinical optimization for CEDM, we integrated an optical marker into PFOB droplets for microscopic assessment (≪50 µm). To develop PFOB droplets as a new nanoscale mammographic contrast agent, PFOB droplets were labelled with fluorescent quantum dots (QDs). The droplets had mean diameters of 160 nm, fluoresced at 635 nm and attenuated x-ray spectra at 30.5 keV mean energy with a relative attenuation of 5.6 ± 0.3 Hounsfield units (HU) mg-1 mL-1 QD-PFOB. With the agent loaded into tissue phantoms, good correlation between x-ray attenuation and optical fluorescence was found (R2 = 0.96), confirming co-localization of the QDs with PFOB for quantitative assessment using x-ray or optical methods. Furthermore, the QDs can be removed from the PFOB agent without affecting its x-ray attenuation or structural properties for expedited translation of optimized PFOB droplet formulations into patients.

  9. Combined AKT and MEK Pathway Blockade in Pre-Clinical Models of Enzalutamide-Resistant Prostate Cancer

    PubMed Central

    Toren, Paul; Kim, Soojin; Johnson, Fraser; Zoubeidi, Amina

    2016-01-01

    Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting these pathways in AR-positive prostate cancer models. Using various in vitro models of prostate cancer disease states including androgen dependent (LNCaP), CRPC (V16D and 22RV1) and ENZ-resistant prostate cancer (MR49C and MR49F), we evaluate the relevance of targeting both AKT and MEK pathways. Our data reveal that AKT inhibition induces apoptosis and inhibits cell growth in PTEN null cell lines independently of their sensitivity to hormone therapy; however, AKT inhibition had no effect on the PTEN positive 22RV1 cell line. Interestingly, we found that MEK inhibition had greater effect on 22RV1 cells compared to LNCaP, V16D or ENZ-resistant cells MR49C and MR49F cells. In vitro, combination AKT and MEK blockade had evidence of synergy observed in some cell lines and assays, but this was not consistent across all results. In vivo, the combination of AKT and MEK inhibition resulted in more consistent tumor growth inhibition of MR49F xenografts and longer disease specific survival compared to AKT inhibitor monotherapy. As in our in vitro study, 22RV1 xenografts were more resistant to AKT inhibition while they were more sensitive to MEK inhibition. Our results suggest that targeting AKT and MEK in combination may be a valuable strategy in prostate cancer when both pathways are activated and further support the importance of characterizing the dominant oncogenic pathway in each patient’s tumor in order to select optimal therapy. PMID:27046225

  10. Influence of Teaching Strategies and its Order of Exposure on Pre-Clinical Teeth Arrangement – A Pilot Study

    PubMed Central

    Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar

    2016-01-01

    Introduction Teeth arrangement is a vital skill for the undergraduate dental student. The attainment of skills depends largely on the methodology of teaching. In a dental curriculum, the students are exposed to a wide variety of inputs and teaching methodologies from different sources. The educational unit in dental school must identify the sequence of teaching methods that enhance the learning and practising ability of students. Aim The aim of this study was to evaluate the effectiveness of three different teaching methodologies for teeth arrangement and compare the differences between the orders of exposure to each teaching methodology on the development of teeth arrangement skills. Materials and Methods The first year B.D.S students were study participants and were divided into three groups A, B, C. They were exposed to three teaching patterns namely live demonstration with video assisted teaching, group discussion with hand-outs and lectures with power point presentation. After each teaching methodology, their skill was assessed. The groups were exposed to three methodologies in different order for three arrangements. The scores obtained were analysed using Kruskal Wallis rank sum test and Dunn test for statistical significance. Results Significantly higher scores in the teeth arrangement procedure were obtained by the Group A students who were exposed initially to live demonstration with video-assisted teaching. Difference in the scores was noted among and within the groups. The difference between Group A and Group C was statistically significant after both first and third teeth arrangement (p=0.0031, p=0.0057). Conclusion The study suggests each pre-clinical practice should begin with a live demonstration to enhance immediate learning absorption followed by lectures with power point presentation and group discussion for retention of knowledge and memory retrieval. PMID:27891468

  11. Perceived Benefits of Pre-Clinical Simulation-based Training on Clinical Learning Outcomes among Omani Undergraduate Nursing Students

    PubMed Central

    Madhavanprabhakaran, Girija; Al-Khasawneh, Esra; Wittmann, Lani

    2015-01-01

    Objectives: This study aimed to explore the benefits perceived by Omani undergraduate maternity nursing students regarding the effect of pre-clinical simulation-based training (PSBT) on clinical learning outcomes. Methods: This non-experimental quantitative survey was conducted between August and December 2012 among third-year baccalaureate nursing students at Sultan Qaboos University in Muscat, Oman. Voluntary participants were exposed to faculty-guided PSBT sessions using low- and medium-fidelity manikins, standardised scenarios and skill checklists on antenatal, intranatal, postnatal and newborn care and assessment. Participants answered a purposely designed self-administered questionnaire on the benefits of PSBT in enhancing learning outcomes. Items were categorised into six subscales: knowledge, skills, patient safety, academic safety, confidence and satisfaction. Scores were rated on a four-point Likert scale. Results: Of the 57 participants, the majority (95.2%) agreed that PSBT enhanced their knowledge. Most students (94.3%) felt that their patient safety practices improved and 86.5% rated PSBT as beneficial for enhancing skill competencies. All male students and 97% of the female students agreed that PSBT enhanced their confidence in the safe holding of newborns. Moreover, 93% of participants were satisfied with PSBT. Conclusion: Omani undergraduate nursing students perceived that PSBT enhanced their knowledge, skills, patient safety practices and confidence levels in providing maternity care. These findings support the use of simulation training as a strategy to facilitate clinical learning outcomes in future nursing courses in Oman, although further research is needed to explore the objective impact of PSBT on learning outcomes. PMID:25685368

  12. Elevation of serum immunoglobulin free light chains during the pre-clinical period of rheumatoid arthritis: impact on mortality

    PubMed Central

    Deng, Xiaoli; Crowson, Cynthia S.; Rajkumar, S. Vincent; Dispenzieri, Angela; Larson, Dirk R.; Therneau, Terry M.; Matteson, Eric L.; Kyle, Robert A.; Katzmann, Jerry; Gabriel, Sherine E.; Davis, John M.

    2015-01-01

    Objective Immunoglobulin free light chains (FLCs) represent biomarkers of B-cell activity in rheumatoid arthritis (RA) and are associated with all-cause mortality in the general population. Our objective was to evaluate the relationships of serum FLCs to pre-clinical disease, RA characteristics, and mortality in RA compared to non-RA subjects. Methods A population-based study in Olmsted County, Minnesota, was performed by cross-linking a large cohort in the general population having available serum FLC measurements with established RA incidence and prevalence cohorts. Serum κ, λ, and total FLCs and their trends relative to RA incidence were compared between RA and non-RA subjects. Regression models were used to determine the associations between FLCs, disease characteristics and mortality, testing for differential effects of FLCs on mortality in RA. Results Among 16,609 subjects, 270 fulfilled the criteria for RA at the time of FLC measurement. Mean total FLCs were significantly higher in RA compared to non-RA subjects (4.2 vs. 3.3 mg/dL; p<0.001). FLCs became elevated 3 – 5 years before the clinical onset of RA and remained elevated during follow-up. Polyclonal FLCs were found to predict higher mortality in persons with RA, though elevation to the highest decile had a relatively lower impact on mortality in RA compared to non-RA subjects. Conclusions Elevation of serum FLCs precedes the development of RA and may be useful in monitoring B-cell activity and disease progression. FLCs are confirmed predictors of mortality, though the highest elevations of FLCs have a lower impact on mortality in RA than the general population. PMID:25593227

  13. Influence of Teaching Strategies and its Order of Exposure on Pre-Clinical Teeth Arrangement - A Pilot Study.

    PubMed

    Jeyapalan, Karthigeyan; Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar

    2016-10-01

    Teeth arrangement is a vital skill for the undergraduate dental student. The attainment of skills depends largely on the methodology of teaching. In a dental curriculum, the students are exposed to a wide variety of inputs and teaching methodologies from different sources. The educational unit in dental school must identify the sequence of teaching methods that enhance the learning and practising ability of students. The aim of this study was to evaluate the effectiveness of three different teaching methodologies for teeth arrangement and compare the differences between the orders of exposure to each teaching methodology on the development of teeth arrangement skills. The first year B.D.S students were study participants and were divided into three groups A, B, C. They were exposed to three teaching patterns namely live demonstration with video assisted teaching, group discussion with hand-outs and lectures with power point presentation. After each teaching methodology, their skill was assessed. The groups were exposed to three methodologies in different order for three arrangements. The scores obtained were analysed using Kruskal Wallis rank sum test and Dunn test for statistical significance. Significantly higher scores in the teeth arrangement procedure were obtained by the Group A students who were exposed initially to live demonstration with video-assisted teaching. Difference in the scores was noted among and within the groups. The difference between Group A and Group C was statistically significant after both first and third teeth arrangement (p=0.0031, p=0.0057). The study suggests each pre-clinical practice should begin with a live demonstration to enhance immediate learning absorption followed by lectures with power point presentation and group discussion for retention of knowledge and memory retrieval.

  14. Design and Effectiveness of a Required Pre-Clinical Simulation-based Curriculum for Fundamental Clinical Skills and Procedures

    PubMed Central

    Lofaso, Daryl P.; DeBlieux, Peter M.; DiCarlo, Richard P.; Hilton, Charles; Yang, Tong; Chauvin, Sheila W.

    2011-01-01

    Background For more than 20 years, medical literature has increasingly documented the need for students to learn, practice and demonstrate competence in basic clinical knowledge and skills. In 2001, the Louisiana State University Health Science Centers (LSUHSC) School of Medicine – New Orleans replaced its traditional Introduction in to Clinical Medicine (ICM) course with the Science and Practice of Medicine (SPM) course. The main component within the SPM course is the Clinical Skills Lab (CSL). The CSL teaches 30 plus skills to all pre-clinical medical students (Years 1 and 2). Methods Since 2002, an annual longitudinal evaluation questionnaire was distributed to all medical students targeting the skills taught in the CSL. Students were asked to rate their self- confidence (Dreyfus and Likert-type) and estimate the number of times each clinical skill was performed (clinically/non-clinically). Of the 30 plus skills taught, 8 were selected for further evaluation. Results An analysis was performed on the eight skills selected to determine the effectiveness of the CSL. All students that participated in the CSL reported a significant improvement in self-confidence and in number performed in the clinically/non-clinically setting when compared to students that did not experience the CSL. For example, without CSL training, the percentage of students reported at the end of their second year self-perceived expertise as “novice” ranged from 21.4% (CPR) to 84.7% (GU catheterization). Students who completed the two-years CSL, only 7.8% rated their self-perceived expertise at the end of the second year as “novice” and 18.8% for GU catheterization. Conclusion The CSL design is not to replace real clinical patient experiences. It's to provide early exposure, medial knowledge, professionalism and opportunity to practice skills in a patient free environment. PMID:22190848

  15. The Potential Use of Pharmacological Agents to Modulate Orthodontic Tooth Movement (OTM)

    PubMed Central

    Kouskoura, Thaleia; Katsaros, Christos; von Gunten, Stephan

    2017-01-01

    The biological processes that come into play during orthodontic tooth movement (OTM) have been shown to be influenced by a variety of pharmacological agents. The effects of such agents are of particular relevance to the clinician as the rate of tooth movement can be accelerated or reduced as a result. This review aims to provide an overview of recent insights into drug-mediated effects and the potential use of drugs to influence the rate of tooth movement during orthodontic treatment. The limitations of current experimental models and the need for well-designed clinical and pre-clinical studies are also discussed. PMID:28228735

  16. Social pharmacology: expanding horizons.

    PubMed

    Maiti, Rituparna; Alloza, José Luis

    2014-01-01

    In the current modern and global society, social changes are in constant evolution due to scientific progress (technology, culture, customs, and hygiene) and produce the freedom in individuals to take decisions by themselves or with their doctors toward drug consumption. In the arena of marketed drug products which includes society, individual, administration, and pharmaceutical industry, the young discipline emerged is social pharmacology or sociopharmacology. This science arises from clinical pharmacology, and deals with different parameters, which are important in creating knowledge on marketed drugs. However, the scope of "social pharmacology" is not covered by the so-called "Phase IV" alone, but it is the science that handles the postmarketing knowledge of drugs. The social pharmacology studies the "life cycle" of any marketed pharmaceutical product in the social terrain, and evaluates the effects of the real environment under circumstances totally different in the drug development process. Therefore, there are far-reaching horizons, plural, and shared predictions among health professionals and other, for beneficial use of a drug, toward maximizing the benefits of therapy, while minimizing negative social consequences.

  17. Pharmacology. Teacher Edition.

    ERIC Educational Resources Information Center

    Oklahoma State Dept. of Vocational and Technical Education, Stillwater. Curriculum and Instructional Materials Center.

    This instructor's guide contains the materials required to teach a competency-based course in pharmacology for practical nursing. The following are covered in the five instructional units: calculating medication dosages, documenting medications, identifying classification and effects of medications, administering medications, and assisting with…

  18. Pharmacological management of obesity.

    PubMed

    Velazquez, Amanda; Apovian, Caroline M

    2017-04-28

    Current management of obesity includes three main arms: behavioral modification, pharmacologic therapy, and bariatric surgery. Decades prior, the only pharmacological agents available to treat obesity were approved only for short-term use (≤ 12 weeks) by the Food and Drug Administration (FDA). However, in the last several years, the FDA has approved several medications for longer term treatment of obesity. This highlights the important progression that we, as a society, better appreciate now the chronicity and complexity of obesity as a disease. Also, availability of more medication options gives healthcare providers more possibilities to consider in the management of obesity. Medications for obesity can be simply categorized as FDA approved short-term use (diethylproprion, phendimetrazine, benzphetamine, and phentermine) and long-term use (orlistat, phentermine/topiramate ER, lorcaserin, naltrexone/bupropion ER and liraglutide). Additionally, type 2 diabetes (T2DM) is commonly seen in patients with obesity and necessitates consideration of pharmacological options that do not hinder patients' weight loss. Finally, weight-centric prescribing is also an important component to pharmacological management of obesity. It warrants that healthcare providers thoroughly review their patients' medication lists to determine if any of these agents could be contributing to weight gain.

  19. Pharmacological management of sepsis

    SciTech Connect

    Fletcher, J.R.

    1985-01-01

    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 clinical 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.

  20. SU-E-I-84: MRI Relaxation Properties of a Pre-Clinical Hypoxia-Sensitive MRI Contrast Agent

    SciTech Connect

    Yee, S; Wilson, G; Chavez, F

    2014-06-01

    Purpose: A possible hypoxia-sensitive MRI agent, hexamethyldisiloxane (HMDSO), has been tried to image oxygen level in proton-based MRI (Kodibagkar et al, NMR Biomed, 2008). The induced changes of T1 (or R1) value by the HMDSO as the oxygenation level changes are the principle that the hypoxia agent is based on: the R1 increases as the oxygen level increases. However, as reported previously, the range of R1 values (0.1–0.3 s-1, corresponding to 3–10 s of T1) is not in the range where a regular MRI technique can easily detect the change. In order for this agent to be widely applied in an MRI environment, more relaxation properties of this agent, including T1 in the rotating frame (T1rho) and T2, need to be explored. Here, the relaxation properties of this agent are explored. Methods: A phantom was made with HMDSO, water and mineral oil, each of which was prepared with oxygen and nitrogen, and was imaged in a 3T MRI system. The T1 properties were explored by the inversion recovery (TR=3000ms, TE=65ms) while varying the inversion time (TI), and also by the fast-field-echo (TR=2 ms, TE=2.8ms) while varying the flip angle (FA). T1rho was explored with a 5-pulse spin-locking technique (TR=5000ms, TE=10ms, spin-lock field=500Hz) while varying the spin-lock duration. T2 was explored with multi-shot TSE (TR=2500ms) while varying TE. Results: With the variable FA and TI, the signals of HMDSO with oxygen and nitrogen change in a similar way and do not respond well by the change of oxygen level, which confirms the large T1 value of HMDSO. The T1rho and T2, however, have a better sensitivity. Conclusion: For the possible pre-clinical hypoxia MRI agent (HMDSO), the detection of T1 (or R1) changes may be more challenging than the detection of other relaxation properties, particularly T2, as the oxygen level changes.

  1. The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator.

    PubMed

    Grant, Claire; Ewart, Lorna; Muthas, Daniel; Deavall, Damian; Smith, Simon A; Clack, Glen; Newham, Pete

    2016-04-01

    Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive "pica" behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting.

  2. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models

    PubMed Central

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-01-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

  3. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

    PubMed

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-09-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin.

  4. Pharmacological advances in addiction treatment.

    PubMed

    Preston, K L; Bigelow, G E

    1985-01-01

    In the past 20 years significant advances in the pharmacological treatment of opioid dependence have been made, and research in this area is continuing. Therapeutic applications and current research in the use of pharmacological agents in maintenance therapy, treatment with narcotic antagonists, and narcotic detoxification are discussed. In addition, an overview is presented of recent developments in opioid pharmacology and of recently developed novel pharmacological agents which may prove useful in the future treatment and/or prevention of opioid dependence.

  5. Pharmacological strategies for detoxification

    PubMed Central

    Diaper, Alison M; Law, Fergus D; Melichar, Jan K

    2014-01-01

    Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2-adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti-glutamatergics and γ-aminobutyric acid (GABA)-ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination. PMID:24118014

  6. Is chromium pharmacologically relevant?

    PubMed

    Vincent, John B

    2014-10-01

    Recent research, combined with reanalysis of previous results, has revealed that chromium can no longer be considered an essential trace element. Clinical studies are ambiguous at best as to whether Cr has a pharmacological effect in humans. Observed effects of Cr on rodent models of insulin resistance and diabetes are best interpreted in terms of a pharmacological role for Cr. Studies on the effects of Cr on rat models of diabetes are reviewed herein and suggest Cr increases insulin sensitivity in peripheral tissues of the rodent models. The lack of effects in human studies may stem from humans receiving a comparably smaller dose than the rodent models. However, given the different responses to Cr in the rodent models, humans could potentially have different responses to Cr.

  7. [Pharmacological biomodulation in cancer].

    PubMed

    Arvelo, F; Merentes, E

    2001-01-01

    The discovery of the P-glycoprotein as a mediator of multidrug resistance (MDR) represents one of the most important research accomplishments in antineoplastic pharmacology during the last decade. Demonstration of Pgp in epithelial tissues, untreated and chemotherapeutically pretreated human malignancies, and identification of various agents capable of reversing in vitro resistance has generated enthusiasm for clinical studies throughout the world. This review discusses recent developments of experimental and clinical investigations of MDR reversing agents in cancer.

  8. Pharmacology of Periodontal Disease.

    DTIC Science & Technology

    1986-06-23

    AD-AL6S 614 PHARNACOLOSY OF PERIODOINTAL DISEASE (U) UNIVERSITY OF vi1 HEALTH SCIENCES/CHICAGO NEDICAL SCHOOL DEPT OF PHRNACOLOGY S F HOFF 23 JUN 86...Capital Region Bethesda, MD 20814-5044 RE: Annual Letter Report ONC Contract #N00014-84-K-0562 "Pharmacology of Periodontal Disease " Dear Capt. Hancock...Periodontal Disease " ist Steven F. Hoff, Ph.D. (Principal Investigator) A. ’Progress Report: We are attempting to dentifyrntibacterial and anti

  9. Social Pharmacology: Expanding horizons

    PubMed Central

    Maiti, Rituparna; Alloza, José Luis

    2014-01-01

    In the current modern and global society, social changes are in constant evolution due to scientific progress (technology, culture, customs, and hygiene) and produce the freedom in individuals to take decisions by themselves or with their doctors toward drug consumption. In the arena of marketed drug products which includes society, individual, administration, and pharmaceutical industry, the young discipline emerged is social pharmacology or sociopharmacology. This science arises from clinical pharmacology, and deals with different parameters, which are important in creating knowledge on marketed drugs. However, the scope of “social pharmacology” is not covered by the so-called “Phase IV” alone, but it is the science that handles the postmarketing knowledge of drugs. The social pharmacology studies the “life cycle” of any marketed pharmaceutical product in the social terrain, and evaluates the effects of the real environment under circumstances totally different in the drug development process. Therefore, there are far-reaching horizons, plural, and shared predictions among health professionals and other, for beneficial use of a drug, toward maximizing the benefits of therapy, while minimizing negative social consequences. PMID:24987168

  10. Pharmacological interactions of vasoconstrictors.

    PubMed

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-01-01

    This article is the first of a series on pharmacological interactions involving medicaments commonly prescribed and/or used in odontology: vasoconstrictors in local anaesthetics and anti-inflammatory and anti-microbial analgesics. The necessity for the odontologist to be aware of adverse reactions as a result of the pharmacological interactions is due to the increase in medicament consumption by the general population. There is a demographic change with greater life expectancy and patients have increased chronic health problems and therefore have increased medicament intake. The presence of adrenaline (epinephrine) and other vasoconstrictors in local odontological anaesthetics is beneficial in relation to the duration and depth of anaesthesia and reduces bleeding and systemic toxicity of the local anaesthetic. However, it might produce pharmacological interactions between the injected vasoconstrictors and the local anaesthetic and adrenergic medicament administered exogenically which the odontologist should be aware of, especially because of the risk of consequent adverse reactions. Therefore the importance of conducting a detailed clinical history of the general state of health and include all medicaments, legal as well as illegal, taken by the patient.

  11. NOTE: Pre-clinical evaluation of respiratory-gated delivery of volumetric modulated arc therapy with RapidArc

    NASA Astrophysics Data System (ADS)

    Nicolini, Giorgia; Vanetti, Eugenio; Clivio, Alessandro; Fogliata, Antonella; Cozzi, Luca

    2010-06-01

    conditions. Δ(Gantry angle) = 0.38 ± 0.01° for 2 Gy (all gate periods), 0.24 ± 0.01° for 5 Gy, and 0.10 ± 0.01° for 15 Gy deliveries. Average deviations for multileaf collimator (MLC) positions (root mean square over all 120 leaves) were 0.45 ± 0.01 mm for 2 Gy (all gate periods), 0.32 ± 0.01 mm for 5 Gy and 0.14 ± 0.01 mm for 15 Gy. Results in terms of dose measurements confirmed that the application of gating to RapidArc delivery does not affect the quality of the dose delivery. With criteria of ΔD = 3%, DTA = 3 mm, the gamma test was passing in a range of 99 to 100% of the measured points for most of the cases (with maximum number of interruptions of about 20 per arc) and from 97 to 98% for the extreme case of 15 Gy and 8 s gate-open signal (corresponding to almost 50 interruptions per arc). In conclusion, RapidArc delivery proved, in a pre-clinical phase and non-clinically released framework, to be reliable and dosimetrically accurate also when applied in conjunction with gating procedures.

  12. Pre-clinical evaluation of respiratory-gated delivery of volumetric modulated arc therapy with RapidArc.

    PubMed

    Nicolini, Giorgia; Vanetti, Eugenio; Clivio, Alessandro; Fogliata, Antonella; Cozzi, Luca

    2010-06-21

    gating conditions. Delta(Gantry angle) = 0.38 +/- 0.01 degrees for 2 Gy (all gate periods), 0.24 +/- 0.01 degrees for 5 Gy, and 0.10 +/- 0.01 degrees for 15 Gy deliveries. Average deviations for multileaf collimator (MLC) positions (root mean square over all 120 leaves) were 0.45 +/- 0.01 mm for 2 Gy (all gate periods), 0.32 +/- 0.01 mm for 5 Gy and 0.14 +/- 0.01 mm for 15 Gy. Results in terms of dose measurements confirmed that the application of gating to RapidArc delivery does not affect the quality of the dose delivery. With criteria of Delta D = 3%, DTA = 3 mm, the gamma test was passing in a range of 99 to 100% of the measured points for most of the cases (with maximum number of interruptions of about 20 per arc) and from 97 to 98% for the extreme case of 15 Gy and 8 s gate-open signal (corresponding to almost 50 interruptions per arc). In conclusion, RapidArc delivery proved, in a pre-clinical phase and non-clinically released framework, to be reliable and dosimetrically accurate also when applied in conjunction with gating procedures.

  13. Molecular Pharmacology of Phytocannabinoids.

    PubMed

    Turner, Sarah E; Williams, Claire M; Iversen, Leslie; Whalley, Benjamin J

    Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years. The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ(9)-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content. Δ(9)-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2. Δ(9)-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ(9)-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis. This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene. The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond. The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects. The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.

  14. Pharmacologic agents targeting autophagy

    PubMed Central

    Vakifahmetoglu-Norberg, Helin; Xia, Hong-guang; Yuan, Junying

    2015-01-01

    Autophagy is an important intracellular catabolic mechanism critically involved in regulating tissue homeostasis. The implication of autophagy in human diseases and the need to understand its regulatory mechanisms in mammalian cells have stimulated research efforts that led to the development of high-throughput screening protocols and small-molecule modulators that can activate or inhibit autophagy. Herein we review the current landscape in the development of screening technology as well as the molecules and pharmacologic agents targeting the regulatory mechanisms of autophagy. We also evaluate the potential therapeutic application of these compounds in different human pathologies. PMID:25654545

  15. The pharmacology game.

    PubMed

    Batscha, Catherine

    2002-09-01

    This article gives instructions for designing a visually attractive, entertaining, faculty-led computer game for pharmacology review in a nursing education program. The game uses Microsoft PowerPoint, a presentation program that is inexpensive, easy to master, and widely available. Instructions for using Visual Basic for Applications to customize the game are included to allow tracking questions asked and the score of groups playing the game. The game can be easily adapted to material by specific nursing programs with access to PowerPoint.

  16. Analytical pharmacology: the impact of numbers on pharmacology.

    PubMed

    Kenakin, Terry; Christopoulos, Arthur

    2011-04-01

    Analytical pharmacology strives to compare pharmacological data to detailed quantitative models. The most famous tool in this regard is the Black/Leff operational model, which can be used to quantify agonism in a test system and predict it in any other system. Here we give examples of how and where analytical pharmacology has been used to classify drugs and predict mechanism of action in pharmacology. We argue for the importance of analytical pharmacology in drug classification and in prediction of drug mechanisms of action. Although some of the specifics of Black's models have been updated to account for new developments, the principles of analytical pharmacology should shape drug discovery for many years to come.

  17. Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): a complementary drug with historical and clinical significance.

    PubMed

    Dajani, E Z; Shahwan, T G; Dajani, N E

    2016-12-01

    Nigella sativa (N. sativa, black seeds; or sometimes known by many other names such as the blessed seed by the Arabs, black cumin in the Holy Bible, black caraway and Kalonji in South Asia) has been traditionally used for many years not only as a food but also as complementary drug. It is the objective of this communication to review the evidence-based pre-clinical pharmacological actions of N. sativa as a basis of its existing and potential new human clinical uses. Primary PubMed literature searches and secondary Medline searches were conducted to define N. sativa pre-clinical pharmacological and toxicological actions using a retrospective narrative review of the published studies. The ground seeds, its oil and its various extracts exhibit very broad pharmacological actions in laboratory studies, which are predictive of human clinical efficacy. In laboratory studies, N. sativa possesses anti-inflammatory, analgesic, anti-diabetic, anti-hyperlipidemic, anti-convulsant, anti-microbial, anti-ulcer, anti-hypertensive, anti-asthmatic and anti-cancer activities. Its mode of action is mediated via several mechanisms, which include anti-oxidant, immunomodulating, cytoprotective and an inhibitory effect on some mediators of inflammation. Although the seeds contain many chemical components, thymoquinone and alpha-hederin are proven to be pharmacologically active. Despite N. sativa broad and worldwide pharmacological characterization, only limited non-clinical safety studies were reported. N. sativa has many potentially important therapeutic applications. The black seeds clearly warrant formal preclinical drug development consideration to investigate the pharmacology of its components, to standardize the contents of the dosage forms, to define the methods of the pharmaceutical preparation, to determine its pharmacokinetics characteristics and its safety profile. It is our opinion that N. sativa should be considered for clinical development initially for unmet therapeutic

  18. Epigenetics and pharmacology.

    PubMed

    Stefanska, Barbara; MacEwan, David J

    2015-06-01

    Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity 'beyond' simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered - it is pharmacology that will have to keep pace.

  19. Epigenetics and pharmacology

    PubMed Central

    Stefanska, Barbara; MacEwan, David J

    2015-01-01

    Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity ‘beyond’ simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered – it is pharmacology that will have to keep pace. PMID:25966315

  20. Radiochemical studies, pre-clinical investigation and preliminary clinical evaluation of (170)Tm-EDTMP prepared using in-house freeze-dried EDTMP kit.

    PubMed

    Das, Tapas; Shinto, Ajit; Kamaleshwaran, Koramadai K; Sarma, Haladhar D; Mohammed, Sahiralam Khan; Mitra, Arpit; Lad, Sangita; Rajan, M G R; Banerjee, Sharmila

    2017-01-05

    The objective of the present work is to formulate (170)Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of (170)Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration.

  1. Gaining the hard yard: pre-clinical evaluation of lentiviral-mediated gene therapy for the treatment of beta-thalassemia.

    PubMed

    Milsom, Michael D; Williams, David A

    2010-08-01

    Gene therapy is one potential novel therapeutic avenue for the treatment of inherited monogenic disorders. Diseases of the blood are frequent targets for gene therapy because it is relatively easy to harvest haematopoiesis stem cells (HSCs) from the bone marrow, genetically modify the cells ex vivo, and then re-administer the corrected cells back into the patient via intra-venous injection. In this Closeup, Milsom and Williams discuss the work of Roselli et al, who describe the pre-clinical evaluation of the treatment for beta-thalassemia in erythroid cells via the genetic correction of patient HSCs using a lentiviral vector.

  2. Pharmacology of antiplatelet agents.

    PubMed

    Kalra, Kiran; Franzese, Christopher J; Gesheff, Martin G; Lev, Eli I; Pandya, Shachi; Bliden, Kevin P; Tantry, Udaya S; Gurbel, Paul A

    2013-12-01

    Pharmacotherapies with agents that inhibit platelet function have proven to be effective in the treatment of acute coronary syndromes, and in the prevention of complications during and after percutaneous coronary intervention. Because of multiple synergetic pathways of platelet activation and their close interplay with coagulation, current treatment strategies are based not only on platelet inhibition, but also on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current strategies can be broadly categorized as anticoagulants, antiplatelet agents, and fibrinolytics. This review focuses on the pharmacology of current antiplatelet therapy primarily targeting the inhibition of the enzyme cyclooxygenase 1, the P2Y12 receptor, the glycoprotein IIb/IIIa receptor, and protease-activated receptor 1.

  3. Pharmacology of fenofibrate.

    PubMed

    Chapman, M J

    1987-11-27

    This discussion outlines the major aspects of the human pharmacology of fenofibrate, a hypolipidemic agent. In view of its short half-life, efficient absorption, and elimination, fenofibrate would not appear to accumulate in either plasma or tissues. It is extensively absorbed only in the presence of food and is transported through the bloodstream by albumin. Fenofibrate is taken up by both the liver and kidney. Except for a small percentage (about 5 percent) reduced at the ketone moiety before conjugation, most drug is excreted as a conjugate in the urine. Less than 20 percent is excreted through the bile. In normal persons, at steady state with usual doses of 100 mg three times daily, the plasma half-life approximates 30 hours. Because fenofibrate is not dialyzable, it has a markedly prolonged half life in patients with renal failure and should not be used.

  4. Pharmacologic stress imaging

    SciTech Connect

    Beller, G.A. )

    1991-02-06

    Pharmacologic stress imaging has increasingly been employed as an alternative to exercise imaging for detection of coronary artery disease and risk stratification particularly in patients who are unable to perform adequate exercise. Sensitivity and specificity of thallium 201 scintigraphy using intravenous dipyridamole infusion as a stress for coronary artery disease detection average 85% and 91%, respectively. Dipyridamole imaging is also useful for differentiating between ischemia and scar and identifying patients who have an increased risk for subsequent cardiac events. Dipyridamole imaging is particularly useful for preoperative risk stratification in patients undergoing surgery for peripheral vascular or aortic disease. Dipyridamole imaging is also useful for identifying residual myocardial ischemia after myocardial infarction and detecting restenosis after coronary angioplasty. Adverse side effects of dipyridamole are promptly reversed by aminophylline. Dipyridamole stress can also be employed in association with echocardiography for detection of ischemia-induced regional wall motion abnormalities. 69 references.

  5. Pharmacologic therapy of asthma.

    PubMed

    Ellis, E F

    1976-04-01

    Asthma is treated by avoiding the precipitants of symptoms, by a trial of hyposensitization (immunotherapy) if the precipitant cannot be avoided, and principally by pharmacologic therapy. Acute attacks have been most widely treated with epinephrine, but adrenergic aerosol bronchodilators and aminophylline are being used increasingly. When an acute attack of asthma does not respond to treatment, a diagnosis of status asthmaticus should be considered and the patient treated in a hospital intensive care unit because of the potentially life-threatening sequela of respiratory failure. Periodic mild episodes of asthma usually respond to administration of an oral bronchodilator. Chronic low-grade asthma is best treated with an around-the-clock regimen of theophylline. Patients whose asthma is not under satisfactory control with conventional bronchodilators may be given a trial of cromolyn sodium. Chronic severe cases may be treated with corticosteroids, but these drugs must be skillfully administered to avoid adverse effects.

  6. Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies.

    PubMed

    Donaldson, Mitzi M; Kao, Shing-Fen; Eslamizar, Leila; Gee, Connie; Koopman, Gerrit; Lifton, Michelle; Schmitz, Joern E; Sylwester, Andrew W; Wilson, Aaron; Hawkins, Natalie; Self, Steve G; Roederer, Mario; Foulds, Kathryn E

    2012-12-14

    Vaccination and SIV challenge of macaque species is the best animal model for evaluating candidate HIV vaccines in pre-clinical studies. As such, robust assays optimized for use in nonhuman primates are necessary for reliable ex vivo measurement of immune responses and identification of potential immune correlates of protection. We optimized and qualified an 8-color intracellular cytokine staining assay for the measurement of IFNγ, IL-2, and TNF from viable CD4 and CD8 T cells from cryopreserved rhesus macaque PBMC stimulated with peptides. After optimization, five laboratories tested assay performance using the same reagents and PBMC samples; similar results were obtained despite the use of flow cytometers with different configurations. The 8-color assay was then subjected to a pre-qualification study to quantify specificity and precision. These data were used to set positivity thresholds and to design the qualification protocol. Upon completion of the qualification study, the assay was shown to be highly reproducible with low inter-aliquot, inter-day, and inter-operator variability according to the qualification criteria with an overall variability of 20-40% for each outcome measurement. Thus, the 8-color ICS assay was formally qualified according to the ICH guidelines Q2 (R1) for specificity and precision indicating that it is considered a standardized/robust assay acceptable for use in pre-clinical trial immunogenicity testing.

  7. Practical review of pharmacology concepts.

    PubMed

    Janda, Sue M; Fagan, Nancy L

    2010-01-01

    Pharmacology concepts are used routinely in nursing practice. These concepts may be as simple as drug names and side effects, or as complex as pharmacokinetics or pharmacodynamics. All play major roles in drug efficacy and safety. A practical review of pharmacology, including pharmacokinetic and pharmacodynamic concepts, will be presented.

  8. Medicinal herb research: serum pharmacological method and plasma pharmacological method.

    PubMed

    Ge, Jinwen; Wang, Dongsheng; He, Rong; Zhu, Huibin; Wang, Yuhong; He, Shilin

    2010-01-01

    Serum pharmacological method has generally been used in herb studies. However, preparation of test serum for ex vivo experiment is an intricate process: besides pretreatment (heat or chemicals), it involves the proteolytic cascades of coagulation along with fibrinolysis, complement and kinin systems, as well as platelet and leukocyte activation resulting in release reactions. These processes deviate serum sample components away from the original in vivo state, and possibly also have effects on the absorbed herbal components and their downstream effectors in blood. The conclusions drawn from serum pharmacological method are at least partially uncertain in its validity. These processes can be avoided by anticoagulation. Compared to those of the serum, constituents of plasma are better reflectors of the in vivo physiological/pathological state and medicinal herb-induced changes. Therefore, we have advocated the adoption of plasma pharmacological method in ex vivo experiments of herb studies. Recent studies including our work demonstrated that the constituents and biological activities are partially different between absorbed medicinal herbs in plasma and serum. This review summarizes the experimental evidence supporting the feasibility of plasma pharmacological method and discusses the reasons and facts that flaw the serum pharmacological method. But serum pharmacological method can be used if anticoagulants interfere with experiments. It should be emphasized that the domination between plasma and serum pharmacological methods is different depending on the usage. Indeed, the pros and cons of both methods as well as the appropriate choices of coagulants in different ex vivo experimental settings remain to be further elucidated.

  9. Pharmacological treatment of vertigo.

    PubMed

    Hain, Timothy C; Uddin, Mohammed

    2003-01-01

    This review discusses the physiology and pharmacological treatment of vertigo and related disorders. Classes of medications useful in the treatment of vertigo include anticholinergics, antihistamines, benzodiazepines, calcium channel antagonists and dopamine receptor antagonists. These medications often have multiple actions. They may modify the intensity of symptoms (e.g. vestibular suppressants) or they may affect the underlying disease process (e.g. calcium channel antagonists in the case of vestibular migraine). Most of these agents, particularly those that are sedating, also have a potential to modulate the rate of compensation for vestibular damage. This consideration has become more relevant in recent years, as vestibular rehabilitation physical therapy is now often recommended in an attempt to promote compensation. Accordingly, therapy of vertigo is optimised when the prescriber has detailed knowledge of the pharmacology of medications being administered as well as the precise actions being sought. There are four broad causes of vertigo, for which specific regimens of drug therapy can be tailored. Otological vertigo includes disorders of the inner ear such as Ménière's disease, vestibular neuritis, benign paroxysmal positional vertigo (BPPV) and bilateral vestibular paresis. In both Ménière's disease and vestibular neuritis, vestibular suppressants such as anticholinergics and benzodiazepines are used. In Ménière's disease, salt restriction and diuretics are used in an attempt to prevent flare-ups. In vestibular neuritis, only brief use of vestibular suppressants is now recommended. Drug treatments are not presently recommended for BPPV and bilateral vestibular paresis, but physical therapy treatment can be very useful in both. Central vertigo includes entities such as vertigo associated with migraine and certain strokes. Prophylactic agents (L-channel calcium channel antagonists, tricyclic antidepressants, beta-blockers) are the mainstay of treatment

  10. Pharmacology of appetite suppression.

    PubMed

    Halford, J C; Blundell, J E

    2000-01-01

    Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i

  11. Pharmacology of cannabinoids.

    PubMed

    Grotenhermen, Franjo

    2004-01-01

    Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.

  12. Pharmacological inhibition of FTO.

    PubMed

    McMurray, Fiona; Demetriades, Marina; Aik, WeiShen; Merkestein, Myrte; Kramer, Holger; Andrew, Daniel S; Scudamore, Cheryl L; Hough, Tertius A; Wells, Sara; Ashcroft, Frances M; McDonough, Michael A; Schofield, Christopher J; Cox, Roger D

    2015-01-01

    In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity.

  13. Pharmacology of parturition.

    PubMed

    Roy, A C; Arulkumaran, S

    1991-01-01

    Uterine contractions in labour are influenced by endogenous substances such as oestrogens, progesterone, cortisol, oxytocin, prostaglandins, relaxin, adrenergic and cholinergic secretions, cyclic nucleotides and calcium ions. Effects of progesterone and oestrogens are complimentary as well as antagonistic to each other. They regulate formation of gap junctions, influx of calcium ions, synthesis of oxytocin, adrenergic receptors and of prostaglandins and cyclic nucleotides. Cortisol shares a role in a more complex endocrine trigger but is ineffective alone in the initiation of human labour. Adrenaline inhibits and noradrenaline promotes uterine contractions. Cholinergic stimulation increases cyclic GMP promoting uterine contractions. Calcium ions play a key role in uterine contractility. Oxytocin, prostaglandins E and F are powerful stimulants of uterine contractions. Prostaglandins stimulate pregnant uterus from early gestation unlike oxytocin which has little effect in the first and second trimester. They are extensively used for initiating labour and to arrest intractable atonic postpartum haemorrhage. In experiments and in vivo, their effects are modulated by other hormones and substances. With discovery of new drugs, knowledge of how they act on the uterus becomes important. The pharmacology of parturition that may help to understand the interaction of various agents on the pregnant uterus has been discussed.

  14. Narcolepsy: pathophysiology and pharmacology.

    PubMed

    Nishino, Seiji

    2007-01-01

    Narcolepsy, which affects 1 in 2000 people in the general population, is characterized by excessive daytime sleepiness (EDS), cataplexy, and other dissociated manifestations of rapid eye movement sleep (hypnagogic hallucinations and sleep paralysis). The disease is currently treated with amphetamine-like central nervous system stimulants (for EDS) and antidepressants (for cataplexy). Some compounds from other classes, such as modafinil (a non-amphetamine wake-promoting compound for EDS) and sodium oxybate (a short-acting sedative for EDS and cataplexy, administered at night), are also employed. The major pathophysiology of human narcolepsy has recently been revealed by the extension of discoveries of narcolepsy genes in animal models: hypocretin/orexin ligand deficiency has been shown in about 90% of human narcolepsy-cataplexy. This finding led directly to the development of new diagnostic tests (i.e., cerebrospinal fluid hypocretin measures). Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but is still not available in humans. In this review, the pharmacologic and pathophysiologic aspects of narcolepsy are discussed.

  15. Pharmacologic Management of Cough

    PubMed Central

    Bolser, Donald C.

    2009-01-01

    This review is an update of recent advances in our understanding of cough suppressants and impairment of cough. Low dose oral morphine has recently been shown to significantly suppress chronic cough, but the side effect profile of this opioid may limit its widespread utility. Several studies have demonstrated a dissociation between the efficacy of antitussives in some metrics of pathological cough and their effects on cough sensitivity to inhaled irritants. The relevance of widely used inhaled irritants in understanding pathological cough and its response to antitussives is questionable. A recent advance in the field is the identification and measurement of an index of sensation related to cough, the urge-to-cough. This measure highlights the potential involvement of suprapontine regions of the brain in the genesis and potential suppression of cough in the awake human. There are no new studies showing that mucolytic agents are of value as monotherapies for chronic cough. However, some of these drugs may be of use as adjunct therapies or in selected patient populations, presumably due to their antioxidant activity. The term dystussia (impairment of cough) has been coined recently and represents a common and life-threatening problem in patients with neurological disease. Dystussia is strongly associated with severe dysphagia and the occurrence of both indicates that the patient has a high risk for aspiration. There are no pharmacological treatments for dystussia, but the community of scientists and clinicians that have experience in studying chronic cough is uniquely well qualified to develop methodologies that enhance impaired cough. PMID:20172264

  16. Pharmacologic treatment of alcoholism.

    PubMed

    Anton, Raymond F; Schacht, Joseph P; Book, Sarah W

    2014-01-01

    Progress in understanding the neuroscience of addiction has significantly advanced the development of more efficacious medications for the treatment of alcohol use disorders (AUD). While several medications have been approved by regulatory bodies around the world for the treatment of AUD, they are not universally efficacious. Recent research has yielded improved understanding of the genetics and brain circuits that underlie alcohol reward and its habitual use. This research has contributed to pharmacogenetic studies of medication response, and will ultimately lead to a more "personalized medicine" approach to AUD pharmacotherapy. This chapter summarizes work on clinically available medications (both approved by regulatory bodies and investigational) for the treatment of alcohol dependence, as well as the psychiatric disorders that are commonly comorbid with AUD. Studies that have evaluated genetic influences on medication response and those that have employed neuroimaging to probe mechanisms of medication action or response are highlighted. Finally, new targets discovered in animal models for possible pharmacologic intervention in humans are overviewed and future directions in medications development provided. © 2014 Elsevier B.V. All rights reserved.

  17. Pharmacological research in neonatology.

    PubMed

    Dotta, Andrea; Braguglia, Annabella; Salvatori, Guglielmo

    2011-10-01

    In neonatology unit 40 to 80% of the drugs are used as off-label or unlicensed, particularly in Neonatal Intensive Care Unit (NICU), where it has been described that in a single patient up to 60 parenteral drugs can be administered. The course of a drug inside the organism can be defined in 4 different phases: absorption, distribution, metabolism, elimination; for each of these phases the newborn infant has different characteristics than child and adult. In the last years much more attention has been put in pharmacological research specific for the neonatal age and a good trial design should take into account the following points: (1) to define the pediatric disease in terms of natural history, prevalence, severity, treatment and impact of the new drug; (2) to avoid the "try and error" method based on the adult dose corrected for weight or age; (3) to use adapted methodologies (pharmacokinetics); (4) to avoid small clinical trials (limited number of patients), the use of Randomized Controlled Trials rather than observational studies; (5) to consider ethics providing clear information and reducing pain and stress to the baby and its family.

  18. Pharmacology of taurine.

    PubMed

    Oja, Simo S; Saransaari, Pirjo

    2007-01-01

    Taurine has a number of physiological functions, e.g., in cell volume regulation and inhibitory neuromodulation. Taurine and its derivatives have also been tested as potential pharmacological agents in many pathological states. We endeavor here to review the present status of this investigation. Taurine (2-aminoethanesulfonic acid) is a simple sulfur-containing amino acid present in virtually all cells throughout the animal kingdom. In particular, it is enriched in electrically excitable tissues such as brain, retina, heart and skeletal muscles. In the central nervous system, taurine has been implicated in two major phenomena; in cell volume regulation [1-3] and in inhibitory neuromodulation or neurotransmission [4-7]. Its function as a neurotransmitter implies the existence of specific taurine receptors and the neuromodulatory role, an interference with functions of other transmitter systems. There is scant evidence to corroborate the first assumption, but ample for the latter. In other tissues taurine has also been thought to act as an antioxidant in cell protection and to have beneficial effects on cardiovascular functions. These taurine properties are only partially explored so far but taurine and many of its derivatives have been tested as potential pharmaceutical agents in a number of pathological states.

  19. [Pharmacological treatment of obesity].

    PubMed

    Gomis Barbará, R

    2004-01-01

    The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. Orlistat is an inhibitor of pancreatic lipase which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite.

  20. Clinical Pharmacology of Sisomicin

    PubMed Central

    Rodriguez, Victorio; Bodey, Gerald P.; Valdivieso, Manuel; Feld, Ronald

    1975-01-01

    Studies were conducted in 30 patients with neoplastic diseases. Twelve patients received sisomicin intramuscularly at doses of 20 mg/m2 and 40 mg/m2. The mean peak serum concentration occurred at 1 h and was 2.5 μg/ml and 4.0 μg/ml, respectively. Ten patients received intravenous sisomicin at doses of 30 mg/m2 during 30-min infusion. Mean peak serum level determined at 30 min was 5.1 μg/ml. The levels gradually decreased and at 6 h was 0.6 μg/ml. The serum half-life was 160 min. Serum levels determined in eight patients who received sisomicin by continuous infusion at doses of 30 mg/m2 every 6 h were greater than 1.4 μg/ml during the 6-h period. The urinary excretion of sisomicin during the 6-h period after intramuscular administration of 20 mg/m2 and 40 mg/m2 was 49 and 61%, respectively. The pharmacology of sisomicin is similar to gentamicin. PMID:1137357

  1. [Pharmacological effects of hordenine].

    PubMed

    Hapke, H J; Strathmann, W

    1995-06-01

    Hordenine is an ingredient of some plants which are used as feed for animals, i.e. in sprouting barley. After ingestion of such feed hordenine may be detected in blood or urine of horses which in case of racing horses may be the facts of using prohibited compounds. Results of some experiments in pharmacological models show that hordenine is an indirectly acting adrenergic drug. It liberates norepinephrine from stores. In isolated organs and those structures with reduced epinephrine contents the hordenine-effect is only very poor. Experiments in intact animals (rats, dogs) show that hordenine has a positive inotropic effect upon the heart, increases systolic and diastolic blood pressure, peripheral blood flow volume, inhibits gut movements but has no effect upon the psychomotorical behaviour of mice. All effects are short and only possible after high doses which are not to be expected after ingestion of hordenine containing feed for horses. A measurable increase of the performance of racing horses is quite improbable.

  2. Pharmacological Inhibition of FTO

    PubMed Central

    McMurray, Fiona; Demetriades, Marina; Aik, WeiShen; Merkestein, Myrte; Kramer, Holger; Andrew, Daniel S.; Scudamore, Cheryl L.; Hough, Tertius A.; Wells, Sara; Ashcroft, Frances M.; McDonough, Michael A.; Schofield, Christopher J.; Cox, Roger D.

    2015-01-01

    In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity. PMID:25830347

  3. Pharmacological profile of sulodexide.

    PubMed

    Hoppensteadt, D A; Fareed, J

    2014-06-01

    Since its introduction, sulodexide has been used on and off for several indications. More recently this agent has become revitalized and tested in newer indications. Sulodexide is composed of glycosaminoglycan that includes a mixture of fast-moving heparin and dermatan sulfate. It exerts its anticoagulant and antithrombotic action through interactions with both AT and HCII. Sulodexide has been proven to have effects on the fibrinolytic system, platelets, endothelial cells, inflammation and more recently metalloproteases. The administration of sulodexide results in the release of lipoprotein lipase and has been shown to reduce the circulating level of lipids. It has also shown to decrease the viscosity of both whole blood and plasma. Sulodexide differs from heparin in its oral bioavailability and longer half-life. There is also less bleeding associated with sulodexide. In addition, oral administration of sulodexide does not interfere with the pharmacologic actions of commonly used agents. Similar to heparin, sulodexide releases TFPI which contributes to its antithrombotic effect and anti-inflammatory properties. Sulodexide has been proven to be effective in peripheral arterial thrombosis and venous thrombosis. It is also clinically active in the treatment of venous leg ulcers and intermittent claudication. More recent data suggest that sulodexide can be used in tinnitus and in vascular vertigo. Additional studies in these indications are required. Sulodexide was generally safe and well tolerated in the clinical trials, without any severe bleeding complications. Therefore sulodexide appears to be a good treatment for all arterial and venous diseases and for the prevention of progression of disease.

  4. Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies

    PubMed Central

    Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.

    2011-01-01

    Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72 h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible

  5. Comparison of region-of-interest-averaged and pixel-averaged analysis of DCE-MRI data based on simulations and pre-clinical experiments

    NASA Astrophysics Data System (ADS)

    He, Dianning; Zamora, Marta; Oto, Aytekin; Karczmar, Gregory S.; Fan, Xiaobing

    2017-09-01

    Differences between region-of-interest (ROI) and pixel-by-pixel analysis of dynamic contrast enhanced (DCE) MRI data were investigated in this study with computer simulations and pre-clinical experiments. ROIs were simulated with 10, 50, 100, 200, 400, and 800 different pixels. For each pixel, a contrast agent concentration as a function of time, C(t), was calculated using the Tofts DCE-MRI model with randomly generated physiological parameters (K trans and v e) and the Parker population arterial input function. The average C(t) for each ROI was calculated and then K trans and v e for the ROI was extracted. The simulations were run 100 times for each ROI with new K trans and v e generated. In addition, white Gaussian noise was added to C(t) with 3, 6, and 12 dB signal-to-noise ratios to each C(t). For pre-clinical experiments, Copenhagen rats (n  =  6) with implanted prostate tumors in the hind limb were used in this study. The DCE-MRI data were acquired with a temporal resolution of ~5 s in a 4.7 T animal scanner, before, during, and after a bolus injection (<5 s) of Gd-DTPA for a total imaging duration of ~10 min. K trans and v e were calculated in two ways: (i) by fitting C(t) for each pixel, and then averaging the pixel values over the entire ROI, and (ii) by averaging C(t) over the entire ROI, and then fitting averaged C(t) to extract K trans and v e. The simulation results showed that in heterogeneous ROIs, the pixel-by-pixel averaged K trans was ~25% to ~50% larger (p  <  0.01) than the ROI-averaged K trans. At higher noise levels, the pixel-averaged K trans was greater than the ‘true’ K trans, but the ROI-averaged K trans was lower than the ‘true’ K trans. The ROI-averaged K trans was closer to the true K trans than pixel-averaged K trans for high noise levels. In pre-clinical experiments, the pixel-by-pixel averaged K trans was ~15% larger than the ROI-averaged K trans. Overall, with the Tofts model, the extracted

  6. Meta-Analysis of Pre-Clinical Studies of Early Decompression in Acute Spinal Cord Injury: A Battle of Time and Pressure

    PubMed Central

    Skeers, Peta; Battistuzzo, Camila R.; Macleod, Malcolm R.; Howells, David W.; Sena, Emily S.

    2013-01-01

    Background The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression. Methods We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression. Results Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I2=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r2=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours. Conclusion These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close

  7. The pharmacology of regenerative medicine.

    PubMed

    Christ, George J; Saul, Justin M; Furth, Mark E; Andersson, Karl-Erik

    2013-07-01

    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.

  8. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS

  9. A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation

    PubMed Central

    Kleikers, Pamela WM.; Hooijmans, Carlijn; Göb, Eva; Langhauser, Friederike; Rewell, Sarah SJ.; Radermacher, Kim; Ritskes-Hoitinga, Merel; Howells, David W.; Kleinschnitz, Christoph; HHW Schmidt, Harald

    2015-01-01

    Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2-/y studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias. PMID:26310318

  10. Increased Cost of Motor Activity and Heat Transfer between Non-Shivering Thermogenesis, Motor Activity, and Thermic Effect of Feeding in Mice Housed at Room Temperature – Implications in Pre-Clinical Studies

    PubMed Central

    Even, Patrick C.; Blais, Anne

    2016-01-01

    The components of energy expenditure, total metabolic rate (TMR), resting metabolic rate (RMR), thermogenic response to feeding (TEF), activity, and cost of activity were measured in fed and fasted mice housed at 22 and 30°C. Mice housed at 22°C had more than two times larger TMR and RMR. Mice at 22°C were less active when fasted but more active when fed. Cost of activity was nearly doubled in the fasted and in the fed state. Analysis of the short-term relation between TMR, RMR, and bouts of activity showed that, at 22°C, the bouts of activity induced a decrease in the intensity of RMR that reflected the reduced need for thermal regulation induced by the heat released from muscular contraction. This phenomenon induced a considerable underestimation of TEF and prevented its reliable measurement when mice were housed at 22°C. Correlation between TMR and activity measured across time in individual mice was very strong at both 22 and 30°C, but the correlation measured across mice was much weaker at 30°C and no longer significant at 22°C. We suspect that this phenomenon was due to the fact that RMR is a much more reliable predictor of TMR than activity. RMR is more variable at 22°C than at 30°C because of heat transfers between thermal regulation and heat released by other discontinuous processes, such as activity and TEF. Therefore, more noise is introduced into the correlations performed across multiple mice between TMR and activity at 22°C. On the other hand, it should be kept in mind that the doubling of TMR and RMR at 22°C is fueled by an increased non-shivering thermogenesis that can obviously modify how the mouse responds to pharmacological and nutritional challenges. Taken together, these results suggest that in pre-clinical studies, mice should be housed in conditions where thermal regulation is limited as is generally the case in humans. However, the increased sensitivity of mice to small changes in ambient temperature can also be used as a

  11. 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.

  12. Monitoring of anti-cancer treatment with 18F-FDG and 18F-FLT PET: a comprehensive review of pre-clinical studies

    PubMed Central

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and 3’-deoxy-3’-[18F]fluorothymidine(18F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With 18F-FDG and 18F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether 18F-FDG and/or 18F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in 18F-FDG and 18F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used 18F-FDG and/or 18F-FLT PET for response monitoring of cancer therapeutics. PMID:26550536

  13. The relation between aged blood products and onset of transfusion-related acute lung injury. A review of pre-clinical data.

    PubMed

    Vlaar, A P; Straat, M; Juffermans, N P

    2011-01-01

    Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion related morbidity and mortality. TRALI is suggested to be a "two hit" event. The "first hit" is the underlying condition of the patient which results in sequestration and priming of neutrophils in the pulmonary compartment. The "second hit" is the transfusion of either human leukocyte antibodies or aged blood products which results in activation of the primed neutrophils and finally in pulmonary edema. The present review focuses on pre-clinical studies investigating the role of blood products containing aged cells (red blood cells, RBCs, and platelet concentrates, PLTs) and the onset of TRALI. Several mechanisms are under scrutiny. The first suggested mechanism is that soluble mediators accumulating during storage of RBCs and PLTs may play a role, including bio-active lipids or soluble CD40L. These soluble factors were found to cause lung injury in the presence of a "first hit". Another proposed mechanism involves the aged erythrocyte itself. During storage, the erythrocyte undergoes numerous changes in its biochemical and structural condition and acquires pro-inflammatory properties, sometimes collectively referred to as the "red cell storage lesion". Although it could be speculated that all of these factors may be involved in the onset of TRALI, only one pre-clinical study shows an association between the aged erythrocyte and the onset of TRALI. The suggested mechanism is a decrease in the chemokine scavenging function of the erythrocyte by reduction of the Duffy antigen expression resulting in an increase in lung injury. Further research is needed to elucidate possible mechanisms of onset of TRALI by aged blood products.

  14. Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform.

    PubMed

    Almeida, Gilberto S; Panek, Rafal; Hallsworth, Albert; Webber, Hannah; Papaevangelou, Efthymia; Boult, Jessica Kr; Jamin, Yann; Chesler, Louis; Robinson, Simon P

    2017-09-05

    The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated. Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T2-weighted imaging, quantitation of the native longitudinal relaxation time (T1) and the transverse relaxation rate (R2*), and dynamic contrast-enhanced (DCE)-MRI, was used to assess tumour volume, phenotype and response to cyclophosphamide or cabozantinib. Excellent T2-weighted image contrast enabled clear tumour delineation at 3T. Significant correlations of tumour volume (R=0.98, P<0.0001) and R2* (R=0.87, P<0.002) measured at 3 and 7T were established. Mice with neuroblastomas harbouring the anaplastic lymphoma kinase mutation exhibited a significantly slower R2* (P<0.001), consistent with impaired tumour perfusion. DCE-MRI was performed simultaneously on three transgenic mice, yielding estimates of K(trans) for each tumour (median K(trans) values of 0.202, 0.168 and 0.114 min(-1)). Cyclophosphamide elicited a significant reduction in both tumour burden (P<0.002) and native T1 (P<0.01), whereas cabozantinib induced significant (P<0.01) tumour growth delay. Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials.

  15. Temporary skin grafts based on hybrid graphene oxide-natural biopolymer nanofibers as effective wound healing substitutes: pre-clinical and pathological studies in animal models.

    PubMed

    Mahmoudi, N; Eslahi, N; Mehdipour, A; Mohammadi, M; Akbari, M; Samadikuchaksaraei, A; Simchi, A

    2017-05-01

    In recent years, temporary skin grafts (TSG) based on natural biopolymers modified with carbon nanostructures have received considerable attention for wound healing. Developments are required to improve physico-mechanical properties of these materials to match to natural skins. Additionally, in-deep pre-clinical examinations are necessary to ensure biological performance and toxicity effect in vivo. In the present work, we show superior acute-wound healing effect of graphene oxide nanosheets embedded in ultrafine biopolymer fibers (60 nm) on adult male rats. Nano-fibrous chitosan-based skin grafts crosslinked by Genepin with physico-mechanical properties close to natural skins were prepared by electrospinning of highly concentrated chitosan- polyvinylpyrrolidone solutions containing graphene oxide (GO) nanosheets. No surfactants and organic solvents were utilized to ensure high biocompatibility of the fibrous structure. In vitro evaluations by human skin fibroblast cells including live and dead assay and MTT results show that GO promote cell viability of porous nanofibrous membrane while providing enhanced bactericidal capacity. In vivo studies on rat's skin determine accelerated healing effect, i.e. a large open wound (1.5 × 1.5 cm(2)) is fully regenerated after 14-day of post operation while healing is observed for sterile gauze sponge (as the control). Pathological studies support thick dermis formation and complete epithelialization in the presence of 1.5 wt% GO nanosheets. Over 99% wound healing occurs after 21 days for the injury covered with TSG containing 1.5 wt% GO while this would takes weeks for the control. Therefore, the developed materials have a high potential to be used as TSG as pre-clinical testing has shown.

  16. Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

    NASA Astrophysics Data System (ADS)

    Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

    2014-02-01

    Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

  17. Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

    PubMed Central

    Almeida, Gilberto S; Panek, Rafal; Hallsworth, Albert; Webber, Hannah; Papaevangelou, Efthymia; Boult, Jessica KR; Jamin, Yann; Chesler, Louis; Robinson, Simon P

    2017-01-01

    Background: The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated. Methods: Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T2-weighted imaging, quantitation of the native longitudinal relaxation time (T1) and the transverse relaxation rate (R2*), and dynamic contrast-enhanced (DCE)-MRI, was used to assess tumour volume, phenotype and response to cyclophosphamide or cabozantinib. Results: Excellent T2-weighted image contrast enabled clear tumour delineation at 3T. Significant correlations of tumour volume (R=0.98, P<0.0001) and R2* (R=0.87, P<0.002) measured at 3 and 7T were established. Mice with neuroblastomas harbouring the anaplastic lymphoma kinase mutation exhibited a significantly slower R2* (P<0.001), consistent with impaired tumour perfusion. DCE-MRI was performed simultaneously on three transgenic mice, yielding estimates of Ktrans for each tumour (median Ktrans values of 0.202, 0.168 and 0.114 min−1). Cyclophosphamide elicited a significant reduction in both tumour burden (P<0.002) and native T1 (P<0.01), whereas cabozantinib induced significant (P<0.01) tumour growth delay. Conclusions: Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials. PMID:28787429

  18. Controlling for apolipoprotein A-I concentrations changes the inverse direction of the relationship between high HDL-C concentration and a measure of pre-clinical atherosclerosis.

    PubMed

    Sung, Ki-Chul; Wild, Sarah H; Byrne, Christopher D

    2013-12-01

    The independent effect of high density lipoprotein cholesterol (HDL-C) concentration to confer cardiovascular disease protection has been questioned. We investigated whether the inverse association between HDL-C concentration and a measure of preclinical atherosclerosis was modified by other risk factors. Cross-sectional data were analysed from an occupational cohort of 12,031 men who had measurements of cardiovascular risk factors and a cardiac computed tomography (CT) estimation of coronary artery calcium (CAC) score, a measure of pre-clinical atherosclerosis. Logistic regression was used to describe associations between both HDL-C and Apo-A-I concentrations and their ratio as exposures, and CAC scores > 0, ≥ 20 and ≥ 100, as outcomes. 1351 (11.2%), 665 (5.5%) and 230 (1.9%) of participants had a CAC score > 0, ≥ 20 and ≥ 100, respectively. Adjusting for age, glucose, triglyceride, LDL-C, systolic blood pressure, waist circumference, prior cerebrovascular accident, prior coronary artery disease, prior hypertension, alcohol consumption, smoking status and exercise, a negative association existed between HDL-C and CAC score. (E.g. odds ratio (OR) for top compared to bottom HDL-C quartile for CAC > 0 = 0.78 [95%CI 0.64, 0.94], p = 0.01). Further adjustment for Apo A-I changed the direction of the association between HDL-C and CAC score > 0 (OR for top compared to bottom quartiles 1.61 [95%CI 1.18, 2.21], p = 0.003). Sensitivity analyses showed that point estimates for ORs were very similar regardless of CAC score threshold (CAC > 0, ≥ 20 and ≥ 100). Controlling for Apo A-I concentrations changes the inverse direction of relationship between high HDL-C concentration and a measure of pre-clinical atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Effects of NSAID treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: Findings from the randomized controlled ADAPT trial

    PubMed Central

    Leoutsakos, Jeannie-Marie S.; Muthen, Bengt O.; Breitner, John C.S.; Lyketsos, Constantine G.

    2011-01-01

    Objective We examined effects of non-steroidal anti-inflammatory drugs (NSAID) on cognitive decline as a function of phase of pre-clinical Alzheimer’s disease (AD). Methods Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer’s disease. We fit growth mixture models of Modified Mini-Mental State Examination (3MS) trajectories with data from 2,388 participants in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT), and included class-specific effects of naproxen and celecoxib. Results We identified 3 classes: “no-decline”, “slow-decline”, and “fast-decline”, and examined effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (−2 log likelihood difference: 369.23; p<0.001), but resulted in reversal of effects over time. Over four years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, while those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), while those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Conclusions Our results appeared statistically robust, but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then to attenuate change in fast decliners. PMID:21560159

  20. Semi-automatic cone beam CT segmentation of in vivo pre-clinical subcutaneous tumours provides an efficient non-invasive alternative for tumour volume measurements.

    PubMed

    Brodin, N P; Tang, J; Skalina, K; Quinn, T J; Basu, I; Guha, C; Tomé, W A

    2015-06-01

    To evaluate the feasibility and accuracy of using cone beam CT (CBCT) scans obtained in radiation studies using the small-animal radiation research platform to perform semi-automatic tumour segmentation of pre-clinical tumour volumes. Volume measurements were evaluated for different anatomical tumour sites, the flank, thigh and dorsum of the hind foot, for a variety of tumour cell lines. The estimated tumour volumes from CBCT and manual calliper measurements using different volume equations were compared with the "gold standard", measured by weighing the tumours following euthanasia and tumour resection. The correlation between tumour volumes estimated with the different methods, compared with the gold standard, was estimated by the Spearman's rank correlation coefficient, root-mean-square deviation and the coefficient of determination. The semi-automatic CBCT volume segmentation performed favourably compared with manual calliper measures for flank tumours ≤2 cm(3) and thigh tumours ≤1 cm(3). For tumours >2 cm(3) or foot tumours, the CBCT method was not able to accurately segment the tumour volumes and manual calliper measures were superior. We demonstrated that tumour volumes of flank and thigh tumours, obtained as a part of radiation studies using image-guided small-animal irradiators, can be estimated more efficiently and accurately using semi-automatic segmentation from CBCT scans. This is the first study evaluating tumour volume assessment of pre-clinical subcutaneous tumours in different anatomical sites using on-board CBCT imaging. We also compared the accuracy of the CBCT method to manual calliper measures, using various volume calculation equations.

  1. Effects of MK-801 treatment across several pre-clinical analyses including a novel assessment of brain metabolic function utilizing PET and CT fused imaging in live rats.

    PubMed

    Daya, R P; Bhandari, J K; Hui, P A; Tian, Y; Farncombe, T; Mishra, R K

    2014-02-01

    Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. The validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days. Acute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. While PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions. These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.

    PubMed

    Fiskus, W; Sharma, S; Saha, S; Shah, B; Devaraj, S G T; Sun, B; Horrigan, S; Leveque, C; Zu, Y; Iyer, S; Bhalla, K N

    2015-06-01

    The canonical wingless-type MMTV integration site (WNT)-β-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (AML) stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator T-cell factor (TCF) 4/lymphoid enhancer factor 1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein transducin β-like 1 and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs, exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.

  3. Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

    PubMed

    Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

    2017-02-01

    Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD.

  4. Monitoring of anti-cancer treatment with (18)F-FDG and (18)F-FLT PET: a comprehensive review of pre-clinical studies.

    PubMed

    Jensen, Mette Munk; Kjaer, Andreas

    2015-01-01

    Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine((18)F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With (18)F-FDG and (18)F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether (18)F-FDG and/or (18)F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in (18)F-FDG and (18)F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used (18)F-FDG and/or (18)F-FLT PET for response monitoring of cancer therapeutics.

  5. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection.

    PubMed

    Anderson, Peter L; Kiser, Jennifer J; Gardner, Edward M; Rower, Joseph E; Meditz, Amie; Grant, Robert M

    2011-02-01

    The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.

  6. Teaching Pharmacology by Case Study.

    ERIC Educational Resources Information Center

    Jordan, Sue

    1997-01-01

    Using pharmacology case studies with nursing students encourages theory-practice links and infuses real-life content. Cases provide rich qualitative data for evaluating curriculum. However, they are not a substitute for evidence-based practice. (SK)

  7. 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.

  8. 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.

  9. [Pharmacological therapy of obesity].

    PubMed

    Pagotto, Uberto; Vanuzzo, Diego; Vicennati, Valentina; Pasquali, Renato

    2008-04-01

    Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and

  10. Practicing the skills of evidence-based veterinary medicine through case-based pharmacology rounds.

    PubMed

    Fajt, Virginia R; Brown, Dimitri; Scott, Maya M

    2009-01-01

    Accessing new knowledge and using it to make decisions is the foundation of evidence-based veterinary medicine (EBVM), the integration of best research evidence with clinical expertise and owner/manager values. Reflecting on our experience with an EBVM-based clinical pharmacology assignment during a clinical rotation, we present the justification for the addition of an EBVM assignment to the clinical (fourth) year at the College of Veterinary Medicine and Biomedical Sciences at Texas A&M University. We also present an in-depth analysis of the addition, recommendations for the assessment of this exercise as a method of improving evidence-based veterinary practice, and recommendations and implications for other instructors interested in adding EBVM-related learning to their professional curricula. We recommend adding EBVM skill practice in pre-clinical training, abbreviated exercises in EBVM skills on clinical rotations, and increased attention to critical-thinking skills in veterinary education.

  11. Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date.

    PubMed

    Hart, Sarah J; Visootsak, Jeannie; Tamburri, Paul; Phuong, Patrick; Baumer, Nicole; Hernandez, Maria-Clemencia; Skotko, Brian G; Ochoa-Lubinoff, Cesar; Liogier D'Ardhuy, Xavier; Kishnani, Priya S; Spiridigliozzi, Gail A

    2017-09-08

    Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome. © 2017 Wiley Periodicals, Inc.

  12. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies

    PubMed Central

    Kühl, Susanne J.; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R.; Kühl, Michael

    2017-01-01

    Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee “New Media” [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires

  13. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies.

    PubMed

    Kühl, Susanne J; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R; Kühl, Michael

    2017-01-01

    Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee "New Media" [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the

  14. Network analyses in systems pharmacology

    PubMed Central

    Berger, Seth I.; Iyengar, Ravi

    2009-01-01

    Systems pharmacology is an emerging area of pharmacology which utilizes network analysis of drug action as one of its approaches. By considering drug actions and side effects in the context of the regulatory networks within which the drug targets and disease gene products function, network analysis promises to greatly increase our knowledge of the mechanisms underlying the multiple actions of drugs. Systems pharmacology can provide new approaches for drug discovery for complex diseases. The integrated approach used in systems pharmacology can allow for drug action to be considered in the context of the whole genome. Network-based studies are becoming an increasingly important tool in understanding the relationships between drug action and disease susceptibility genes. This review discusses how analysis of biological networks has contributed to the genesis of systems pharmacology and how these studies have improved global understanding of drug targets, suggested new targets and approaches for therapeutics, and provided a deeper understanding of the effects of drugs. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of existing medications. Contact: ravi.iyengar@mssm.edu PMID:19648136

  15. Volume CT with a flat-panel detector on a mobile, isocentric C-arm: pre-clinical investigation in guidance of minimally invasive surgery.

    PubMed

    Siewerdsen, J H; Moseley, D J; Burch, S; Bisland, S K; Bogaards, A; Wilson, B C; Jaffray, D A

    2005-01-01

    A mobile isocentric C-arm (Siemens PowerMobil) has been modified in our laboratory to include a large area flat-panel detector (in place of the x-ray image intensifier), providing multi-mode fluoroscopy and cone-beam computed tomography (CT) imaging capability. This platform represents a promising technology for minimally invasive, image-guided surgical procedures where precision in the placement of interventional tools with respect to bony and soft-tissue structures is critical. The image quality and performance in surgical guidance was investigated in pre-clinical evaluation in image-guided spinal surgery. The control, acquisition, and reconstruction system are described. The reproducibility of geometric calibration, essential to achieving high three-dimensional (3D) image quality, is tested over extended time scales (7 months) and across a broad range in C-arm angulation (up to 45 degrees), quantifying the effect of improper calibration on spatial resolution, soft-tissue visibility, and image artifacts. Phantom studies were performed to investigate the precision of 3D localization (viz., fiber optic probes within a vertebral body) and effect of lateral projection truncation (limited field of view) on soft-tissue detectability in image reconstructions. Pre-clinical investigation was undertaken in a specific spinal procedure (photodynamic therapy of spinal metastases) in five animal subjects (pigs). In each procedure, placement of fiber optic catheters in two vertebrae (L1 and L2) was guided by fluoroscopy and cone-beam CT. Experience across five procedures is reported, focusing on 3D image quality, the effects of respiratory motion, limited field of view, reconstruction filter, and imaging dose. Overall, the intraoperative cone-beam CT images were sufficient for guidance of needles and catheters with respect to bony anatomy and improved surgical performance and confidence through 3D visualization and verification of transpedicular trajectories and tool placement

  16. Awareness, knowledge and perception of HIV/AIDS and sexual behaviour amongst pre-clinical, medical students in a Nigerian university.

    PubMed

    Unadike, B C; Ekrikpo, U E; Bassey, E A

    2012-01-01

    Youths are the most vulnerable group affected by the HIV pandemic and its spread is most rapid amongst them. Their knowledge and awareness about this disease could transform to positive habits which could stem the tide of the pandemic. This study therefore set out to find out about the knowledge and awareness of HIV/AIDS and sexual behaviour amongst pre-clinical medical student in a Nigerian University. This was a cross sectional descriptive study carried out in the University of Uyo Medical School. Structured questionnaire was administered to consenting students to gather relevant information about socio-demographic characteristic, HIV/AIDS awareness, sexual behaviour, willingness to screen for HIV/AIDS amongst others. One hundred and fourteen students completed the questionnaire. Majority (82) were males, with most of them aged between 16-24 years. All of them (100%) had heard about HIV/IADS, before, and majority heard it from the first time through the electronic media. Majority (83.9%) could identify all the routes of transmission of HIV/AIDS while all respondents identified HIV virus as being. Ninety five percent agreed there is no cure for the disease. Thirty seven percent of then were sexually active with the mean age of sexual debut being 17.2 +/- 3.95 years. Only 70% of the sexually active respondent admitted using a condom during sexual intercourse. Majority (94.3%) agreed to undergo voluntary counselling and testing with 73% saying they will seek medical attention if infected. Only 40.2% of the respondent agreed to disclose their status if they test positive to the virus. Awareness and knowledge among certain aspects of HIV/AIDS amongst pre-clinical medical students in Uyo is high. However certain risk behaviour like no consistent use of condom during sexual intercourse still persist with many students not readil accepting to disclose their HIV status if they test positive to the virus. We advocate increased awareness, sensitization and education of the

  17. [Prebiotic inulin/oligofructose in Yacón root (Smallanthus sonchifolius), phytochemistry and standardization as basis for clinical and pre-clinical research].

    PubMed

    Alvarez F, Pedro P; Jurado T, Bertha; Calixto C, María; Incio V, Nelly; Silva A, Jesús

    2008-01-01

    Experiments have demonstrated that the association between inulin and oligofructose can prevent colitis by modifying the intestinal microflora by acting as a prebiotic. It has also been found that this association is naturally present in the roots of the Yacón root (Smallanthus sonchifolius) making phytochemical and standardization studies well worth pursuing. These studies could contribute to the safe use of improved strains of Yacón, to significant savings in health resources, and to promoting additional clinical and pre-clinical research. So far, studies have been made on organically cultivated Yacón in the coast, on varieties adapted from those cultivated in the Andes. The aim is to promote consumption of Yacón in the sectors of society that need it most. To determine the general chemical composition of the Yacón tuberous root cultivated in the coast by means of a phytochemical screening, as well as standardizing its inulin content in order to contribute knowledge on its conditions of use. The roots harvested in the Lima Botanical Garden of the National Health Institute were used to prepare aqueous extracts through decoction and juice for the phytochemical screening with conventional reagents. The aqueous extracts were standardized for insulin content by using a fructose standard method and a validated analytical technique. The samples were read in a TU-1810S Split Beam UV-VIS spectrophotometer. The trials confirmed the presence of phenolic compounds, flavonoids, alkaloids, steroids, glycosides and carbohydrates. The standardization found values of 7,8% inulin in the hydrolyzed extract and of 7, 01% in the non-hydrolyzed extract. The extracts of the Yacón roots were screened and standardized Ander known cultivation conditions. The possibilities of its use are being considered due to its prebiotic properties. These properties are considered useful in treating certain types of colitis by stimulating the growth of the Lactobacillus and Bifidobacterium

  18. Safety Pharmacology of Anticancer Agents.

    PubMed

    Martin, Pauline L

    2015-01-01

    The safety pharmacology testing for anticancer agents has historically differed for small molecule pharmaceutical drugs versus large-molecule biopharmaceuticals. For pharmaceutical drugs, dedicated safety pharmacology studies have been conducted according to the ICH M3 (R2), ICH 7A, and ICH S7B guidance documents. For biopharmaceuticals, safety pharmacology endpoints have been incorporated into the repeated-dose toxicology studies according to ICHS6 (R1). However, the introduction of the ICH S9 guidance document for the nonclinical evaluation for anticancer pharmaceuticals has allowed for a streamlined approach for both types of molecules to facilitate access of new potential therapeutics to cancer patients and to reduce the number of animal studies. Examples of the testing strategies that have previously been employed for some representative anticancer agents are provided, and their predictivity to adverse events noted in the clinic is discussed.

  19. 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

  20. Clinical pharmacology for the orthodontist.

    PubMed

    Rinchuse, D J; Rinchuse, D J; Sprecher, R

    1981-03-01

    The practice of orthodontics encompasses all other aspects of dentistry, but at the same time it also is very different. Therefore, the pharmacologic agents that would be practical for orthodontic practice are much more limited than those used in other disciplines of dentistry. This, however, does not imply that a full understanding of pharmacologic drug action, side effects, and contraindications is unnecessary. Some common drugs, such as the antibiotics, anticholinergics, fluoride, antianxiety agents, and drugs for myofacial pain, are reviewed according to their application to orthodontic practice.

  1. Pharmacological effects of rosa damascena.

    PubMed

    Boskabady, Mohammad Hossein; Shafei, Mohammad Naser; Saberi, Zahra; Amini, Somayeh

    2011-07-01

    Rosa damascena mill L., known as Gole Mohammadi in is one of the most important species of Rosaceae family flowers. R. damascena is an ornamental plant and beside perfuming effect, several pharmacological properties including anti-HIV, antibacterial, antioxidant, antitussive, hypnotic, antidiabetic, and relaxant effect on tracheal chains have been reported for this plant. This article is a comprehensive review on pharmacological effects of R. damascena. Online literature searches were performed using Medline, medex, Scopus, and Google Scholar websites backed to 1972 to identify researches about R. damascena. Searches also were done by going through the author's files and the bibliographies of all located papers.

  2. Pharmacological Effects of Rosa Damascena

    PubMed Central

    Boskabady, Mohammad Hossein; Shafei, Mohammad Naser; Saberi, Zahra; Amini, Somayeh

    2011-01-01

    Rosa damascena mill L., known as Gole Mohammadi in is one of the most important species of Rosaceae family flowers. R. damascena is an ornamental plant and beside perfuming effect, several pharmacological properties including anti-HIV, antibacterial, antioxidant, antitussive, hypnotic, antidiabetic, and relaxant effect on tracheal chains have been reported for this plant. This article is a comprehensive review on pharmacological effects of R. damascena. Online literature searches were performed using Medline, medex, Scopus, and Google Scholar websites backed to 1972 to identify researches about R. damascena. Searches also were done by going through the author's files and the bibliographies of all located papers. PMID:23493250

  3. 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

  4. Numerical Analysis of a Flexible Dual Loop Coil and its Experimental Validation for pre-Clinical Magnetic Resonance Imaging of Rodents at 7 T

    NASA Astrophysics Data System (ADS)

    Solis-Najera, S.; Vazquez, F.; Hernandez, R.; Marrufo, O.; Rodriguez, A. O.

    2016-12-01

    A surface radio frequency coil was developed for small animal image acquisition in a pre-clinical magnetic resonance imaging system at 7 T. A flexible coil composed of two circular loops was developed to closely cover the object to be imaged. Electromagnetic numerical simulations were performed to evaluate its performance before the coil construction. An analytical expression of the mutual inductance for the two circular loops as a function of the separation between them was derived and used to validate the simulations. The RF coil is composed of two circular loops with a 5 cm external diameter and was tuned to 300 MHz and 50 Ohms matched. The angle between the loops was varied and the Q factor was obtained from the S11 simulations for each angle. B1 homogeneity was also evaluated using the electromagnetic simulations. The coil prototype was designed and built considering the numerical simulation results. To show the feasibility of the coil and its performance, saline-solution phantom images were acquired. A correlation of the simulations and imaging experimental results was conducted showing a concordance of 0.88 for the B1 field. The best coil performance was obtained at the 90° aperture angle. A more realistic phantom was also built using a formaldehyde-fixed rat phantom for ex vivo imaging experiments. All images showed a good image quality revealing clearly defined anatomical details of an ex vivo rat.

  5. From Proteomic Analysis to Potential Therapeutic Targets: Functional Profile of Two Lung Cancer Cell Lines, A549 and SW900, Widely Studied in Pre-Clinical Research

    PubMed Central

    Soto-Cerrato, Vanessa; Vitorino, Rui; Fardilha, Margarida; Pérez-Tomás, Ricardo

    2016-01-01

    Lung cancer is a serious health problem and the leading cause of cancer death worldwide. The standard use of cell lines as in vitro pre-clinical models to study the molecular mechanisms that drive tumorigenesis and access drug sensitivity/effectiveness is of undisputable importance. Label-free mass spectrometry and bioinformatics were employed to study the proteomic profiles of two representative lung cancer cell lines and to unravel the specific biological processes. Adenocarcinoma A549 cells were enriched in proteins related to cellular respiration, ubiquitination, apoptosis and response to drug/hypoxia/oxidative stress. In turn, squamous carcinoma SW900 cells were enriched in proteins related to translation, apoptosis, response to inorganic/organic substances and cytoskeleton organization. Several proteins with differential expression were related to cancer transformation, tumor resistance, proliferation, migration, invasion and metastasis. Combined analysis of proteome and interactome data highlighted key proteins and suggested that adenocarcinoma might be more prone to PI3K/Akt/mTOR and topoisomerase IIα inhibitors, and squamous carcinoma to Ck2 inhibitors. Moreover, ILF3 overexpression in adenocarcinoma, and PCNA and NEDD8 in squamous carcinoma shows them as promising candidates for therapeutic purposes. This study highlights the functional proteomic differences of two main subtypes of lung cancer models and hints several targeted therapies that might assist in this type of cancer. PMID:27814385

  6. Application of 212Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

    PubMed Central

    Yong, Kwon; Brechbiel, Martin

    2015-01-01

    Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer. PMID:26858987

  7. Application of (212)Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation.

    PubMed

    Yong, Kwon; Brechbiel, Martin

    Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. (212)Pb is the longer-lived parent radionuclide of (212)Bi and serves as an in vivo generator of (212)Bi. (212)Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of (212)Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of (212)Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of (212)Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.

  8. Differential Effect of Soy Isoflavones in Enhancing High Intensity Radiotherapy and Protecting Lung Tissue in a Pre-Clinical Model of Lung Carcinoma

    PubMed Central

    Hillman, Gilda G.; Singh-Gupta, Vinita; Hoogstra, David J.; Abernathy, Lisa; Rakowski, Joseph; Yunker, Christopher K.; Rothstein, Shoshana E.; Sarkar, Fazlul H.; Gadgeel, Shirish; Konski, Andre A.; Lonardo, Fulvio; Joiner, Michael C.

    2013-01-01

    Background Radiotherapy of locally-advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. We have further investigated the role of soy isoflavones to improve the effect of a high intensity radiation and reduce lung damage in a pre-clinical lung tumor model. Methods Human A549 NSCLC cells were injected i.v. in nude mice to generate a large tumor burden in the lungs. Mice were treated with lung irradiation at 10 Gy and with oral soy. The therapy effect on the tumor cells and surrounding lung tissue was analyzed on lung sections stained with H&E, Ki-67 and Masson’s Trichrome. Pneumonitis and vascular damage were evaluated by measurements of alveolar septa and immunofluorescent staining of vessel walls. Results Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels. Conclusions These studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while radioprotecting normal lung tissue and support using soy to alleviate radiotoxicity in lung cancer. PMID:24021346

  9. Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

    PubMed Central

    Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

    2014-01-01

    Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1−/−NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1−/−NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

  10. 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,…

  11. Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

    PubMed

    Du, Juan; Cieslak, John A; Welsh, Jessemae L; Sibenaller, Zita A; Allen, Bryan G; Wagner, Brett A; Kalen, Amanda L; Doskey, Claire M; Strother, Robert K; Button, Anna M; Mott, Sarah L; Smith, Brian; Tsai, Susan; Mezhir, James; Goswami, Prabhat C; Spitz, Douglas R; Buettner, Garry R; Cullen, Joseph J

    2015-08-15

    The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

  12. 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…

  13. 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,…

  14. The pharmacological activities of (-)-anonaine.

    PubMed

    Li, Hsing-Tan; Wu, Hui-Ming; Chen, Hsin-Liang; Liu, Chi-Ming; Chen, Chung-Yi

    2013-07-12

    Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (-)-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (-)-anonaine.

  15. 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…

  16. 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

  17. Phosphodiesterase inhibitors: history of pharmacology.

    PubMed

    Schudt, Christian; Hatzelmann, Armin; Beume, Rolf; Tenor, Hermann

    2011-01-01

    The first pharmacological investigations of phosphodiesterase (PDE) inhibitors were developed with the clinical efficacies of drugs isolated from coffee, cacao and tea but only later their relevant ingredients were identified as xanthines that act as PDE. With its diuretic, inotropic and bronchodilating clinical efficacy, use of theophylline anticipated the clinical goals, which were later approached with the first-generation of weakly selective PDE inhibitors in the period from 1980 to 1990. Pharmacological and clinical research with these early compounds provided a vast pool of information regarding desired and adverse actions - although most of these new drugs had to be discontinued due to severe adverse effects. The pharmacological models for cardiac, vascular and respiratory indications were analysed for their PDE isoenzyme profiles, and when biochemical and molecular biological approaches expanded our knowledge of the PDE superfamily, the purified isoenzymes that were now available opened the door for more systematic studies of inhibitors and for generation of highly selective isoenzyme-specific drugs. The development of simple screening models and clinically relevant indication models reflecting the growing knowledge about pathomechanisms of disease are summarised here for today's successful application of highly selective PDE3, PDE4 and PDE5 inhibitors. The interplay of serendipitous discoveries, the establishment of intelligent pharmacological models and the knowledge gain by research results with new substances is reviewed. The broad efficacies of new substances in vitro, the enormous biodiversity of the PDE isoenzyme family and the sophisticated biochemical pharmacology enabled Viagra to be the first success story in the field of PDE inhibitor drug development, but probably more success stories will follow.

  18. Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology.

    PubMed

    Kaddurah-Daouk, R; Weinshilboum, R M

    2014-02-01

    Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.

  19. Quantitative systems pharmacology: a promising approach for translational pharmacology.

    PubMed

    Gadkar, K; Kirouac, D; Parrott, N; Ramanujan, S

    Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody. In the second case study, a mitogen-activated protein kinase (MAPK) pathway signaling model is used to make translational predictions on clinical response and evaluate novel combination therapies. In the third case study, a physiologically based pharmacokinetic (PBPK) model it used to guide administration of oseltamivir in pediatric patients.

  20. Digital Droplet PCR for the Absolute Quantification of Exon Skipping Induced by Antisense Oligonucleotides in (Pre-)Clinical Development for Duchenne Muscular Dystrophy

    PubMed Central

    Verheul, Ruurd C.; van Deutekom, Judith C. T.; Datson, Nicole A.

    2016-01-01

    Antisense oligonucleotides (AONs) in clinical development for Duchenne muscular dystrophy (DMD) aim to induce skipping of a specific exon of the dystrophin transcript during pre-mRNA splicing. This results in restoration of the open reading frame and consequently synthesis of a dystrophin protein with a shorter yet functional central rod domain. To monitor the molecular therapeutic effect of exon skip-inducing AONs in clinical studies, accurate quantification of pre- and post-treatment exon skip levels is required. With the recent introduction of 3rd generation digital droplet PCR (ddPCR), a state-of-the-art technology became available which allows absolute quantification of transcript copy numbers with and without specific exon skip with high precision, sensitivity and reproducibility. Using Taqman assays with probes targeting specific exon-exon junctions, we here demonstrate that ddPCR reproducibly quantified cDNA fragments with and without exon 51 of the DMD gene over a 4-log dynamic range. In a comparison of conventional nested PCR, qPCR and ddPCR using cDNA constructs with and without exon 51 mixed in different molar ratios using, ddPCR quantification came closest to the expected outcome over the full range of ratios (0–100%), while qPCR and in particular nested PCR overestimated the relative percentage of the construct lacking exon 51. Highest accuracy was similarly obtained with ddPCR in DMD patient-derived muscle cells treated with an AON inducing exon 51 skipping. We therefore recommend implementation of ddPCR for quantification of exon skip efficiencies of AONs in (pre)clinical development for DMD. PMID:27612288

  1. SU-D-304-04: Pre-Clinical Feasibility Study for Intensity Modulated Grid Proton Therapy (IMgPT) Using a Newly Developed Delivery System

    SciTech Connect

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J

    2015-06-15

    Purpose: The purpose of the current study was to characterize and evaluate intensity-modulated proton grid therapy (IMgPT) using a clinical proton beam. Methods: A TOPAS MC model of a new developmental mode (pre-clinical) of the Hitachi proton therapy system (PROBEAT) was used for simulation and characterization of proton grid therapy. TOPAS simulations of different energy ranges, depths and spot separation distances were performed. LET spectra for various energies and depths were produced with FLUKA MC code for evaluation potential interplay between planning parameters and their effect on the characterization of areas (valley) between spots. IMgPT planning aspects (spot spacing, skin dose, peak-to-valley ratios, beam selection, etc.) were evaluated for different phantom and patient cases. Raysearch software (v4.51) was used to perform the evaluation. Results: Calculated beam peak-to-valley ratios scenarios showed strong energy and depth dependence with ratios to be larger for higher energies and shallower depths. Peak-to-valley ratios for R90 range and for spot spacing of 1cm varied from 30% (E = 221.3 MeV, depth 30.6 cm) to 80% (E = 70.3 MeV, depth 4 cm). LET spectra calculations showed spectral hardening with depth, which might potential increase, spot separation distance and improve peak-to-valley ratios. IMgPT optimization, using constant spot spacing, showed skin dose reduction between peak regions of dose due to the irradiation of less skin. Single beam for bulky shallower tumors might be a potential candidate for proton grid therapy. Conclusions: Proton grid therapy using a clinical beam is a promising technique that reduces skin dose between peak regions of dose and may be suitable for the treatment of shallow tumors. IMgPT may be considered for use when bystander effects in off peak regions would be appropriate.

  2. H5N2 Highly Pathogenic Avian Influenza Viruses from the US 2014-2015 outbreak have an unusually long pre-clinical period in turkeys.

    PubMed

    Spackman, Erica; Pantin-Jackwood, Mary J; Kapczynski, Darrell R; Swayne, David E; Suarez, David L

    2016-11-22

    From December 2014 through June 2015, the US experienced the most costly highly pathogenic avian influenza (HPAI) outbreak to date. Most cases in commercial poultry were caused by an H5N2 strain which was a reassortant with 5 Eurasian lineage genes, including a clade 2.3.4.4 goose/Guangdong/1996 lineage hemagglutinin, and 3 genes from North American wild waterfowl low pathogenicity avian influenza viruses. The outbreak primarily affected turkeys and table-egg layer type chickens. Three isolates were selected for characterization in turkeys: the US index isolate from December 2014 (A/northern pintail/WA/40964/2014), and two poultry isolates from April 2015 (A/chicken/IA/13388/2015 and A/turkey/MN/12528/2015). Four week old broad-breasted white turkeys were inoculated with one of three doses (10(2), 10(4) or 10(6) 50% egg infectious doses [EID50] per bird) of each of the isolates to evaluate infectious dose and pathogenesis. The mean bird infectious dose of A/northern pintail/WA/40964/2014 and A/turkey/MN/12528/2015 was 10(5) EID50 per bird, but was 10(3) EID50 per bird for A/chicken/IA/13388/2015, suggesting the latter had greater adaptation to gallinaceous birds. All three isolates had unusually long mean death time of 5.3-5.9 days post challenge, and the primary clinical signs were severe lethargy and neurological signs which started no more than 24 h before death (the average pre-clinical period was 4 days). Infected turkeys also shed high levels of virus by both the oropharyngeal and cloacal routes. The unusually long mean death times, high levels of virus in feces, and increased adaptation of the later viruses may have contributed to the rapid spread of the virus during the peak of the outbreak.

  3. Epithelial-to-mesenchymal transition leads to disease-stage differences in circulating tumor cell detection and metastasis in pre-clinical models of prostate cancer

    PubMed Central

    Lowes, Lori E.; Goodale, David; Xia, Ying; Postenka, Carl; Piaseczny, Matthew M.; Paczkowski, Freeman; Allan, Alison L.

    2016-01-01

    Metastasis is the cause of most prostate cancer (PCa) deaths and has been associated with circulating tumor cells (CTCs). The presence of ≥5 CTCs/7.5mL of blood is a poor prognosis indicator in metastatic PCa when assessed by the CellSearch® system, the “gold standard” clinical platform. However, ~35% of metastatic PCa patients assessed by CellSearch® have undetectable CTCs. We hypothesize that this is due to epithelial-to-mesenchymal transition (EMT) and subsequent loss of necessary CTC detection markers, with important implications for PCa metastasis. Two pre-clinical assays were developed to assess human CTCs in xenograft models; one comparable to CellSearch® (EpCAM-based) and one detecting CTCs semi-independent of EMT status via combined staining with EpCAM/HLA (human leukocyte antigen). In vivo differences in CTC generation, kinetics, metastasis and EMT status were determined using 4 PCa models with progressive epithelial (LNCaP, LNCaP-C42B) to mesenchymal (PC-3, PC-3M) phenotypes. Assay validation demonstrated that the CellSearch®-based assay failed to detect a significant number (~40-50%) of mesenchymal CTCs. In vivo, PCa with an increasingly mesenchymal phenotype shed greater numbers of CTCs more quickly and with greater metastatic capacity than PCa with an epithelial phenotype. Notably, the CellSearch®-based assay captured the majority of CTCs shed during early-stage disease in vivo, and only after establishment of metastases were a significant number of undetectable CTCs present. This study provides important insight into the influence of EMT on CTC generation and subsequent metastasis, and highlights that novel technologies aimed at capturing mesenchymal CTCs may only be useful in the setting of advanced metastatic disease. PMID:27764810

  4. Paradoxical pharmacology: turning our pharmacological models upside down.

    PubMed

    Page, Clive

    2011-04-01

    Paradoxical pharmacology is a term first suggested by Richard Bond to refer to intriguing observations that chronic use of some drug types can have the opposite biological effect(s) to those seen following acute administration of the same drug. A good example of 'paradoxical pharmacology' is the research Richard has pioneered showing that whereas acute administration of β-blockers is contraindicated in the treatment of asthma, chronic use of certain β-blockers can have therapeutic benefit. It would appear that those β-blockers that can act as inverse agonists at the β2 receptor particularly show this paradoxical effect and the findings of Richard's research not only challenge the dogma of the treatment of asthma but also challenge many of the pharmacological principles of ligand/receptor interactions established by Sir James Black and others. In this paper, I discuss Richard's efforts to evaluate the chronic effects of β-blockers in the airways and how this research caught the imagination of Sir James Black.

  5. 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.

  6. Translocator protein: pharmacology and steroidogenesis.

    PubMed

    Midzak, Andrew; Zirkin, Barry; Papadopoulos, Vassilios

    2015-08-01

    The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis. © 2015 Authors; published by Portland Press Limited.

  7. 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

  8. Pharmacological effects of Sapindus mukorossi.

    PubMed

    Upadhyay, Aparna; Singh, D K

    2012-01-01

    Sapindus mukorossi is an extremely valuable medicinal plant, distributed in tropical and sub-tropical regions of Asia. The aim of present review is to form a short compilation of the phytochemical composition and pharmacological properties of this multipurpose tree. The main phytoconstituents isolated and identified from different parts of this plant are triterpenoidal saponins of oleanane, dammarane and tirucullane type. The structure and chemical names of all the types of triterpenoidal saponins reported in Sapindus mukorossi are included in this review. Many research studies have been conducted to prove the plant's potential as being spermicidal, contraceptive, hepatoprotective, emetic, anti-inflammatory and anti-protozoal. The present review highlights some of the salient pharmacological uses of Sapindus mukorossi.

  9. 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

  10. Pharmacologic Preconditioning: Translating the Promise

    PubMed Central

    Gidday, Jeffrey M.

    2010-01-01

    A transient, ischemia-resistant phenotype known as “ischemic tolerance” can be established in brain in a rapid or delayed fashion by a preceding noninjurious “preconditioning” stimulus. Initial preclinical studies of this phenomenon relied primarily on brief periods of ischemia or hypoxia as preconditioning stimuli, but it was later realized that many other stressors, including pharmacologic ones, are also effective. This review highlights the surprisingly wide variety of drugs now known to promote ischemic tolerance, documented and to some extent mechanistically characterized in preclinical animal models of stroke. Although considerably more experimentation is needed to thoroughly validate the ability of any currently identified preconditioning agent to protect ischemic brain, the fact that some of these drugs are already clinically approved for other indications implies that the growing enthusiasm for translational success in the field of pharmacologic preconditioning may be well justified. PMID:21197121

  11. 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

  12. 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.

  13. [Problems and prospects of space pharmacology].

    PubMed

    Shashkov, V S; Sabaev, V V

    1980-01-01

    The paper reviews the Soviet and foreign literature on the pharmacological support of manned space flights with emphasis on pharmacological prophylaxis and therapy of adverse effects of the space environment. The paper discusses future development of pharmacological studies as part of space medicine.

  14. Pharmacological optimization of tissue perfusion

    PubMed Central

    Mongardon, N.; Dyson, A.; Singer, M.

    2009-01-01

    After fluid resuscitation, vasoactive drug treatment represents the major cornerstone for correcting any major impairment of the circulation. However, debate still rages as to the choice of agent, dose, timing, targets, and monitoring modalities that should optimally be used to benefit the patient yet, at the same time, minimize harm. This review highlights these areas and some new pharmacological agents that broaden our therapeutic options. PMID:19460775

  15. 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

  16. Preclinical pharmacology and opioid combinations.

    PubMed

    Pasternak, Gavril W

    2012-03-01

    Although effective alone, opioids are often used in combination with other drugs for relief of moderate to severe pain. Guidelines for acute perioperative pain recommend the use of multimodal therapy for pain management, although combinations of opioids are not specifically recommended. Mu opioid drugs include morphine, heroin, fentanyl, methadone, and morphine 6β-glucuronide (M6G). Their mechanism of action is complex, resulting in subtle pharmacological differences among them and with unpredictable differences in their potency, effectiveness, and tolerability among patients. Highly selective mu opioids do not bind to a single receptor. Rather, they interact with a large number of mu receptor subtypes with different activation profiles for the various drugs. Thus, mu-receptor-based drugs are not all the same and it may be possible to utilize these differences for enhanced pain control in a clinical setting. These differences among the drugs raise the question of whether combinations might result in better pain relief with fewer side effects. This concept has already been demonstrated between two mu opioids in preclinical studies and clinical trials on other combinations are ongoing. This article reviews the current state of knowledge about mu opioid receptor pharmacology, summarizes preclinical evidence for synergy from opioid combinations, and highlights the complex nature of the mu opioid receptor pharmacology.

  17. Pharmacologic vitreodynamics and molecular flux.

    PubMed

    Goldenberg, David T; Trese, Michael T

    2009-01-01

    Several enzymatic agents, such as autologous plasmin enzyme and recombinant microplasmin, are able to cause vitreous liquefaction and a complete posterior vitreous detachment (PVD). Advancements in research have helped to explain the complex interactions that occur in the vitreous cavity after a PVD is created. The development of a PVD is a dynamic process that is thought to have a larger impact on the vitreous cavity milieu than just a separation of the posterior cortical vitreous from the retina. Pharmacologic vitreodynamics attempts to explain the mechanical and biochemical changes that occur at the vitreoretinal junction after a PVD is formed. The flow of molecules into and out of the vitreous cavity and across the vitreoretinal junction is thought to be influenced by the presence or absence of a PVD. A microplasmin-induced PVD has been shown to alter the vitreous levels of several molecules, and a PVD may have a protective role in multiple diseases. Significant progress has been made in the field of pharmacologic vitreodynamics. As we improve our understanding of the molecular flux in the vitreous cavity, pharmacologic vitreodynamics will likely become more important as it may allow for improved manipulation of intravitreal molecules.

  18. Enzymatic Vitrectomy and Pharmacologic Vitreodynamics.

    PubMed

    Shah, Ankoor R; Trese, Michael T

    2016-01-01

    The field of vitreoretinal surgery has evolved substantially over the last several decades. Scientific advances have improved our understanding of disease pathophysiology, and new surgical adjuncts and techniques have decreased surgical time and improved patient outcomes. Pharmacologic agents have recently been developed for intraocular use in order to enhance vitreous removal and even as a nonsurgical treatment for pathology due to an abnormal vitreoretinal interface. Plasmin can successfully cause vitreous liquefaction and induce a posterior vitreous detachment. Additionally, ocriplasmin has been approved for symptomatic vitreomacular adhesion and others appear to be promising for pharmacologic manipulation of the vitreous. The ability to induce vitreous liquefaction and a complete posterior vitreous detachment (PVD) with a single intravitreal injection has potential implications for the management of multiple vitreoretinopathies. Enzymatic vitrectomy may help to reduce vitreous viscosity, thereby facilitating removal during vitrectomy and reducing surgical time, especially when using smaller-gauge vitrectomy instruments. The induction of a PVD also has the potential to reduce intraoperative complications. As we improve our understanding of the molecular flux in the vitreous cavity, pharmacologic vitreodynamics will likely become more important as it may allow for improved manipulation of intravitreal molecules.

  19. Pharmacological treatment of trigeminal neuralgia.

    PubMed

    Di Stefano, Giulia; Truini, Andrea

    2017-10-01

    Unique among the different neuropathic pain conditions, trigeminal neuralgia frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of these drugs and the few alternative options. Areas covered: This article, based on a systematic literature review, describes the pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia. The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including starting dose, titration and side effects. Expert commentary: Carbamazepine and oxcarbazepine are the reference standard drugs for treating patients with trigeminal neuralgia. They are effective in most patients. The undesired effects however cause withdrawal from treatment or a dosage reduction to an insufficient level in many patients. Sodium channel blockers selective for the sodium channel 1.7 (Nav1.7) receptor, currently under development, might be an alternative, better-tolerated pharmacological option in the next future.

  20. Acetylcholinesterase inhibitors: pharmacology and toxicology.

    PubMed

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

    2013-05-01

    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.

  1. Pharmacological Chaperoning: A Primer on Mechanism and Pharmacology

    PubMed Central

    Ryder, Katelyn G.

    2014-01-01

    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 is 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

  2. Information technology in veterinary pharmacology instruction.

    PubMed

    Kochevar, Deborah T

    2003-01-01

    Veterinary clinical pharmacology encompasses all interactions between drugs and animals and applies basic and clinical knowledge to improve rational drug use and patient outcomes. Veterinary pharmacology instructors set educational goals and objectives that, when mastered by students, lead to improved animal health. The special needs of pharmacology instruction include establishing a functional interface between basic and clinical knowledge, managing a large quantity of information, and mastering quantitative skills essential to successful drug administration and analysis of drug action. In the present study, a survey was conducted to determine the extent to which veterinary pharmacology instructors utilize information technology (IT) in their teaching. Several IT categories were investigated, including Web-based instructional aids, stand-alone pharmacology software, interactive videoconferencing, databases, personal digital assistants (PDAs), and e-book applications. Currently IT plays a largely ancillary role in pharmacology instruction. IT use is being expanded primarily through the efforts of two veterinary professional pharmacology groups, the American College of Veterinary Clinical Pharmacology (ACVCP) and the American Academy of Veterinary Pharmacology and Therapeutics (AAVPT). The long-term outcome of improved IT use in pharmacology instruction should be to support the larger educational mission of active learning and problem solving. Creation of high-quality IT resources that promote this goal has the potential to improve veterinary pharmacology instruction within and across institutions.

  3. Pre-clinical evaluation of [111In]-benzyl-DOTA-Z(HER2:342), a potential agent for imaging of HER2 expression in malignant tumors.

    PubMed

    Orlova, Anna; Tran, Thuy; Widström, Charles; Engfeldt, Torun; Eriksson Karlström, Amelie; Tolmachev, Vladimir

    2007-09-01

    Imaging of expression of human epidermal growth factor receptor type 2 (HER2) in breast carcinomas may help to select patients eligible for trastuzumab therapy. The Affibody molecule Z(HER2:342) is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of Z(HER2:342) was labeled with 111In and demonstrated good targeting in murine xenografts. We considered that the use of the macrocyclic chelator DOTA could increase the label stability and enhance a choice of nuclides, which could be used as a label for Z(HER2:342). The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of Z(HER2:342). Isothiocyanate-benzyl-DOTA was coupled to recombinant Z(HER2:342), and the conjugate was efficiently labeled with 111In at 60 degrees C. The specificity of 111In-benzyl-DOTA-Z(HER2:342) binding to HER2 was confirmed in vitro using HER2-expressing breast carcinoma BT474 and ovarian carcinoma SKOV-3 cell lines. Biodistribution of 111In-benzyl-DOTA-Z(HER2:342) was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-Z(HER2:342). In vivo, 111In-benzyl-DOTA-Z(HER2:342) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-Z(HER2:342) (4.4+/-1.0% IA/g) was specific and the tumor-to-blood ratio was 23. The use of benzyl-DTPA provided higher tumor-to-blood and tumor-to-liver ratios. gamma-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-Z(HER2:342). 111In-benzyl-DOTA-Z(HER2:342) has a potential for imaging of HER2 expression in malignant tumors.

  4. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 4: pre-clinical efficacy and complication data required to justify a clinical trial.

    PubMed

    Cooper, David K C; Bottino, Rita; Gianello, Pierre; Graham, Melanie; Hawthorne, Wayne J; Kirk, Allan D; Korsgren, Olle; Park, Chung-Gyu; Weber, Collin

    2016-01-01

    In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and "recommendations" (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted "rigorous pre-clinical studies using the most relevant animal models" and were based on "non-human primate testing." We now report our discussion following a careful review of the 2009 guidelines as they relate to pre-clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre-clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation.

  5. 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

  6. Pharmacologic considerations for Shuttle astronauts

    NASA Technical Reports Server (NTRS)

    Santy, Patricia A.; Bungo, Michael W.

    1991-01-01

    Medication usage by crewmembers in the preflight and inflight mission periods is common in the Shuttle Program. The most common medical reports for which medication is used are: space motion sickness (SMS), sleeplessness, headache, and backache. A number of medications are available in the Shuttle Medical Kit to treat these problems. Currently, astronauts test all frequently used medications before mission assignment to identify potential side-effects, problems related to performance, personal likes/dislikes, and individual therapeutic effect. However, microgravity-induced changes in drug pharmacokinetics, in combination with multiple operational factors, may significantly alter crewmember responses inflight. This article discusses those factors that may impact pharmacologic efficacy during Shuttle missions.

  7. [SQUALENE: PHYSIOLOGICAL AND PHARMACOLOGICAL PROPERTIES].

    PubMed

    Muzalevskaya, E N; Miroshnichenko, L A; Nikolaevskii, V A; Ushakov, I B; Chernov, Yu N; Alabovskii, V V; Batishcheva, G A; Buzlama, A V

    2015-01-01

    The review of literature demonstrates that squalene, known to most experts as an intermediate product in the synthesis of cholesterol, has several pharmacological properties including hypolipidemic, hepatoprotective, cardioprotective, antioxidant, and antitoxicant activity. Squalene is effective in the treatment of diabetes mellitus type 2 and can potentiate the activity of some antitumor (antiblastoma) preparations and reduce their undesired side effects. This bioactive substance has low toxicity and, in therapeutic doses, does not produce any damaging action on the human organism. A promising source of raw material for the commercial production of squalene is offered by amaranth seed oil.

  8. Pharmacologic Therapies for Pediatric Concussions

    PubMed Central

    Halstead, Mark E.

    2016-01-01

    Context: Pediatric concussions are common, and emphasis on correct diagnosis and management is stressed in consensus guidelines. Medications may have a role in management of concussion, but no consensus exists regarding appropriate pharmacologic therapy. Evidence Acquisition: Nonsystematic review. Study Design: Clinical review. Level of Evidence: Level 4. Results: There is limited evidence for hypertonic saline to improve posttraumatic headache in the emergency department setting. There is essentially no evidence for the use of any other medication in management of pediatric sport-related concussion. Conclusion: Further research is necessary to determine whether there is benefit to the use of any pharmacotherapy in the management of pediatric-aged athletes with concussions. PMID:26660460

  9. Pharmacologic considerations for Shuttle astronauts

    NASA Technical Reports Server (NTRS)

    Santy, Patricia A.; Bungo, Michael W.

    1991-01-01

    Medication usage by crewmembers in the preflight and inflight mission periods is common in the Shuttle Program. The most common medical reports for which medication is used are: space motion sickness (SMS), sleeplessness, headache, and backache. A number of medications are available in the Shuttle Medical Kit to treat these problems. Currently, astronauts test all frequently used medications before mission assignment to identify potential side-effects, problems related to performance, personal likes/dislikes, and individual therapeutic effect. However, microgravity-induced changes in drug pharmacokinetics, in combination with multiple operational factors, may significantly alter crewmember responses inflight. This article discusses those factors that may impact pharmacologic efficacy during Shuttle missions.

  10. Clinical Pharmacology in Old Persons

    PubMed Central

    Jansen, Paul A. F.; Brouwers, Jacobus R. B. J.

    2012-01-01

    The epidemiological transition, with a rapid increase in the proportion in the global population aged over 65 years from 11% in 2010 to 22% in 2050 and 32% in 2100, represents a challenge for public health. More and more old persons have multimorbidities and are treated with a large number of medicines. In advanced age, the pharmacokinetics and pharmacodynamics of many drugs are altered. In addition, pharmacotherapy may be complicated by difficulties with obtaining drugs or adherence and persistence with drug regimens. Safe and effective pharmacotherapy remains one of the greatest challenges in geriatric medicine. In this paper, the main principles of geriatric pharmacology are presented. PMID:24278735

  11. Local anesthetics: pharmacology and toxicity.

    PubMed

    Moore, Paul A; Hersh, Elliot V

    2010-10-01

    The development of safe and effective local anesthetic agents has possibly been the most important advancement in dental science to occur in the last century. The agents currently available in dentistry are extremely safe and fulfill most of the characteristics of an ideal local anesthetic. These local anesthetic agents can be administered with minimal tissue irritation and with little likelihood of inducing allergic reactions. A variety of agents are available that provide rapid onset and adequate duration of surgical anesthesia. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. The behavioral pharmacology of hallucinogens

    PubMed Central

    Fantegrossi, William E.; Murnane, Aeneas C.; Reissig, Chad J.

    2008-01-01

    Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds. PMID:17977517

  13. Pharmacologic interventions in aging hair

    PubMed Central

    Trüeb, Ralph M

    2006-01-01

    The appearance of hair plays an important role in people’s overall physical appearance and self-perception. With today’s increasing life-expectations, the desire to look youthful plays a bigger role than ever. The hair care industry has become aware of this and is delivering active products directed towards meeting this consumer demand. The discovery of pharmacological targets and the development of safe and effective drugs also indicate strategies of the drug industry for maintenance of healthy and beautiful hair. Hair aging comprises weathering of the hair shaft, decrease of melanocyte function, and decrease in hair production. The scalp is subject to intrinsic and extrinsic aging. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variation: prototypes are familial premature graying, and androgenetic alopecia. Currently available pharmacologic treatment modalities with proven efficacy for treatment of androgenetic alopecia are topical minoxidil and oral finasteride. Extrinsic factors include ultraviolet radiation and air pollution. Experimental evidence supports the hypothesis that oxidative stress also plays a role in hair aging. Topical anti-aging compounds include photoprotectors and antioxidants. In the absence of another way to reverse hair graying, hair colorants remain the mainstay of recovering lost hair color. Topical liposome targeting for melanins, genes, and proteins selectively to hair follicles are currently under investigation. PMID:18044109

  14. Let's 'play' with molecular pharmacology.

    PubMed

    Choudhury, Supriyo; Pradhan, Richeek; Sengupta, Gairik; Das, Manisha; Chatterjee, Manojit; Roy, Ranendra Kumar; Chatterjee, Suparna

    2015-01-01

    Understanding concepts of molecular mechanisms of drug action involves sequential visualization of physiological processes and drug effects, a task that can be difficult at an undergraduate level. Role-play is a teaching-learning methodology whereby active participation of students as well as clear visualization of the phenomenon is used to convey complex physiological concepts. However, its use in teaching drug action, a process that demands understanding of a second level of complexity over the physiological process, has not been investigated. We hypothesized that role-play can be an effective and well accepted method for teaching molecular pharmacology. In an observational study, students were guided to perform a role-play on a selected topic involving drug activity. Students' gain in knowledge was assessed comparing validated pre- and post-test questionnaires as well as class average normalized gain. The acceptance of role-play among undergraduate medical students was evaluated by Likert scale analysis and thematic analysis of their open-ended written responses. Significant improvement in knowledge (P < 0.001) was noted in the pre- to post-test knowledge scores, while a high gain in class average normalized score was evident. In Likert scale analysis, most students (93%) expressed that role-play was an acceptable way of teaching. In a thematic analysis, themes of both strengths and weaknesses of the session emerged. Role-play can be effectively utilized while teaching selected topics of molecular pharmacology in undergraduate medical curricula.

  15. Pharmacology of cardiac potassium channels.

    PubMed

    Li, Gui-Rong; Dong, Ming-Qing

    2010-01-01

    Cardiac K(+) channels are cardiomyocyte membrane proteins that regulate K(+) ion flow across the cell membrane on the electrochemical gradient and determine the resting membrane potential and the cardiac action potential morphology and duration. Several K(+) channels have been well studied in the human heart. They include the transient outward K(+) current I(to1), the ultra-rapidly activating delayed rectifier current I(Kur), the rapidly and slowly activating delayed rectifier currents I(Kr) and I(Ks), the inward rectifier K(+) current I(K1), and ligand-gated K(+) channels, including adenosine-5'-triphosphate (ATP)-sensitive K(+) current (I(KATP)) and acetylcholine-activated current (I(KACh)). Regional differences of K(+) channel expression contribute to the variable morphologies and durations of cardiac action potentials from sinus node and atrial to ventricular myocytes, and different ventricular layers from endocardium and midmyocardium to epicardium. They also show different responses to endogenous regulators and/or pharmacological agents. K(+) channels are well-known targets for developing novel anti-arrhythmic drugs that can effectively prevent/inhibit cardiac arrhythmias. Especially, atrial-specific K(+) channel currents (I(Kur) and I(KACh)) are the targets for developing atrial-selective anti-atrial fibrillation drugs, which has been greatly progressed in recent years. This chapter concentrates on recent advances in intracellular signaling regulation and pharmacology of cardiac K(+) channels under physiological and pathophysiological conditions.

  16. 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

  17. The behavioral pharmacology of hallucinogens.

    PubMed

    Fantegrossi, William E; Murnane, Kevin S; Reissig, Chad J

    2008-01-01

    Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.

  18. The pharmacological tables of Rhazes.

    PubMed

    Kahl, Oliver

    2011-01-01

    This article deals with the 22nd volume of Muḥammad ibn Zakarīyāʾ al-Rāzīʾs (Rhazes, d. 313/925) medical encyclopedia al-Ḥāwī fī l-ṭibb. Volume twenty-two is dedicated to pharmacology and pharmacological tables, and introduced by a short treatise in which Rhazes explains his unusual choice of tabular design and terminological arrangement. Following upon a brief bio-bibliographical survey and forming the core of this article, Rhazesʾ introductory treatise is re-edited here in the original Arabic and further made accessible through an annotated English translation. Edition and translation, in turn, are followed by a detailed study of both the treatise and the tables, including explanatory diagrams, statistical evaluations, a source-critical analysis, and some observations regarding the tradition of synoptic tables in Arabic pharmaceutical literature — thus gradually emerges the conceptual originality of Rhazesʾ implementation, and new light is thrown on his broad linguistic interests and abilities. The article concludes with an excursion into the realm of Persian-Chinese intellectual exchange, suggesting the possibility of a stimulus to Rhazesʾ imagination from a remote and otherwise mostly hidden corner.

  19. Pre-clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence

    PubMed Central

    Rollema, H; Shrikhande, A; Ward, KM; Tingley, FD; Coe, JW; O'Neill, BT; Tseng, E; Wang, EQ; Mather, RJ; Hurst, RS; Williams, KE; de Vries, M; Cremers, T; Bertrand, S; Bertrand, D

    2010-01-01

    Background and purpose: Smoking cessation trials with three high-affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs. Experimental approach: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over. Key results: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs. Conclusions and implications: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy. PMID:20331614

  20. British citizens in a regional community of southeastern Spain with a pre-clinical organ xenotransplantation program. A study of attitude toward xenotransplantation.

    PubMed

    Ríos, A; Ramírez, P; Martínez, L; Jarvis, N; Sánchez, J; Rodríguez, M M; Alcaraz, J; Montoya, M J; Parrilla, P

    2007-05-01

    It is important to find out about the social acceptance of xenotransplantation, especially in populations where there are pre-clinical xenotransplantation projects, and therefore the possibility of xenotransplantation to humans. In the native population of southeastern Spain this situation is well-known, but in recent years there has been an important social change because of a considerable migrational flow into Spain, especially from the British Isles. To analyze the attitude toward xenotransplantation among the population living in southeastern Spain born in the British Isles and to determine the variables that affect this attitude. A random sample was taken of British and Irish citizens resident in southeast Spain and stratified according to a respondent's nationality (n = 1700). The data were obtained between November 2005 and April 2006. Attitude was evaluated using a validated questionnaire that was completed anonymously and self-administered. The control group comprised a random sample (n = 250) of the native population. Student's t-test, the chi-squared test, Fischer's exact test and a logistic regression analysis were used in the statistical analysis. The questionnaire completion rate was 91% (n = 1546), with 69% of respondents in favor of xenotransplantation, 8% against and 23% unsure, an attitude that is similar to that of the control group (P = 0.1616). These attitudes were based on the assumption that transplanted animal organs had the same outcomes and involved the same risks as human ones. This attitude is related to the following factors: (i) being of male sex (P = 0.0477); (ii) level of education (P = 0.012); (iii) being natives from England or Wales (P = 0.016); (iv) participation in voluntary pro-social activities (P = 0.035); (v) the respondent's religion (P < 0.001); (vi) knowing that one's religion has a favorable attitude toward transplantation (P < 0.001); (vii) having discussed the subject of organ donation and transplantation within the

  1. Progress in Pharmacological Sciences in China.

    PubMed

    Wang, Jian-Cheng; Zhu, Yuangui; Wu, Lei; Dong, Erdan

    2017-09-01

    Pharmacology is the science that investigates the interactions between organisms and drugs and their mechanisms. Pharmacology plays a translational role in modern medicine, bridging basic research and the clinic. With its economy booming, China has invested an enormous amount of financial and human resources in pharmacological research in the recent decade. As a result, major breakthroughs have been achieved in both basic and clinical research, with the discovery of many potential drug targets and biomarkers that has made a sizable contribution to the overall advancement of pharmacological sciences. In this article, we review recent research efforts and representative scientific achievements and discuss future challenges and directions for the pharmacological sciences in China. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  2. The First 50 Years of Molecular Pharmacology.

    PubMed

    Brown, Joan Heller; Catterall, William A; Conn, P Jeffrey; Cull-Candy, Stuart G; Dingledine, Ray; Harden, T Kendall; Insel, Paul A; Milligan, Graeme; Traynelis, Stephen F

    2015-07-01

    In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets.

  3. Pharmacologic management of overactive bladder

    PubMed Central

    Lam, Sum; Hilas, Olga

    2007-01-01

    Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy. PMID:18044184

  4. The pharmacological properties of antidepressants.

    PubMed

    Racagni, Giorgio; Popoli, Maurizio

    2010-05-01

    Antidepressant drugs represent one of the main forms of effective treatment for the amelioration of depressive symptoms. Most available antidepressants increase extracellular levels of monoamines. However, it is now recognized that monoamine levels and availability are only part of the story, and that antidepressants whose mechanism of action is mainly based on the modulation of monoaminergic systems may not be able to satisfy the unmet needs of depression. Therefore, a number of compounds, developed for their potential antidepressant activity, are endowed with putative mechanisms of action not affecting traditional monoamine targets. This article briefly reviews, within a mechanistic perspective, the pharmacological profiles of representative antidepressants from each class, including monoamine oxidase inhibitors, tricyclics, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors, antidepressants interacting with dopaminergic, melatonergic, glutamatergic, or neuropeptide systems. The undesirable side effects of currently used antidepressants, which can often be a reason for lack of compliance, are also considered.

  5. Pharmacologic vitreolysis in diabetic retinopathy.

    PubMed

    El-Asrar, Ahmed M Abu; Al-Mezain, Hani S

    2011-03-01

    Diabetic retinopathy remains a major cause of worldwide preventable blindness. The vitreo-retinal interface plays a critical role in the pathogenesis of diabetic retinopathy. The term pharmacologic vitreolysis refers to the use of enzymes to liquefy the vitreous gel, and to induce posterior vitreous detachment (PVD). Intravitreal ovine hyaluronidase injection was effective in clearing vitreous hemorrhage. Several human case series demonstrated that intravitreal injection of autologous plasmin enzyme was a safe and effective adjunct to vitreous surgery for the treatment of diabetic macular edema and proliferative diabetic retinopathy. Recently, it was shown that intravitreal injection of plasmin enzyme without the performance of vitrectomy induced complete PVD and reduced macular thickening due to refractory diabetic macular edema.

  6. Pharmacologic Treatment of Erectile Dysfunction

    PubMed Central

    Steers, William D

    2002-01-01

    Penile erection occurs in response to cavernous smooth muscle relaxation, increased blood flow to the penis, and restriction of venous outflow. These events are regulated by a spinal reflex relying on visual, imaginative, and olfactory stimuli generated within the central nervous system (CNS) and on tactile stimuli to the penis. Drugs can have a facilitatory or inhibitory effect either on the nerves regulating this reflex or on the cavernous smooth muscle. A balance between contractile and relaxant factors governs flaccidity/rigidity within the penis. Drugs that raise cytosolic calcium either prevent or abort erection. Conversely, drugs that lower cytosolic calcium relax smooth muscle and can initiate penile erection. Efficacy in treating erectile dysfunction (ED) with phosphodiesterase inhibitors, especially type 5; α-adrenergic-receptor antagonists; and dopamine agonists exploit these mechanisms within the penis or CNS. Recent advances in our understanding of the pharmacology of penile erection are being translated into effective therapies for ED. PMID:16986010

  7. 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

  8. Cluster headache: conventional pharmacological management.

    PubMed

    Becker, Werner J

    2013-01-01

    Cluster headache pain is very intense, usually increases in intensity very rapidly from onset, and attacks are often frequent. These clinical features result in significant therapeutic challenges. The most effective pharmacological treatment options for acute cluster attack include subcutaneous sumatriptan, 100% oxygen, and intranasal zolmitriptan. Subcutaneous or intramuscular dihydroergotamine and intranasal sumatriptan are additional options. Transitional therapy is applicable mainly for patients with high-frequency (>2 attacks per day) episodic cluster headache, and options include short courses of high-dose oral corticosteroids, dihydroergotamine, and occipital nerve blocks with local anesthetic and steroids. Prophylactic therapy is important both for episodic and chronic cluster headache, and the main options are verapamil and lithium. Verapamil is drug of first choice but may cause cardiac arrhythmias, and periodic electrocardiograms (EKGs) during dose escalation are important. Many other drugs are also in current use, but there is an insufficient evidence base to recommend them.

  9. Pharmacological treatment of uterine fibroids.

    PubMed

    Moroni, Rm; Vieira, Cs; Ferriani, Ra; Candido-Dos-Reis, Fj; Brito, Lgo

    2014-09-01

    Uterine fibroids (UF) are common, benign gynecologic tumors, affecting one in three to four women, with estimates of up to 80%, depending on the population studied. Their etiology is not well established, but it is under the influence of several risk factors, such as early menarche, nulliparity and family history. More than 50% of affected women are asymptomatic, but the lesions may be related to bothersome symptoms, such as abnormal uterine bleeding, pelvic pain and bloating or urinary symptoms. The treatment of UF is classically surgical; however, various medical options are available, providing symptom control while minimizing risks and complications. A large number of clinical trials have evaluated commonly used medical treatments and potentially effective new ones. Through a comprehensive literature search using PubMed, EMBASE, CENTRAL, Scopus and Google Scholar databases, through which we included 41 studies out of 7658 results, we thoroughly explored the different pharmacological options available for management of UF, their indications, advantages and disadvantages.

  10. Pharmacology of human experimental anxiety.

    PubMed

    Graeff, F G; Parente, A; Del-Ben, C M; Guimarães, F S

    2003-04-01

    This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

  11. Pharmacological treatments in pathological gambling.

    PubMed

    Grant, Jon E; Odlaug, Brian L; Schreiber, Liana R N

    2014-02-01

    Pathological gambling (PG) is a relatively common and often disabling psychiatric condition characterized by intrusive urges to engage in deleterious gambling behaviour. Although common and financially devastating to individuals and families, there currently exist no formally approved pharmacotherapeutic interventions for this disorder. This review seeks to examine the history of medication treatments for PG. A systematic review of the 18 double-blind, placebo-controlled pharmacotherapy studies conducted for the treatment of pathological gambling was conducted. Study outcome and the mean dose of medication administered was documented in an effort to determine a preferred medication choice in this population. A variety of medication classes have been examined in the treatment of PG with varying results. Antidepressants, atypical antipsychotics and mood stabilizers have demonstrated mixed results in controlled clinical trials. Although limited information is available, opioid antagonists and glutamatergic agents have demonstrated efficacious outcomes, especially for individuals with PG suffering from intense urges to engage in the behaviour. Given that several studies have demonstrated their efficacy in treating the symptoms associated with PG, opioid antagonists should be considered the first line treatment for PG at this time. Most published studies, however, have employed relatively small sample sizes, are of limited duration and involve possibly non-representative clinical groups (e.g. those without co-occurring psychiatric disorders). Response measures have varied across studies. Heterogeneity of PG treatment samples may also complicate identification of effective treatments. Identification of factors related to treatment response will help inform future studies and advance treatment strategies for PG. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  12. Safety pharmacology in focus: new methods developed in the light of the ICH S7B guidance document.

    PubMed

    Pugsley, Michael K; Curtis, Michael J

    2006-01-01

    'Safety' continues to be a growth area in 'Pharmacology'. This issue of Journal of Pharmacological and Toxicological Methods is the third to be focused on methods development in the safety pharmacology area. The unusual nature of safety pharmacology mandates that methods development be done with, not only scientific validation, but also, adherence to the mandates of legislation to the forefront. This focused issue draws on a broad range of global safety pharmacology experts, many of whom operate in the industrial milieu. They have reviewed and updated current models, validated modifications, and have also introduced novel methodology important to the conduct of non-clinical safety pharmacology studies. The contributors were all active participants at the 5th Annual Safety Pharmacology Society (SPS) meeting held in Mannheim, Germany September 25-28, 2005. The publications presented here describe in vitro and in vivo pharmacological methods development that has been informed by the S7A regulatory guidance document for pre-clinical safety testing of drugs. While S7A describes the 'core battery' of methods used to characterize the safety pharmacology profile of a compound, the most recent news in Safety Pharmacology involves ratification of the related S7B safety guidance document. Unlike the past, S7B heralds a new era for the pharmaceutical industry since it now sets out how to address safety concerns of a new chemical entity (NCE) in relation to adverse actions on ventricular repolarization, a topic that has vexed industry and regulatory authorities for many years. Unsurprisingly there are many papers in the present issue that address this specific aspect of safety pharmacology. These include results from the Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) initiative, in which non-clinical in vitro (hERG and Purkinje fiber) and in vivo (QT dog study) assays were found to be useful in the determination of drug

  13. Pharmacologic management of pattern hair loss.

    PubMed

    Haber, Robert S

    2004-05-01

    Pharmacologic management of pattern hair loss is an active area of research, and clinicians should be aware of new data and treatment modalities. Under-standing the proper role of pharmacology as it relates to surgical hair restoration and nonmedical options is crucial to provide patients with the best clinical,aesthetic, and psychological benefits.

  14. 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…

  15. 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…

  16. Applications of stable isotopes in clinical pharmacology.

    PubMed

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

    2011-12-01

    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. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  17. [Pharmacological action of bromazepam suppository].

    PubMed

    Kasama, T; Fujii, Y; Aida, Y; Mayuzumi, K; Mayuzumi, Y; Goto, M; Gomita, Y; Moriyama, M; Ichimaru, Y

    1983-02-01

    Differences between the pharmacological effects of bromazepam given by oral and rectal administration were investigated in mice and rats. 1) Bromazepam dose-dependently prolonged the sleeping time induced by thiopental-Na, ethanol and ether by both administration routes. 2) The analgesic action of bromazepam was recognized by the hot-plate method and the algolytic test. In the hot-plate test, analgesic actions of morphine and pentazocine were potentiated by bromazepam in a dose of 0.5 mg/kg by both routes. 3) The muscle relaxant effect of bromazepam administered rectally was more potent than that administered orally in the inclined screen test and the rotarod test. This effect of bromazepam by rectal administration was approximately 2 times as potent as that by oral administration. 4) Bromazepam inhibited the convulsion induced by maximum electric shock, pentylenetetrazol and picrotoxin. In pentylenetetrazol-induced convulsion, the inhibitory effect of bromazepam administered rectally was 2 times as potent as that administered orally. In the other convulsion test, no significant differences between oral and rectal administration could be recognized. 5) Hyperemotionality and muricide (mouse-killing behaviour) of rats with bilateral olfactory bulb ablations (OB rat) were reduced by oral and rectal administrations of bromazepam in a dose-dependent manner. The effects by rectal administration were more potent than that by oral administration. Bromazepam was approximately 20 times as potent as diazepam administered by the same route. Fighting behaviour in mice subjected to footshock was suppressed by rectal administration of bromazepam, and this effect was as same as that by oral administration. 6) The rate of lever pressing response in the lateral hypothalamic self-stimulation test in the Skinner box was markedly increased by rectal administration of 0.2 mg/kg bromazepam. 7) Methamphetamine-induced hyperactivity of mice was significantly suppressed only by bromazepam

  18. Pharmacology of sexually compulsive behavior.

    PubMed

    Codispoti, Victoria L

    2008-12-01

    In a meta-analysis on controlled outcomes evaluations of 22,000 sex offenders, Losel and Schmucker found 80 comparisons between treatment and control groups. The recidivism rate averaged 19% in treated groups, and 27% in controls. Most other reviews reported a lower rate of sexual recidivism in treated sexual offenders. Of 2039 citations in this study (including literature in five languages), 60 studies held independent comparisons. Problematic issues included the control groups; various hormonal, surgical, cognitive behavioral, and psychotherapeutic treatments; and sample sizes. In the 80 studies compared after the year 2000, 32% were reported after 2000, 45% originated in the United States, 45% were reported in journals, and 36% were unpublished. Treatment characteristics showed a significant lack of pharmacologic treatment (7.5%), whereas use cognitive and classical behavioral therapy was 64%. In 68% of the studies, no information was available on the integrity of the treatment implementation; 36% of the treatment settings were outpatient only, 31% were prison settings, and 12% were mixed settings (prison, hospital, and outpatient). Integrating research interpretations is complicated by the heterogeneity of sex offenders, with only 56% being adult men and 17.5% adolescents. Offense types reported included 74% child molestation, 48% incest, and 30% exhibitionism. Pedophilia was not singled out. Follow-up periods varied from 12 months to greater than 84 months. The definition of recidivism ran the gamut from arrest (24%), conviction (30%), charges (19%), and no indication (16%). Results were difficult to interpret because of the methodological problems with this type of study. Overall, a positive outcome was noted with sex offender treatment. Cognitive-behavioral and hormonal treatment were the most promising. Voluntary treatment led to a slightly better outcome than mandatory participation. When accounting for a low base rate of sexual recidivism, the reduction

  19. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.

    PubMed

    Camerino, Giulia Maria; Cannone, Maria; Giustino, Arcangela; Massari, Ada Maria; Capogrosso, Roberta Francesca; Cozzoli, Anna; De Luca, Annamaria

    2014-11-01

    Weakness and fatigability are typical features of Duchenne muscular dystrophy patients and are aggravated in dystrophic mdx mice by chronic treadmill exercise. Mechanical activity modulates gene expression and muscle plasticity. Here, we investigated the outcome of 4 (T4, 8 weeks of age) and 12 (T12, 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in the gastrocnemius muscle of mdx and wild-type (WT) mice using quantitative real-time PCR. Basal expression of the exercise-sensitive genes peroxisome-proliferator receptor γ coactivator 1α (Pgc-1α) and Sirtuin1 (Sirt1) was higher in mdx versus WT mice at both ages. Exercise increased Pgc-1α expression in WT mice; Pgc-1α was downregulated by T12 exercise in mdx muscles, along with Sirt1, Pparγ and the autophagy marker Bnip3. Sixteen weeks old mdx mice showed a basal overexpression of the slow Mhc1 isoform and Serca2; T12 exercise fully contrasted this basal adaptation as well as the high expression of follistatin and myogenin. Conversely, T12 exercise was ineffective in WT mice. Damage-related genes such as gp91-phox (NADPH-oxidase2), Tgfβ, Tnfα and c-Src tyrosine kinase were overexpressed in mdx muscles and not affected by exercise. Likewise, the anti-inflammatory adiponectin was lower in T12-exercised mdx muscles. Chronic exercise with minor adaptive effects in WT muscles leads to maladaptation in mdx muscles with a disequilibrium between protective and damaging signals. Increased understanding of the pathways involved in the altered mechanical-metabolic coupling may help guide appropriate physical therapies while better addressing pharmacological interventions in translational research.

  20. [Pharmacologic treatment of osteoporosis--2011].

    PubMed

    Lakatos, Péter

    2011-08-14

    Osteoporosis affects approximately 9% of the population in Hungary resulting in about 100 000 osteoporotic fractures annually. Thirty-five percent of patients with hip fractures due to osteoporosis will die within 1 year. Direct costs of osteoporosis exceed 25 billion forints per year. Apparently, cost-effective reduction of bone loss and consequent fracture risk will add up to not only financial savings but improvement in quality of life, as well. A number of pharmacological modalities are available for this purpose. The mainstay of the treatment of osteoporosis is the bisphosphonate group that includes effective anti-resorptive compounds mitigating bone loss and fragility. The recently registered denosumab exhibits similar efficacy by neutralizing RANK ligand, however, marked differences can be observed between the two drug classes. Strontium has a unique mechanism of action by rebalancing bone turnover, and thus, providing an efficient treatment option for the not fast bone losers who are at high fracture risk. The purely anabolic teriparatide is available for the extremely severe osteoporotic patients and for those who do not respond to other types of therapy. Older treatment options such as hormone replacement therapy, raloxifene, tibolone or calcitonin may also have a restricted place in the management of osteoporosis.

  1. Pharmacological Fingerprints of Contextual Uncertainty

    PubMed Central

    Ruge, Diane; Stephan, Klaas E.

    2016-01-01

    Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. PMID:27846219

  2. Phage therapy pharmacology phage cocktails.

    PubMed

    Chan, Benjamin K; Abedon, Stephen T

    2012-01-01

    Phage therapy is the clinical or veterinary application of bacterial viruses (bacteriophages) as antibacterial "drugs." More generally, phages can be used as biocontrol agents against plant as well as foodborne pathogens. In this chapter, we consider the therapeutic use of phage cocktails, which is the combining of two or more phage types to produce more pharmacologically diverse formulations. The primary motivation for the use of cocktails is their broader spectra of activity in comparison to individual phage isolates: they can impact either more bacterial types or achieve effectiveness under a greater diversity of conditions. The combining of phages can also facilitate better targeting of multiple strains making up individual bacterial species or covering multiple species that might be responsible for similar disease states, in general providing, relative to individual phage isolates, a greater potential for presumptive or empirical treatment. Contrasting the use of phage banks, or even phage isolation against specific etiologies that have been obtained directly from patients under treatment, here we consider the utility as well as potential shortcomings associated with the use of phage cocktails as therapeutic antibacterial agents.

  3. Pharmacology of HIV Integrase Inhibitors

    PubMed Central

    Adams, Jessica L; Greener, Benjamin N; Kashuba, Angela DM

    2013-01-01

    Purpose of Review The purpose of this paper is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir and elvitegravir (both in Phase III drug development). Recent Findings Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter- and intra-patient pharmacokinetic variability is high. Twice daily 400mg dosing has been shown to be clinically superior to 800mg once daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was FDA approved in December 2011. Cobicistat-boosted elvitegravir, and the second generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, while boosted elvitegravir participates in additional CYP3A mediated interactions. Summary Raltegravir’s potent antiretroviral activity has resulted in widespread use in both treatment naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required. PMID:22789987

  4. Perioperative pharmacology in morbid obesity.

    PubMed

    Lemmens, Hendrikus J m

    2010-08-01

    Morbid obesity alters drug dose requirement and time course of drug response. In addition, morbid obesity's impact on many organ systems decreases the margin of safety of anesthetic drugs. Consequently, incorrect dosing will increase the rate of perioperative complications. In this review, we will discuss factors that affect the pharmacokinetics and pharmacodynamics of anesthetic agents in the obese population, we specify certain dosing scalars, and we relate our current knowledge of obesity's effects on the clinical pharmacology of anesthetic drugs. A morbidly obese individual's increased cardiac output requires administration of higher drug doses than would be required for a standard-size person to attain the same peak-plasma concentration. Lean body weight (LBW) is highly correlated with the increased cardiac output, more so than fat mass or other variables. For most drugs, clearance increases nonlinearly with total body weight but linearly with LBW. Morbid obesity has no clinically significant impact on the uptake of the inhalation anesthetics isoflurane, sevoflurane, and desflurane when used in routine clinical practice. Total body weight dosing of neuromuscular blocking agents will result in a prolonged effect. For the induction dose of hypnotics and the initial dose of other drugs that have a fast onset of effect, cardiac output or LBW are relevant dosing scalars. For maintenance dosing, LBW seems to be a more appropriate dosing scalar than total body weight.

  5. Prostaglandins: pharmacology and clinical application.

    PubMed

    Karim, S M; Hillier, K

    1974-01-01

    Prostaglandin research has been 1 of the most stimulating features of biomedical investigation in the past decade. Interest developed at a time of expanding knowledge of hormonal and neurohormonal behavior and research work received a tremendous impetus in the early 1960s with the elucidation in Sweden of the chemical structures of prostaglandins, followed by the discovery of their biosynthetic pathways. The original findings of large amounts of prostaglandin in the male accessory genital glands and their secretions, and subsequent discovery in the menstrual and amniotic fluids linked these substances with human production. As a result of further investigation, clinical applications of prostaglandins for the induction of labor and termination of early unwanted pregnancies have been developed. Apart from the functions of the prostaglandins in the reproductive area, they have been shown to have a widespread distribution in the body and produce many different pharmacological effects. Prostaglandins are thought to be involved in the regulation of blood pressure and through their vascular effects have therapeutic potential in the treatment of hypertension and peripheral vascular disease. Through their bronchodilator effect, some prostaglandins may become useful in the treatment of asthma.

  6. Physiology and Pharmacology of Ejaculation.

    PubMed

    Clement, Pierre; Giuliano, François

    2016-10-01

    Ejaculation is the final stage of coitus in mammalian male and is mandatory for natural procreation. Two synchronized phases, emission and expulsion, form the ejaculatory response and involve specific organs and anatomical structures. The peripheral events leading to ejaculation are commanded by autonomic (sympathetic and parasympathetic) and somatic divisions of the nervous system. The autonomic and somatic motor efferents originate in spinal nuclei located in thoracolumbar and lumbosacral segments. Co-ordinated activation of autonomic and somatic spinal nuclei is orchestrated by a group of lumbar spinal interneurons defined as the spinal generator of ejaculation. The generator of ejaculation together with the autonomic and somatic spinal nuclei constitutes a spinal network that is under the strong influence of stimulating or inhibiting genital sensory and supraspinal inputs. A brain circuitry dedicated to ejaculation has been delineated that is part of a more global network controlling other aspects of the sexual response. This circuitry includes discrete neuronal populations distributed in all divisions of the brain. The corollary to the expanded CNS network is the variety of neurotransmitter systems participating in the ejaculatory process. Among them, serotonin neurotransmission plays a key role and its targeting led to the development of the first registered pharmacological treatment of premature ejaculation in human beings. Critical gaps remain in the understanding of neurophysiopharmacology of ejaculation and management of ejaculatory disorders in human beings needs improvement. Because the ejaculatory response in laboratory animals and in human beings shares many similarities, the use of animal models will certainly provide further advances in the field.

  7. Pharmacologic Agents for Chronic Diarrhea.

    PubMed

    Lee, Kwang Jae

    2015-10-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

  8. Pharmacologic Agents for Chronic Diarrhea

    PubMed Central

    2015-01-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

  9. [Physiology and pharmacology of ejaculation].

    PubMed

    Rampin, Olivier; Giuliano, François

    2004-01-01

    Ejaculation requires an interplay of peripheral actors comprising, among others, smooth and skeletal fibers, glandular and endothelial cells. These actors are driven by vegetative and somatic innervations, deriving essentially from the spinal cord, in turn controlled by cerebral structures and endocrine factors, mostly steroids; These controls require sensitive afferences and command two steps, emission under autonomic control, and ejaculation per se which further involves somatic motoneurons. This review first describes the peripheral innervation of the part of the genital tract concerned in ejaculation, in which the sympathetic component is predominant and releases noradrenalin and neuropeptides; however parasympathetic and somatic components also play a role. At the spinal level, control circuits are organized into networks influenced by spinal structures, which have been discovered through selective lesions or stimulations, as well as by retrograde trans-synaptic tracing with neurotropic viruses. Among these structures, the median preoptic area and the hypothalamic paraventricular nucleus are major regulation sites. On the other hand, serotoninergic and also dopaminergic and adrenergic systems are implicated as well in the command of ejaculation; the latter constitute priviledged targets for a pharmacological treatment of dysfunctions.

  10. The Swiss Society of Experimental Pharmacology in Times of Change.

    PubMed

    Weitz-Schmidt, Gabriele; Rüegg, Urs

    2016-12-21

    Experimental pharmacology is undergoing fundamental changes. This article describes the challenges and opportunities associated with these changes from the perspective of the Swiss Society of Pharmacology (SSEP), the society which aims to advance experimental pharmacology in Switzerland and abroad.

  11. The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum.

    PubMed

    Lucieer, Susanna M; van der Geest, Jos N; Elói-Santos, Silvana M; de Faria, Rosa M Delbone; Jonker, Laura; Visscher, Chris; Rikers, Remy M J P; Themmen, Axel P N

    2016-03-01

    Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

  12. Current and future pharmacologic treatment of sarcopenia.

    PubMed

    Rolland, Yves; Onder, Graziano; Morley, John E; Gillette-Guyonet, Sophie; Abellan van Kan, Gabor; Vellas, Bruno

    2011-08-01

    Sarcopenia is a complex multifactorial condition that can by treated with multimodal approaches. No pharmacologic agent to prevent or treat sarcopenia has been as efficacious as exercise (mainly resistance training) in combination with nutritional intervention (adequate protein and energy intake). However, performing resistance training sessions and following nutritional advice can be challenging, especially for frail, sarcopenic, elderly patients, and results remain only partial. Therefore, new pharmacologic agents may substantially reduce the functional decline in older people. This article reviews the new pharmacologic agents currently being assessed for treating sarcopenia.

  13. Pharmacological closure of the patent ductus arteriosus

    PubMed Central

    Mehta, SK; Younoszai, A; Pietz, J; Achanti, BP

    2003-01-01

    Pharmacological closure by indomethacin is customary if symptoms of PDA are not controlled adequately with fluid restriction and diuretics. Its use, however, requires a comprehensive clinical assessment of all the vital perinatal factors and a vigilant monitoring of the sick infant. Prophylactic use of indomethacin is discouraged. The decision to use pharmacological versus surgical treatment or both should be individualized based on evidence-based research and clinician's own experience. Surgical ligation remains the primary mode of therapy in cases of pharmacological treatment failure or recurrence. PMID:22368623

  14. [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.

  15. [Non-pharmacological treatment of cognitive impairment].

    PubMed

    Ramos Cordero, Primitivo; Yubero, Raquel

    2016-06-01

    This article reviews the effect of non-pharmacological therapies in persons with cognitive impairment, especially treatments aimed at brain stimulation and functional maintenance, since both pharmacological and non-pharmacological therapies affecting the cognitive and psychoaffective domains are reviewed in another article in this supplement. The article also discusses the close and reciprocal relationship between cognitive impairment, diet and nutritional status and describes the main nutritional risk factors and protective factors in cognitive decline. Copyright © 2016 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

  16. The New 3D Printed Left Atrial Appendage Closure with a Novel Holdfast Device: A Pre-Clinical Feasibility Animal Study

    PubMed Central

    Brzeziński, M.; Bury, K.; Dąbrowski, L.; Holak, P.; Sejda, A.; Pawlak, M.; Jagielak, D.; Adamiak, Z.; Rogowski, J.

    2016-01-01

    Introduction Many patients undergoing cardiac surgery have risk factors for both atrial fibrillation (AF) and stroke. The left atrial appendage (LAA) is the primary site for thrombi formation. The most severe complication of emboli derived from LAA is stroke, which is associated with a 12-month mortality rate of 38% and a 12-month recurrence rate of 17%. The most common form of treatment for atrial fibrillation and stroke prevention is the pharmacological therapy with anticoagulants. Nonetheless this form of therapy is associated with high risk of major bleeding. Therefore LAA occlusion devices should be tested for their ability to reduce future cerebral ischemic events in patients with high-risk of haemorrhage. Aim The aim of this study was to evaluate the safety and feasibility of a novel left atrial appendage exclusion device with a minimally invasive introducer in a swine model. Materials and Methods A completely novel LAA device, which is composed of two tubes connected together using a specially created bail, was designed using finite element modelling (FEM) to obtain an optimal support force of 36 N at the closure line. The monolithic form of the occluder was obtained by using additive manufacturing of granular PA2200 powder with the technology of selective laser sintering (SLS). Fifteen swine were included in the feasibility tests, with 10 animals undergoing fourteen days of follow-up and 5 animals undergoing long-term observation of 3 months. For one animal, the follow-up was further prolonged to 6 months. The device was placed via minithoracotomy. After the observation period, all of the animals were euthanized, and their hearts were tested for LAA closure and local inflammatory and tissue response. Results After the defined observation period, all fifteen hearts were explanted. In all cases the full closure of the LAA was achieved. The macroscopic and microscopic evaluation of the explanted hearts showed that all devices were securely integrated in the

  17. Quantitative pharmacologic MRI in mice

    PubMed Central

    Perles-Barbacaru, Teodora-Adriana; Procissi, Daniel; Demyanenko, Andrey V.; Jacobs, Russell E.

    2011-01-01

    Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a non-invasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in differing brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique with temporal resolution of one minute at high magnetic field. The tissue half life of the USPIOs was studied using a nonlinear detrending model. All three studied USPIOs are candidates for CBV weighted phMRI-experiments, with r2/r1 ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo time of about 10 ms or longer results in a fCNR > 75 after USPIO injection, with negligible decrease during 1.5 to 2 hours. phMRI experiments were conducted at 7T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI indicated that CBV was reduced in the normal mouse brain after cocaine challenge, with largest effects in nucleus accumbens, while after acetazolamide the blood volume was increased in both cerebral and extra-cerebral tissue. PMID:21793079

  18. Pharmacology of nimodipine. A review.

    PubMed

    Scriabine, A; van den Kerckhoff, W

    1988-01-01

    The major pharmacological findings with nimodipine reviewed in this chapter are summarized in TABLE 3. On the basis of these findings, the following conclusions appear to be justified: 1. Nimodipine is a 1,4-dihydropyridine with Ca2+ channel antagonist properties. It is more lipophilic than nifedipine and its distribution volume in the brain of rats is higher than that of nifedipine. 2. Nimodipine dilates cerebral vessels at considerably lower concentrations than required for dilatation of peripheral blood vessels. It can, therefore, improve cerebral blood flow at doses that do not reduce systemic arterial pressure. 3. Nimodipine inhibits 45Ca uptake into vascular smooth muscle and neuronal cells. 4. Nimodipine antagonized postischemic cerebral hypoperfusion in cats and prolonged life of stroke-prone spontaneously hypertensive (SH) rats at doses that have little if any effect on arterial blood pressure. 5. Nimodipine reduced neurological deficits in dogs and monkeys with global cerebral ischemia. In focal ischemia (MCA occlusion) nimodipine reduced infarct size and neurological deficits and normalized intracellular brain pH. 6. In addition to its cerebral vasodilator effect, nimodipine appears to have a direct neuronal action. The suggested evidence for the neuronal site of action of nimodipine includes: a. Presence of nimodipine binding sites in brain. b. Blockade by nimodipine of Ca2+ channels in single nerve cells and in endocrine cells under conditions of sustained depolarization. c. Interactions with centrally acting drugs. d. Effects on release of various neurotransmitters from neuronal tissue or endocrine cells. e. Demonstration of anticonvulsant action of nimodipine. f. Blockade of behavioral effects of Ca2+ channel agonists by calcium channel antagonists.

  19. Pharmacology and therapeutics of bronchodilators.

    PubMed

    Cazzola, Mario; Page, Clive P; Calzetta, Luigino; Matera, M Gabriella

    2012-07-01

    regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.

  20. Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

    PubMed Central

    Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril AB; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; De Val, Sarah; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

    2017-01-01

    Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics. DOI: http://dx.doi.org/10.7554/eLife.21221.001 PMID:28137359

  1. Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.

    PubMed

    Gatti, Monica; Wurth, Roberto; Vito, Guendalina; Pattarozzi, Alessandra; Campanella, Chiara; Thellung, Stefano; Maniscalco, Lorella; De Maria, Raffaella; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Bajetto, Adriana; Ratto, Alessandra; Ferrari, Angelo; Barbieri, Federica; Florio, Tullio

    2016-05-01

    Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self-renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem-like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs.

  2. INTERSPECIES DOSIMETRY MODELS FOR PULMONARY PHARMACOLOGY

    EPA Science Inventory

    Interspecies Dosimetry Models for Pulmonary Pharmacology

    Ted B. Martonen, Jeffry D. Schroeter, and John S. Fleming

    Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangl...

  3. Pharmacological prophylaxis of venous thrombo-embolism.

    PubMed

    Flute, P T

    1976-02-07

    The pathogenesis of venous thrombosis is briefly discussed as a basis for the understanding of preventive measures used in this condition. Prophylaxis in venous thrombosis is then reviewed with emphasis on pharmacological treatment, and more particularly on heparin.

  4. INTERSPECIES DOSIMETRY MODELS FOR PULMONARY PHARMACOLOGY

    EPA Science Inventory

    Interspecies Dosimetry Models for Pulmonary Pharmacology

    Ted B. Martonen, Jeffry D. Schroeter, and John S. Fleming

    Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangl...

  5. Anti-aging pharmacology: Promises and pitfalls.

    PubMed

    Vaiserman, Alexander M; Lushchak, Oleh V; Koliada, Alexander K

    2016-11-01

    Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology.

  6. Future pharmacological treatments for substance use disorders.

    PubMed

    Forray, Ariadna; Sofuoglu, Mehmet

    2014-02-01

    Substance use disorders represent a serious public health and social issue worldwide. Recent advances in our understanding of the neurobiological basis of the addictive processes have led to the development of a growing number of pharmacological agents to treat addictions. Despite this progress, there are no approved pharmacological treatments for cocaine, methamphetamine and cannabis addiction. Moving treatment development to the next stage will require novel ways of approaching substance use disorders. One such novel approach is to target individual vulnerabilities, such as cognitive function, sex differences and psychiatric comorbidities. This review provides a summary of promising pharmacotherapies for alcohol, opiate, stimulant and nicotine addictions. Many medications that target positive and negative reinforcement of drugs, as well as individual vulnerabilities to addiction, are in different phases of development. Clinical trials testing the efficacy of these medications for substance use disorder are warranted. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  7. [Early diagnostics, prophylaxis, and non-pharmacological treatment of the preclinical stages of atherosclerosis and arterial hypertension].

    PubMed

    Bykov, A T; Chernyshev, A V; Vartazaryan, M A; Lobastov, R V

    2015-01-01

    Cardiovascular diseases remain the leading cause of death in most countries, including Russia. Non-pharmacological-modalities intended for the primary prevention of cardiovascular disease including hypertension and atherosclerosis currently acquire special significance. The objective of the present*study was to develop a system of methods for early diagnostics, prevention and treatment of the preclinical stages of atherosclerosis and hypertension Another objective was to estimate the effectiveness of these methods. A total of 310 patients at risk-of arterial hypertension and atherosclerosis or with pre-clinical stages of these conditions were examined during a two year observation period. The system of early diagnosis and non-pharmacological primary prevention of cardiovascular disease was developed and evaluated using climatotherapeutic and physiotherapeutic methods in combination with and personalized dietary therapy, hypoxic-hypercapnic factors and educational programs. The study has demonstrated that the proposed system allowed to significantly (p < 0.05) reduce cardiovascular morbidity. The patients of the main group experienced the reduction of abdominal obesity and blood pressure along with the improvement of the blood lipid profile and other indicators. These parameters remained unaltered in the patients comprising the control group. In the main group, the incidence of coronary heart disease and hypertension was 62.5% and 81.25% lower respectively than in the control group.

  8. Neuroimmune pharmacology as a component of pharmacology in medical school curriculum.

    PubMed

    Chen, Yuh F

    2011-03-01

    An introduction to the discipline of pharmacology is a standard part of the scientific foundation of medical school curricula. Neuroimmune pharmacology is a new subtopic that integrates fundamental concepts of neuroscience, immunology, infectious disease, and pharmacology. The integration of these areas is important to medical training in view of the growing concern over neurodegenerative diseases and cognitive disorders. This article introduces a submodule and concomitant syllabus for inclusion of neuroimmune pharmacology as a component of a pharmacology curriculum. The introductory lectures of neuroimmune pharmacology will concentrate on the role of the immune system in (1) schizophrenia and major depression; (2) neurodegenerative disorders; and (3) drug addiction. Emphasis will be placed on the competencies of critical thinking, problem solving, learning interest, and effectiveness of medical students. Problem-based learning and case study discussions will also be applied.

  9. 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.

  10. Review on pharmacological activities of Cinnamomum subavenium.

    PubMed

    Lee, Chien-Hsing; Kuo, Chien-Neng; Chen, Hsin-Liang; Chen, Chung-Yi

    2013-01-01

    This review describes the morphological, phytochemical and pharmacological properties of Cinnamomum subavenium (Lauraceae). The plant grows wild in southern Mainland China, Burma, Cambodia, Taiwan, Malaysia and Indonesia. This plant is recorded as having long been used to treat carcinomatous swelling, stomach ache, chest pain, abdominal pain, hernia, diarrhoea, rheumatism, nausea and vomiting. This article enumerates an overview of phytochemical and pharmacological aspects that is useful to researchers for further exploration for the necessary development of this potential herb.

  11. The pharmacology of topical analgesics.

    PubMed

    Barkin, Robert L

    2013-07-01

    Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain--whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic--a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding

  12. Medical curriculum and pharmacology: An appraisal.

    PubMed

    Haranath, P S R K

    2016-10-01

    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.

  13. Treatment of Pancreatic Cancer with Pharmacological Ascorbate.

    PubMed

    Cieslak, John A; Cullen, Joseph J

    2015-01-01

    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.

  14. 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

  15. Methodological innovations expand the safety pharmacology horizon.

    PubMed

    Pugsley, M K; Curtis, M J

    2012-09-01

    Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on 'best practice' for the conduct of a non-clinical cardiovascular assessment of a NCE. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Antimalarial pharmacology and therapeutics of atovaquone.

    PubMed

    Nixon, Gemma L; Moss, Darren M; Shone, Alison E; Lalloo, David G; Fisher, Nicholas; O'Neill, Paul M; Ward, Stephen A; Biagini, Giancarlo A

    2013-05-01

    Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.

  17. Pharmacological interventions for acute pancreatitis.

    PubMed

    Moggia, Elisabetta; Koti, Rahul; Belgaumkar, Ajay P; Fazio, Federico; Pereira, Stephen P; Davidson, Brian R; Gurusamy, Kurinchi Selvan

    2017-04-21

    In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure. To assess the effects of different pharmacological interventions in people with acute pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials. We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model. We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin

  18. Finding a VOICE for UK clinical pharmacology

    PubMed Central

    Aronson, Jeffrey K

    2012-01-01

    At a James Black Conference held in Oxford on 20–22 June 2011, a group of senior clinical pharmacologists and their junior colleagues, other medical specialists, and pharmacists discussed an agenda for UK clinical pharmacology for the next 5 years, addressing the following broad questions. How should UK clinical pharmacology be further developed and delivered as a discipline in universities, the NHS, pharmaceutical companies, and regulatory authorities? How should teaching and training in UK clinical pharmacology and therapeutics be delivered and assessed? What topics should be priorities for research in UK academic clinical pharmacology? How should clinical pharmacology contribute to UK drugs policy? How should pharmacology and clinical pharmacology be further integrated, to the benefit of both? Numerous recommendations emerged, under the collective acronym VOICE, standing for Visibility, Outreach, Integration, Coverage and Emissaries. Visibility The visibility of the discipline needs to be increased. This could be done, for example, by increased activities in acute general medicine/toxicology, through activities of Medicines and Therapeutics Committees, participation in grand rounds, teaching and training, and monitoring therapeutic interventions, and by offering bolt-on training for other specialists (for example, short courses, MSc courses, and training programmes). Outreach Methods of increasing outreach include roadshows in schools/medical schools, national special study modules, public education, press coverage, and social marketing. Integration Closer collaborations with pharmacologists, clinical pharmacists, other prescribers, and pharmaceutical companies (e.g. through joint training programmes) are desirable. Coverage Attention to neglected areas, such as general practice, paediatrics, obstetrics, geriatrics, anaesthetics, cancer, and immunology. Emissaries Trainees to spread the word. PMID:22360150

  19. Finding a VOICE for UK clinical pharmacology.

    PubMed

    Aronson, Jeffrey K

    2012-06-01

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

  20. Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests.

    PubMed

    Lefranc, Florence; Tabanca, Nurhayat; Kiss, Robert

    2017-06-07

    This review is part of a special issue entitled "Role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment" and describes a pharmacological strategy to determine the potential contribution of food-related components as anticancer agents against established cancer. Therefore, this review does not relate to chemoprevention, which is analysed in several other reviews in the current special issue, but rather focuses on the following: i) the biological events that currently represent barriers against the treatment of certain types of cancers, primarily metastatic cancers; ii) the in vitro and in vivo pharmacological pre-clinical tests that can be used to analyse the potential anticancer effects of food-related components; and iii) several examples of food-related components with anticancer effects. This review does not represent a catalogue-based listing of food-related components with more or less anticancer activity. By contrast, this review proposes an original pharmacological strategy that researchers can use to analyse the potential anticancer activity of any food-related component-e.g., by considering the crucial characteristics of cancer biological aggressiveness. This review also highlights that cancer patients undergoing chemotherapy should restrict the use of "food complements" without supervision by a medical nutritionist. By contrast, an equilibrated diet that includes the food-related components listed herein would be beneficial for cancer patients who are not undergoing chemotherapy. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  1. Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial.

    PubMed

    Leoutsakos, Jeannie-Marie S; Muthen, Bengt O; Breitner, John C S; Lyketsos, Constantine G

    2012-04-01

    We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib. We identified three classes: "no decline", "slow decline", and "fast decline", and examined the effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (-2 log likelihood difference: 369.23; p < 0.001) but resulted in reversal of effects over time. Over 4 years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, whereas those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), whereas those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Our results appeared statistically robust but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then attenuated change in fast decliners. Copyright © 2011 John Wiley & Sons, Ltd.

  2. 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

  3. Cannabinoid Receptors: Nomenclature and Pharmacological Principles

    PubMed Central

    Console-Bram, Linda; Marcu, Jahan; Abood, Mary E.

    2012-01-01

    The CB1 and CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that are pharmacologically well defined. However, the discovery of additional sites of action for endocannabinoids as well as synthetic cannabinoid compounds suggests the existence of additional cannabinoid receptors. Here we review this evidence, as well as the current nomenclature for classifying a target as a cannabinoid receptor. Basic pharmacological definitions, principles and experimental conditions are discussed in order to place in context the mechanisms underlying cannabinoid receptor activation. Constitutive (agonist-independent) activity is observed with the overexpression of many GPCRs, including cannabinoid receptors. Allosteric modulators can alter the pharmacological responses of cannabinoid receptors. The complex molecular architecture of each of the cannabinoid receptors allows for a single receptor to recognize multiple classes of compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. Importantly, the basic biology of the endocannabinoid system will continue to be revealed by ongoing investigations. PMID:22421596

  4. 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.

  5. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    PubMed

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues.

  6. Heterocyclic Amaryllidaceae Alkaloids: Biosynthesis and Pharmacological Applications.

    PubMed

    Hotchandani, Tarun; Desgagne-Penix, Isabel

    2017-01-01

    Amaryllidaceae alkaloids (AAs), which are natural heterocyclic compounds, are isolated from Amaryllidaceae plants such as narcissus, snowdrop and spider lily. AAs have been extensively studied due to their multiple pharmacological properties. Nevertheless, knowledge of AA synthesis in plants is lacking and most genes encoding enzymes involved in their production remain unknown. AAs are structurally complex compounds which are challenging for total chemical synthesis that is economically viable. Therefore the understanding of AA biosynthesis could allow for the development of biotechnologies for the production of natural AAs or analogues, maintaining or improving their pharmacological properties. In this review, we describe the progress regarding the biosynthesis and pharmacological properties of AAs. The most recent developments in neurological, anti-cancer and anti-microbial bioactivities of heterocyclic AAs are covered.

  7. Investigational pharmacology for low back pain.

    PubMed

    Bhandary, Avinash K; Chimes, Gary P; Malanga, Gerard A

    2010-09-06

    Review and reinterpretation of existing literature. This review article summarizes the anatomy and pathogenesis of disease processes that contribute to low back pain, and discusses key issues in existing therapies for chronic low back pain. The article also explains the scientific rationale for investigational pharmacology and highlights emerging compounds in late development. While the diverse and complex nature of chronic low back pain continues to challenge clinicians, a growing understanding of chronic low back pain on a cellular level has refined our approach to managing chronic low back pain with pharmacology. Many emerging therapies with improved safety profiles are currently in the research pipeline and will contribute to a multimodal therapeutic algorithm in the near future. With the heterogeneity of the patient population suffering from chronic low back pain, the clinical challenge will be accurately stratifying the optimal pharmacologic approach for each patient.

  8. Pharmacological treatment of adult ADHD in Europe.

    PubMed

    Retz, Wolfgang; Retz-Junginger, Petra; Thome, Johannes; Rösler, Michael

    2011-09-01

    It is now widely accepted that ADHD is a frequent chronic condition with a lifelong perspective. Adult ADHD is a reliable and valid diagnosis. The disorder and the co-morbid conditions can place a severe burden on the patients, their families and their partners, requiring adequate treatment. A systematic literature search was conducted to review the available pharmacological treatment options for adults with ADHD in European countries. Supported by meta-analyses, stimulant medication is the first-line pharmacological therapy for adult ADHD. However, from a European perspective the pharmacological treatment options are very limited and only a minority of adults with ADHD in European countries receives adequate treatment. With reference to the epidemiological data, it seems very likely that the number of people with ADHD in Europe seeking multimodal treatment including pharmacotherapy, psychotherapy, coaching or other therapeutic services will increase profoundly during the coming years.

  9. 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

  10. 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

  11. 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.

  12. Heteromer Induction: An Approach to Unique Pharmacology?

    PubMed

    Portoghese, Philip S; Akgün, Eyup; Lunzer, Mary M

    2017-03-15

    It is proposed that two types of opioid receptor heteromers exist: a) those that are constitutive and b) those that are induced by bivalent ligands. Mu opioid agonists interact with constitutive MOR-DOR heteromer to mediate tolerance and dependence. Bivalent ligand, MDAN21, is devoid of these adverse effects by virtue of its DOR antagonist pharmacophore. We propose that bivalent ligands MMG22 and MCC22 induce colocalized receptors to form heteromers (MOR-mGluR5 and MOR-CCR5, respectively) that do not occur naturally, thereby promoting unique pharmacology. Heteromer induction with bivalent ligands offers a general approach to unique pharmacology that complements traditional SAR.

  13. Pharmacological treatment effects on eye movement control

    PubMed Central

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

    2011-01-01

    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 learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second-generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson's disease, and Huntington's disease are also reviewed. While greater

  14. Rhein: A Review of Pharmacological Activities

    PubMed Central

    Zhou, Yan-Xi; Xia, Wei; Yue, Wei; Peng, Cheng; Rahman, Khalid; Zhang, Hong

    2015-01-01

    Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is a lipophilic anthraquinone extensively found in medicinal herbs, such as Rheum palmatum L., Cassia tora L., Polygonum multiflorum Thunb., and Aloe barbadensis Miller, which have been used medicinally in China for more than 1,000 years. Its biological activities related to human health are being explored actively. Emerging evidence suggests that rhein has many pharmacological effects, including hepatoprotective, nephroprotective, anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. The present review provides a comprehensive summary and analysis of the pharmacological properties of rhein, supporting the potential uses of rhein as a medicinal agent. PMID:26185519

  15. Strychnos potatorum: Phytochemical and pharmacological review

    PubMed Central

    Yadav, Kavita N.; Kadam, Prasad V.; Patel, Jigna A.; Patil, Manohar J.

    2014-01-01

    In traditional system of medicine, the seeds of Strychnos potatorum Linn. (family: Loganiaceae) are used in the treatment of gonorrhea, leukorrhea leukeorrhea, gastropathy, bronchitis, chronic diarrhea, dysentery, renal and vesicle calculi, diabetes, conjunctivitis, scleritis, ulcers and other eye disease. An attempt has been made to highlight this medicinal seeds through phytochemical and pharmacological study. The present review deals with the phytochemical and pharmacological screening of therapeutic importance from Strychnos potatorum L., an important medicinal plant. This study includes the collective information of different medicinal uses of Strychnos potatorum. The generated data has provided the basis for its wide use as the therapeutant both in the traditional and folk medicines. PMID:24600197

  16. [Hemodynamics of erection: current pharmacological findings].

    PubMed

    Dorémieux, J

    1985-01-01

    Over twenty drugs were injected into the corpora cavernosa. Pharmacologically these drugs come under seven therapeutic categories. Two types of pharmacodynamics explain the mode of action of these agents on the erectile tissues. The discovery of these drugs can be added to the array of investigations and actions normally used to study and remedy the problems of organic impotence, as well as a new test which may provide a therapeutic base for vascular rehabilitation and, in some cases, a substrate for a pharmacological prosthesis.

  17. Orofacial Pain: Pharmacologic Paradigms for Therapeutic Intervention.

    PubMed

    Halpern, Leslie; Willis, Porchia

    2016-04-01

    Pain is a universal experience with profound effects on the physiology, psychology, and sociology of the population. Orofacial pain (OFP) conditions are especially prevalent and can be severely debilitating to a patient's health-related quality of life. Evidence-based clinical trials suggest that pharmacologic therapy may significantly improve patient outcomes either alone or when used as part of a comprehensive treatment plan for OFP. The aim of this article is to provide therapeutic options from a pharmacologic perspective to treat a broad spectrum of OFP. Clinical-based systemic and topical applied pharmaceutical approaches are presented to treat the most common OFP syndromes. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Methods in pharmacology: measurement of cardiac output

    PubMed Central

    Geerts, Bart F; Aarts, Leon P; Jansen, Jos R

    2011-01-01

    Many methods of cardiac output measurement have been developed, but the number of methods useful for human pharmacological studies is limited. The ‘holy grail’ for the measurement of cardiac output would be a method that is accurate, precise, operator independent, fast responding, non-invasive, continuous, easy to use, cheap and safe. This method does not exist today. In this review on cardiac output methods used in pharmacology, the Fick principle, indicator dilution techniques, arterial pulse contour analysis, ultrasound and bio-impedance are reviewed. PMID:21284692

  19. Pharmacological aspects of the safety of gliflozins.

    PubMed

    Faillie, Jean-Luc

    2017-04-01

    Sodium-glucose transporter 2 (SGLT2) inhibitors, also known as gliflozins, are a new class of orally active drugs used in the management of type 2 diabetes. By inhibiting the SGLT responsible for the reabsorption of glucose from the kidney, their use aims primarily to induce glycosuria and, as a consequence, lower glycemic levels. However, their specific mechanism of action involves other pharmacodynamic consequences including potentially harmful adverse reactions. This manuscript reviews the physiological and pharmacological background behind inhibition of SGLTs, and discusses the pharmacological aspects of the safety of gliflozins.

  20. [Pharmacology and clinical aspects of benzodiazepines].

    PubMed

    Mendlewicz, J; Sevy, S

    1985-01-01

    The widespread use of benzodiazepines has led the authors to review the pharmacological and clinical aspects of these substances. On a molecular level, the benzodiazepines have an effect on receptors in relation with the GABA system. Presently, endogenous ligand(s) to these receptors have not yet been fully demonstrated. The main benzodiazepines are also compared for their kinetics which is function of absorption, metabolisation and various factors such as binding to the receptor, age, hepatic and renal disorders. These pharmacological studies have clinical implications. The authors finally make a brief review of the clinical indications of the benzodiazepines.

  1. Statistical reporting of clinical pharmacology research.

    PubMed

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

    2017-03-21

    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.

  2. The pharmacological treatment of nystagmus: a review.

    PubMed

    McLean, Rebecca Jane; Gottlob, Irene

    2009-08-01

    Nystagmus is an involuntary, to-and-fro movement of the eyes that can result in a reduction in visual acuity and oscillopsia. Mechanisms that cause nystagmus are better understood in some forms, such as acquired periodic alternating nystagmus, than in others, for example acquired pendular nystagmus, for which there is limited knowledge. Effective pharmacological treatment exists to reduce nystagmus, particularly in acquired nystagmus and, more recently, infantile nystagmus. However, as there are very few randomized controlled trials in the area, most pharmacological treatment options in nystagmus remain empirical.

  3. Plant cannabinoids: a neglected pharmacological treasure trove.

    PubMed

    Mechoulam, Raphael

    2005-12-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Delta(9)-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  4. [Multimedia methods for the teaching of pharmacology].

    PubMed

    Di Girolamo, G

    2001-01-01

    Pharmacology is by definition a subject of integration. Students take on a passive role during the learning process and do not count with image aids that could foster understanding, fixation and evocation. Therefore, a hypermedia pharmacology CD ROM program was developed. Such a program includes the following features: hypertext format set up as a network of nodes and arcs, multimedia technology, highly interactive and customized navigation. The prototype thoroughly develops cholinergic neurotransmission pharmacology in its historical, anatomic, physiological, biochemical, pharmacological and therapeutic aspects. The program is divided into three modules; namely, information, exercises and evaluation. Each network node may contain a text, hypertext, images, 3D animation and experimental videos. Information resources include the navigation conceptual map for the chosen node, a track record to go back or forward immediately, the possibility of adding text or images, a text search function, images, animation and videos to find such objects in the different nodes together with the possibility of printing any of the contents. Apart from the information framework, the model has manifold useful integration exercises to assess the learning improvement and prompt the student accordingly to review the topic whenever mistakes exceed a certain amount. This program promotes knowledge integration and building through association of contents. To access to the program's demo, consult the following page.

  5. Clinical pharmacology of old age syndromes

    PubMed Central

    Broadhurst, C; Wilson, K C M; Kinirons, M T; Wagg, A; Dhesi, J K

    2003-01-01

    Several syndromes occur in old age. They are often associated with increased mortality and in all there is a paucity of basic and clinical research. The recent developments in the clinical pharmacology of three common syndromes of old age (delirium, urinary incontinence, and falls) are discussed along with directions for future research. PMID:12919174

  6. 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

  7. 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

  8. Disrupting Reconsolidation: Pharmacological and Behavioral Manipulations

    ERIC Educational Resources Information Center

    Soeter, Marieke; Kindt, Merel

    2011-01-01

    We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects…

  9. Systems Pharmacology in Small Molecular Drug Discovery

    PubMed Central

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  10. Pharmacological Interventions for Students with ADD.

    ERIC Educational Resources Information Center

    Austin, Vance L.

    2003-01-01

    A review of the research on pharmacological interventions for students with attention deficit disorder finds that psychostimulants such as methylphenidate (Ritalin) are effective in improving focus and impulse control, but should be used in conjunction with psychosocial and behavioral interventions. Comprehensive medical screenings and guidelines…

  11. 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

  12. 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

  13. Disrupting Reconsolidation: Pharmacological and Behavioral Manipulations

    ERIC Educational Resources Information Center

    Soeter, Marieke; Kindt, Merel

    2011-01-01

    We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects…

  14. 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

  15. Systems Pharmacology in Small Molecular Drug Discovery.

    PubMed

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-02-18

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  16. Novel pharmacological targets from Indian cone snails.

    PubMed

    Ramasamy, M Santhana; Manikandan, S

    2011-02-01

    The oceans are a source of combinatorial library of unique natural products, 'not found in the terrestrial environment'. Marine invertebrates such as sponges, molluscs, bryozoans, tunicates (Urochordata) and their associated microorganisms are the major representatives of promising bioactive compounds. Among these, the predatory molluscan cone snails have evolved with highly structured small and complex array of peptides (more than 50,000) linked to their prey capture and defence. These peptides have become a valuable source of neuro pharmacological targets as many of them selectively modulate ion channels and transporters. A group of scientists from United States, Europe, Australia, Israel and China have been characterized drugs for neuropathic pain and pharmacological targets from the peptides of a few cone snail species. Several are now in Clinical and preclinical development. Less than 1% of the cono peptides are pharmacologically characterized. India has a diversity of 20-30% of total cone snail species distributed worldwide. A group of Indian Scientists have made promising drug discovery programs from Conus peptides. This review will focus on the Conus peptides from Indian cone snails species, their neuro pharmacological targets and future directions.

  17. 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…

  18. Pharmacological Interventions for Students with ADD.

    ERIC Educational Resources Information Center

    Austin, Vance L.

    2003-01-01

    A review of the research on pharmacological interventions for students with attention deficit disorder finds that psychostimulants such as methylphenidate (Ritalin) are effective in improving focus and impulse control, but should be used in conjunction with psychosocial and behavioral interventions. Comprehensive medical screenings and guidelines…

  19. Origins, practices and future of safety pharmacology.

    PubMed

    Bass, Alan; Kinter, Lewis; Williams, Patricia

    2004-01-01

    The origins of safety pharmacology are grounded upon observations that organ functions (like organ structures) can be toxicological targets in humans exposed to novel therapeutic agents, and that drug effects on organ functions (unlike organ structures) are not readily detected by standard toxicological testing. Safety pharmacology is " em leader those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relationship to exposure in the therapeutic range and above em leader " [International Conference on Harmonization (ICH) S7A guidelines; Safety Pharmacology Studies for Human Pharmaceuticals]. This publication provides a comprehensive review of the history of safety pharmacology, international regulatory guidelines that govern the practices of this important field, and the scientific challenges that are being faced by its rapid emergence in pharmaceutical development. The criticality of identifying undesired adverse effects of new drugs in nonclinical models, which reflect the overall human condition, is reflected in the importance of generating an integrated and accurate assessment of possible human risk. The conundrum posed by the challenge of formulating a reliable risk assessment is the importance of improving and enhancing the safe progression of new drugs to the marketplace, while preventing unnecessary delays (or discontinuances), based on nonclinical findings that are not relevant or interpretable in terms of clinical response or human risk.

  20. Multidimensional Screening as a Pharmacology Laboratory Experience.

    ERIC Educational Resources Information Center

    Malone, Marvin H.; And Others

    1979-01-01

    A multidimensional pharmacodynamic screening experiment that addresses drug interaction is included in the pharmacology-toxicology laboratory experience of pharmacy students at the University of the Pacific. The student handout with directions for the procedure is reproduced, drug compounds tested are listed, and laboratory evaluation results are…

  1. Allium ursinum: botanical, phytochemical and pharmacological overview.

    PubMed

    Sobolewska, Danuta; Podolak, Irma; Makowska-Wąs, Justyna

    Ramson-Allium ursinum L. is a medicinal and dietary plant species with a long tradition of use. This mini-review summarizes the current knowledge on the phytochemistry and pharmacological properties of this valuable plant, with special emphasis on antimicrobial, cytotoxic, antioxidant, and cardio-protective effects.

  2. Pharmacology of the phosphate binder, lanthanum carbonate.

    PubMed

    Damment, Stephen J P

    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 [(32)P]-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.

  3. 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…

  4. The Early Development of Pharmacology in America.

    ERIC Educational Resources Information Center

    Parascandola, John

    Presented is a review of the development of the science of pharmacology, the study of the interaction of chemical agents with living matter. The origins of the field are traced from 17th century Europe to the present, with major emphasis upon the scientists and developments made in the field in the United States. (SL)

  5. 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

  6. The mass action equation in pharmacology.

    PubMed

    Kenakin, Terry

    2016-01-01

    The mass action equation is the building block from which all models of drug-receptor interaction are built. In the simplest case, the equation predicts a sigmoidal relationship between the amount of drug-receptor complex and the logarithm of the concentration of drug. The form of this function is also the same as most dose-response relationships in pharmacology (such as enzyme inhibition and the protein binding of drugs) but the potency term in dose-response relationships very often differs in meaning from the similar term in the simple mass action relationship. This is because (i) most pharmacological systems are collections of mass action reactions in series and/or in parallel and (ii) the important assumptions in the mass action reaction are violated in complex pharmacological systems. In some systems, the affinity of the receptor R for some ligand A is modified by interaction of the receptor with the allosteric ligand B and concomitantly the affinity of the receptor for ligand B is modified to the same degree. When this occurs, the observed affinity of the ligand A for the receptor will depend on both the concentration of the co-binding allosteric ligand and its nature. The relationships between drug potency in pharmacological models and the equilibrium dissociation constants defined in single mass action reactions are discussed. More detailed knowledge of efficacy has led to new models of drug action that depend on the relative probabilities of different states, and these have taken knowledge of drug-receptor interactions beyond Guldberg and Waage. © 2015 The British Pharmacological Society.

  7. Pharmacological profile of novel psychoactive benzofurans

    PubMed Central

    Rickli, Anna; Kopf, Simone; Hoener, Marius C; Liechti, Matthias E

    2015-01-01

    Background and Purpose Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. Experimental Approach We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine receptor-binding affinity and 5-HT2A and 5-HT2B receptor activation. Key Results All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated receptor 1 (TA1 receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT2A receptor agonists similar to MDMA, but also 5-HT2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 receptors and also bound to TA1 receptors. Conclusions and Implications Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction. PMID:25765500

  8. Pharmacology and function of melatonin receptors

    SciTech Connect

    Dubocovich, M.L.

    1988-09-01

    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 is 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.

  9. [Non-pharmacologic treatment of atrial fibrillation].

    PubMed

    Csanádi, Zoltán; Fazekas, Tamás; Varró, András

    2003-06-29

    The authors provide an update on non-pharmacological treatment of atrial fibrillation (AF). They emphasize that although antiarrhythmic drugs continue to be first-line therapy for the arrhythmia considered to be a cardiovascular epidemic, clinical research to develop non-pharmacological means of treatment has been unprecedentally intensified during the last decade. Electrical cardioversion is the most successful non-pharmacological method to restore sinus rhythm, also the efficacy and safety of AV node ablation for palliative ventricular rate-controll is established. "Hybrid" therapeutic procedures, involving combinations of pharmacological and non-pharmacological interventions have gained widespread use. Curative transcatheter ablation for arrhythmia prevention is to be considered in case of clinical suggestions that AF is initiated by a primary regular arrhythmia that is amenable to routine catheter ablation (secondary AF). Despite encouraging results, at this point in time, curative catheter ablation for primary AF may offer significant improvement or even cure only for a small subset of patients, mostly young individuals with normal heart, and paroxysmal AF with frequent, symptomatic episodes refractory to multiple antiarrhythmic drugs. These interventions are to be performed in the settings of a clinical research project in some institutions. Regarding pacemaker therapy in case of bradycardia indication, physiologic pacing (AAI or DDD) is associated with significantly lower incidence of atrial fibrillation than ventricular pacing. Large-scale randomized controlled trials are needed to assess the clinical value of specially designed implantable devices to prevent atrial fibrillation in patients with no conventional bradycardia indication. Also, technical optimization and proper clinical evaluation is needed for implantable atrioverters and implantable cardioverter defibrillators capable of atrial cardioversion therapy.

  10. 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.

  11. Comparison of a newly-designed stack-up collimator with conventional parallel-hole collimators in pre-clinical CZT gamma camera systems: a Monte Carlo simulation study

    NASA Astrophysics Data System (ADS)

    Lee, Young-Jin; Kim, Hee-Joung

    2014-10-01

    Recently, many studies have been conducted with pixelated semiconductor detectors that use cadmium zinc telluride (CZT) because these detectors have many advantages in pre-clinical gamma imaging. Collimators play an extremely important role in the imaging performance of pixelated semiconductor gamma cameras. In our previous study, based on the pixelated semiconductor gamma camera system we recommended the use of a pixelated parallel-hole collimator with equal hole and pixel sizes; this approach improved both the sensitivity and the spatial resolution. However, the pixelated parallel-hole collimator had two major limitations: (a) Although its sensitivity was higher than that of pinhole systems, the pixelated parallel-hole collimator may have still resulted in a partial loss of sensitivity due to its small collimator hole size. (b) The pixelated parallel-hole collimator with an adequate septal height was difficult to manufacture due to its small holes. Here, we present a new design for a parallel-hole collimator, which uses the stack-up method and a CZT pixelated semiconductor gamma camera system. The purpose of this study was to compare the performances of various geometric designs of our newly-designed parallel-hole collimator with those of conventional parallel-hole collimators [low-energy high-resolution (LEHR) and low-energy high-sensitivity (LEHS)]. The detector was modeled as an eValuator-2500 (eV Microelectronics Inc., Saxonburg, PA, USA) (3-mm thick, 0.5-mm pixel size) by using a Geant4 Application for Tomographic Emission (GATE) simulation. The proposed parallel-hole collimator consisted of two overlapping parallel-hole collimators. The size of each hole in the proposed parallel-hole collimator was four times that of the hole in the pixelated parallel-hole collimator. The overlap ratios of these collimators were 1 : 1, 1 : 2, 2 : 1, 1 : 5, and 5 : 1. To evaluate and compare the performances of these systems, we evaluated the sensitivity and the spatial

  12. [Non-pharmacological and pharmacological treatment of arterial hypertension: current situation].

    PubMed

    Hoyer, J

    2012-11-01

    A permanent and successful treatment of high blood pressure is based on a combination of non-pharmacological treatment measures and pharmacological therapy. The most proven non-pharmacological measures are physical and sports activities, weight reduction, dietary adaption and reduction of salt intake as well as nicotine abstinence and moderate alcohol consumption. A blood pressure reducing effect of evidence grade A was demonstrated for these 4 pillars of non-pharmacological therapy in studies. For pharmacological treatment five main substance groups are available: thiazide diuretics, ACE inhibitors, AT1 blockers, calcium channel blockers and beta blockers. A very good blood pressure reducing effect with an advantageous side effect profile has been proven for all substances. The initial high blood pressure therapy can be carried out with monotherapy but therapy with several antihypertensives is often necessary for the very varied combination of compounds which are available in a meaningful combination and dosage of effective ingredients. For the treatment of comorbid hypertensive patients recommendations are available for an individualized pharmacological treatment corresponding to the specific cardiovascular risk and comorbidity. High blood pressure therapy must be continuously carried out over many years. For permanent success of the therapy good compliance is indispensible which can be encouraged by integration in the therapy and should be regularly controlled.

  13. 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…

  14. Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease.

    PubMed

    Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K; Martin, Paul T

    2014-02-01

    Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting Aβ amyloid may have clinical benefit in Alzheimer's disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native Aβ amyloid-specific binding peptide, lowers brain Aβ amyloid plaque burden and brain Aβ1-40 and Aβ1-42 peptide levels, improves cognitive learning and memory in Morris water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-Aβ amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited Aβ amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target Aβ amyloid oligomers using an engineered peptide-mimotope strategy. © 2013.

  15. Using “Sub-cement” to simulate the long-term fatigue response of cemented femoral stems in a cadaver model: could a novel pre-clinical screening test have caught the Exeter matte problem?

    PubMed Central

    Race, Amos; Miller, Mark A.; Mann, Kenneth A.

    2010-01-01

    Previously, we formulated cement with degraded fatigue properties (sub-cement) to simulate long-term fatigue in short-term cadaver tests. The present study determined the efficacy of sub-cement in a `pre-clinical' test of a design change with known clinical consequences: the “polished” to “matte” transition of the Exeter stem (revision rates were twice as high for matte stems). Contemporary stems were bead-blasted to give Ra=1micron (matte finish). Matte and polished stems were compared in cadaver pairs under stair-climbing loads (3 pairs size-1, 3 pairs size-3). Stem micromotion was monitored during loading. Post-test, transverse sections were examined for cement damage. Cyclic retroversion decreased for polished stems but increased for matte stems (p<0.0001). Implant size had a substantial effect: retroversion of (larger) size-3 stems was half that of size-1 stems and polished size-3 stems subsided 2½ times more than the others. Cement damage measures were similar and open through-cracks occurred around both stems of two pairs. Stem retroversion within the mantle resulted in stem-cement gaps of 50–150microns. Combining information on cyclic motion, cracks, and gaps, we concluded that this test `predicted' higher revision rates for matte stems (it also implied that polished size-3 stems might be superior to size-1). PMID:20476506

  16. Relevance of Excitable Media Theory and Retinal Spreading Depression Experiments in Preclinical Pharmacological Research

    PubMed Central

    V.M, Fernandes de Lima; W, Hanke

    2014-01-01

    In preclinical neuropharmacological research, molecular, cell-based, and systems using animals are well established. On the tissue level the situation is less comfortable, although during the last decades some effort went into establishing such systems, i.e. using slices of the vertebrate brain together with optical and electrophysiological techniques. However, these methods are neither fast, nor can they be automated or upscaled. By contrast, the chicken retina can be used as a suitable model. It is easy accessible and can be kept alive in vitro for hours up to days. Due to its structure, in addition the retina displays remarkable intrinsic optical signals, which can be easily used in experiments. Also to electrophysiological methods the retina is well accessible. In excitable tissue, to which the brain and the retina belong, propagating excitation waves can be expected, and the spreading depression is such a phenomenon. It has been first observed in the forties of the last century. Later, Martins-Ferreira established it in the chicken retina (retinal spreading depression or RSD). The electrophysiological characteristics of it are identical with those of the cortical SD. The metabolic differences are known and can be taken into account. The experimental advantage of the RSD compared to the cortical SD is the pronounced intrinsic optical signal (IOS) associated with the travelling wave. This is due to the maximum transparency of retinal tissue in the functional state; thus any physiological event will change it markedly and therefore can be easily seen even by naked eye. The theory can explain wave spread in one (action potentials), two (RSDs) and three dimensions (one heart beat). In this review we present the experimental and the excitable media context for the data interpretation using as example the cholinergic pharmacology in relation to functional syndromes. We also discuss the intrinsic optical signal and how to use it in pre-clinical research. PMID:25426010

  17. Physiology and pharmacology of myocardial preconditioning.

    PubMed

    Raphael, Jacob

    2010-03-01

    Perioperative myocardial ischemia and infarction are not only major sources of morbidity and mortality in patients undergoing surgery but also important causes of prolonged hospital stay and resource utilization. Ischemic and pharmacological preconditioning and postconditioning have been known for more than two decades to provide protection against myocardial ischemia and reperfusion and limit myocardial infarct size in many experimental animal models, as well as in clinical studies (1-3). This paper will review the physiology and pharmacology of ischemic and drug-induced preconditioning and postconditioning of the myocardium with special emphasis on the mechanisms by which volatile anesthetics provide myocardial protection. Insights gained from animal and clinical studies will be presented and reviewed and recommendations for the use of perioperative anesthetics and medications will be given.

  18. Pharmacological Tests in Atrial Fibrillation Ablation

    PubMed Central

    Gourraud, Jean-Baptiste; Andrade, Jason G; Macle, Laurent

    2016-01-01

    The invasive management of atrial fibrillation (AF) has been considerably changed by the identification of major sites of AF initiation and/or maintenance within the pulmonary vein antra. Percutaneous catheter ablation of these targets has become the standard of care for sustained maintenance of sinus rhythm. Long-term failure of ablation is related to an inability to create a durable transmural lesion or to identify all of the non-pulmonary vein arrhythmia triggers. Pharmacological challenges during catheter ablation have been suggested to improve outcomes in both paroxysmal and persistent AF. Herein we review the mechanism and evidence for the use of pharmacological adjuncts during the catheter ablation of AF. PMID:28116081

  19. Pharmacological Therapy of Tachyarrhythmias During Pregnancy

    PubMed Central

    Yaksh, Ameeta; van der Does, Lisette JME; Lanters, Eva AH; de Groot, Natasja MS

    2016-01-01

    Tachyarrhythmias are the most frequently observed cardiac complications during pregnancy. The majority of these maternal and foetal arrhythmias are supraventricular tachyarrhythmias; ventricular tachyarrhythmias are rare. The use of anti-arrhythmic drugs (AADs) during pregnancy is challenging due to potential foetal teratogenic effects. Maintaining stable and effective therapeutic maternal drug levels is difficult due to haemodynamic and metabolic alterations. Pharmacological treatment of tachyarrhythmias is indicated in case of maternal haemodynamic instability or hydrops fetalis. Evidenc e regarding the efficacy and safety of AAD therapy during pregnancy is scarce and the choice of AAD should be based on individual risk assessments for both mother and foetus. This review outlines the current knowledge on the development of tachyarrhythmias during pregnancy, the indications for and considerations of pharmacological treatment and its potential side-effects. PMID:27408722

  20. Phytochemistry and Pharmacology of Carthamus tinctorius L.

    PubMed

    Zhang, Le-Le; Tian, Ke; Tang, Zheng-Hai; Chen, Xiao-Jia; Bian, Zhao-Xiang; Wang, Yi-Tao; Lu, Jin-Jian

    2016-01-01

    Carthamus tinctorius L. is a multifunctional cash crop. Its flowers and seeds are extensively used in traditional herbal medicine in China, Korea, Japan, and other Asian countries, for treating various ailments such as gynecological, cardiovascular, and cerebrovascular diseases as well as blood stasis and osteoporosis. More than 100 compounds have been isolated and identified from C. tinctorius. Flavonoids and alkaloids, especially the quinochalcone c-glycoside hydroxysafflor yellow A, N-(p-Coumaroyl)serotonin, and N-feruloylserotonin, are responsible for most of the pharmacological activities of C. tinctorius. In this paper, comprehensive and up-to-date information on the phytochemistry and pharmacology of C. tinctorius is presented. This information will be helpful for further explorations of the therapeutic potential of C. tinctorius and may provide future research opportunities.

  1. PTSD: from neurobiology to pharmacological treatments.

    PubMed

    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.

  2. Systems pharmacology augments drug safety surveillance.

    PubMed

    Lorberbaum, T; Nasir, M; Keiser, M J; Vilar, S; Hripcsak, G; Tatonetti, N P

    2015-02-01

    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 postmarketing 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.

  3. Ethnopharmacology, phytochemistry and pharmacology of Tephrosia purpurea.

    PubMed

    Palbag, Satadru; Dey, Bijay Kr; Singh, Narendra Kumar

    2014-01-01

    Tephrosia purpurea (L.) Pers. is popularly known as 'Sarapunkha' in classical Ayurvedic texts. It is a perennial plant belonging to the family Fabaceae, and occurs throughout the Indian subcontinent. T. purpurea is traditionally used to treat splenomegaly, cirrhosis, cough and cold, abdominal swelling and as an antidote in the Ayurvedic system of medicine. Phytochemical investigations indicate the presence of semiglabrin, pongamole, lanceolatins A and B, rutin, lupeol, and β-sitosterol. Flavonoids including (+)-tephrorin A and B, (+)-tephrosone, an isoflavone, 7, 4'-dihydroxy-3', 5'-dimethoxyisoflavone and a chalcone, (+)-tephropurpurin were isolated from the whole plant. Pharmacological activities of different parts of the plant reported include anti-inflammatory, antiulcer, antimicrobial, antioxidant, antiallergic, antidiabetic, hepatoprotective, antitumor and insect repellent activity. In the present review, the literature on the phytochemical and pharmacological investigations of Tephrosia purpurea (L.) Pers. are summarized to August, 2012.

  4. [Contemporary pharmacological methods of treating hirsutism].

    PubMed

    Łabuzek, Krzysztof; Sikorska, Patrycja; Szkudłapski, Dawid; Oleszczyk, Paulina; Juśko, Maciej; Kozłowski, Michał; Madej, Paweł; Okopień, Bogusław

    2013-12-01

    Hirsutism is a symptom of excessive androgen secretion in women, which in recent years is becoming more common. It is a problem of physical, mental and social background and patients always require application of an appropriate therapy Today's medicine offers a wide variety of treatments for the disease, each of which has a different efficiency. This article describes the pharmacological treatment of hirsutism using, among others: antiandrogenic drugs, corticosteroids and oral contraceptives. We performed an extensive literature looking for articles dealing with various forms of hirsutism treatment, most important items were selected and compiled in this work. Modem medicine distinguishes many forms of hirsutism treatment. A very important form of treatment for this condition is the use of pharmacological agents. Their diversity allows optimal adjustment of therapy to the requirements and needs of the patient. Drug therapy is effective, however, in most cases also requires a dermatological treatment.

  5. Clinical pharmacology considerations in biologics development

    PubMed Central

    Zhao, Liang; Ren, Tian-hua; Wang, Diane D

    2012-01-01

    Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram. PMID:23001474

  6. Pharmacological treatment of chronic obstructive pulmonary disease

    PubMed Central

    Montuschi, Paolo

    2006-01-01

    None of the drugs currently available for chronic obstructive pulmonary disease (COPD) are able to reduce the progressive decline in lung function which is the hallmark of this disease. Smoking cessation is the only intervention that has proved effective. The current pharmacological treatment of COPD is symptomatic and is mainly based on bronchodilators, such as selective β2-adrenergic agonists (short- and long-acting), anticholinergics, theophylline, or a combination of these drugs. Glucocorticoids are not generally recommended for patients with stable mild to moderate COPD due to their lack of efficacy, side effects, and high costs. However, glucocorticoids are recommended for severe COPD and frequent exacerbations of COPD. New pharmacological strategies for COPD need to be developed because the current treatment is inadequate. PMID:18044097

  7. 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.

  8. Clinical pharmacology considerations in biologics development.

    PubMed

    Zhao, Liang; Ren, Tian-hua; Wang, Diane D

    2012-11-01

    Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.

  9. Chemical and pharmacological profiles of Echinacea complex.

    PubMed

    Capek, Peter; Šutovská, Martina; Kocmálová, Michaela; Fraňová, Soňa; Pawlaczyk, Izabela; Gancarz, Roman

    2015-08-01

    Echinacea purpurea has a long history in traditional medicine. To verify the pharmacological efficacy of active principles, a polysaccharide-phenolic-protein complex has been isolated from flowering parts of herb by alkaline extraction. It showed on GPC and HPLC one peak of molecular mass around 10 kDa. Chemical and spectroscopic analyses revealed carbohydrate, phenolic and protein contents in Echinacea complex. Pharmacological tests have shown its marked cough suppressing and bronchodilatory effects. The antitussive effect of Echinacea was similar to the narcotic drug codeine and the bronchodilatory effect was more significant than salbutamol, the antiasthmatic drug used in a clinical practice. Pharmacodynamic study shows the beneficial effects of Echinacea complex on the respiratory system and highlights the great potential for development of antitussive and bronchodilatory drugs from natural sources. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Clinical Pharmacology & Therapeutics: the next five years.

    PubMed

    Waldman, S A; Terzic, A

    2015-01-01

    It has been nearly ten years since we joined the editorial organization of Clinical Pharmacology & Therapeutics (CPT), as part of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) family. During that tenure, the primary mandate has been the growth of CPT, recognized as one of the key voices of the discipline and the Society. Set goals were realized in concert with a strong editorial team, a diverse editorial board, a dedicated editorial staff, and outstanding authors, leveraging a leading publishing infrastructure and responding to the needs of a global readership, expanding membership, and the discipline as a whole. The impending decade anniversary, and the transition to a new publisher, offers a natural juncture to reflect on progress, and chart plans for the future of the Journal.

  11. Aripiprazole: from pharmacological profile to clinical use

    PubMed Central

    Di Sciascio, Guido; Riva, Marco Andrea

    2015-01-01

    Clinical experience with aripiprazole has confirmed the effectiveness and the safety of this novel antipsychotic drug in patients with schizophrenia as well as for the treatment of mania in type I bipolar disorder. However the generalization of the results from clinical trials requires further effort in order to address some issues and to overcome incorrect and partial interpretation of the clinical evidence. This article provides some straightforward guidance that may help clinical psychiatrists to translate the mechanism of action of aripiprazole into clinical setting, thus improving the appropriate use of the drug through rational application of its pharmacological profile. Examples of paradigmatic clinical situations are presented and discussed, suggesting possible intervention strategies, which may contribute to achieving the most appropriate use of the pharmacological properties of aripiprazole in real life settings. PMID:26508859

  12. A Review: The Pharmacology of Isoliquiritigenin.

    PubMed

    Peng, Fu; Du, Qiaohui; Peng, Cheng; Wang, Neng; Tang, Hailin; Xie, Xiaoming; Shen, Jiangang; Chen, Jianping

    2015-07-01

    Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its derivative-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacological activities of ISL. The information published between 1972 and 2014 from a number of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacological properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation.

  13. A Philosophical Framework for Integrating Systems Pharmacology Models Into Pharmacometrics

    PubMed Central

    2016-01-01

    The framework for systems pharmacology style models does not naturally sit with the usual scientific dogma of parsimony and falsifiability based on deductive reasoning. This does not invalidate the importance or need for overarching models based on pharmacology to describe and understand complicated biological systems. However, it does require some consideration on how systems pharmacology fits into the overall scientific approach. PMID:27863137

  14. [Clinical report on pharmacological treatment of autism].

    PubMed

    Thivierge, J

    1998-01-01

    This article reviews the pharmacology of autism and briefly overviews its use, history and novelties. "Autism" does not refer to any pathophysiology currently known. And no drug or class of drugs can cure this illness which includes many. Before using drugs, efficient in relieving symptoms, it is important to consider the potential benefit of behavioral approaches. Developments in research give hope that drugs will cure or prevent this brain illness.

  15. Pharmacology of kinin receptors: recent developments.

    PubMed

    Regoli, D; Gobeil, F

    1995-07-01

    Fifteen years after the classification of kinin receptors into B1 and B2, both receptors have been shown to differ between species. New receptor types have been proposed and named B3, B4, and B5. However, it is not established whether different pharmacologic profiles describing B2 receptors in various species are indicative of different receptor types or of different subtypes (species dependent) subserving the same biological functions. To answer these questions, a systematic search of new pharmacologic tools was undertaken to find monoreceptor systems (isolated organs whose responses are contributed by a single receptor) as well as new selective agonists and competitive or noncompetitive antagonists. Classical pharmacologic experiments were performed in isolated organs for quantifying agonist activities in terms of pD2 and antagonist affinities in terms of pA2. Competitivity of antagonists was established from Schild plots. Results obtained in tissues from rabbits or guinea pigs indicate the existence of two different pharmacological entities, well characterized by selective agonists and competitive antagonists. In vivo experiments performed on anesthetized rabbits and guinea pigs have confirmed the B2 receptor heterogeneity between the two species. Correlations have been established between data obtained in rabbit and guinea pig tissues (biological assays) and in human receptors raised by genic transfection in Chinese hamster ovary (CHO) cells. A good correlation has been found between the IC50 values of kinins and derivatives to displace [3H]bradykinin from the membranes of CHO cells containing the human receptor and the pD2 or pA4 values of the same compounds in the rabbit jugular vein.

  16. Pharmacological treatment of generalized anxiety disorder.

    PubMed

    Baldwin, David S; Ajel, Khalil I; Garner, Matthew

    2010-01-01

    Generalized anxiety disorder (GAD) is common in community and clinical settings. The individual and societal burden associated with GAD is substantial, but many of those who could benefit from treatment are not recognized or treated. Recent evidence-based guidelines for the pharmacological management of patients with GAD have recommended initial treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), on the basis of their proven efficacy and reasonable tolerability in randomized placebo-controlled trials. However, there is much room for improvement in both the efficacy and the tolerability of treatment. Response rates to first-line treatment can be disappointing and it is hard to predict reliably which patients will respond well and which will have only a limited treatment response. Many patients worry about becoming dependent on medication, a substantial proportion experience troublesome adverse effects, and these problems limit the effectiveness of pharmacological treatments in clinical practice. The relative lack of longitudinal studies of clinical outcomes in GAD, and the small number of placebo-controlled relapse prevention studies lead to uncertainty about the optimal duration of treatment after a satisfactory initial response. There have been few investigations of the further management of patients who have not responded to first-line treatment and there is a pressing need for further augmentation studies in patients who have not responded to an SSRI or SNRI, or to other initial pharmacological approaches. Future treatment guidelines for GAD will be influenced by emerging data for established and novel pharmacological approaches, and possibly through the more accurate identification of certain patient subgroups who are likely to respond preferentially to particular interventions.

  17. 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

  18. Pharmacological correction of misfolding of ABC proteins☆

    PubMed Central

    Rudashevskaya, Elena L.; Stockner, Thomas; Trauner, Michael; Freissmuth, Michael; Chiba, Peter

    2014-01-01

    The endoplasmic reticulum (ER) quality control system distinguishes between correctly and incorrectly folded proteins to prevent processing of aberrantly folded conformations along the secretory pathway. Non-synonymous mutations can lead to misfolding of ABC proteins and associated disease phenotypes. Specific phenotypes may at least partially be corrected by small molecules, so-called pharmacological chaperones. Screening for folding correctors is expected to open an avenue for treatment of diseases such as cystic fibrosis and intrahepatic cholestasis. PMID:25027379

  19. Pharmacological management of hypertension in pregnancy.

    PubMed

    Easterling, Thomas R

    2014-12-01

    Hypertension in pregnancy remains a significant public health problem. Pharmacological management of blood pressure in pregnancy is impacted by changes in maternal drug disposition and by the pharmacodynamic effects of specific agents. This article will review the impact of pregnancy on pathways of drug elimination and the associated clinical implications, the pharmacodynamic effects of specific drugs and classes of drugs in pregnancy, and the data to date on the impact of antihypertensive therapy on mothers and their fetuses.

  20. Opiate Pharmacology and Relief of Pain

    PubMed Central

    Pasternak, Gavril W.

    2014-01-01

    Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned. PMID:24799496

  1. Biochemical and pharmacologic comparison of thrombolytic agents.

    PubMed

    Stringer, K A

    1996-01-01

    The number of thrombolytic drugs for the management of acute myocardial infarction is rapidly expanding. New agents, some of which are biochemically modified versions of currently available thrombolytics, will soon arrive in the marketplace. The pharmacologic differences of the new drugs are the basis for clinical differences such as enhanced clot lysis and prolonged elimination half-life. Ultimately, these features may result in improved infarct artery patency and patient survival.

  2. Pharmacological activities on Ephedra nebrodensis Tineo.

    PubMed

    Ballero, Mauro; Foddis, Caterina; Sanna, Cinzia; Scartezzini, Paolo; Poli, Ferruccio; Petitto, Valentina; Serafini, Mauro; Stanzione, Alessandra; Bianco, Armandodoriano; Serilli, Anna Maria; Spina, Liliana; Longoni, Rosanna; Kasture, Sanjay

    2010-07-01

    As a part of our endeavour to screen Mediterranean medicinal plants for various pharmacological activities, we evaluated antihistaminic, adaptogenic, anti-inflammatory, antinociceptive, hypotensive and locomotor properties, and antioxidant potential of Ephedra nebrodensis. (1)H-NMR spectroscopy was carried out to identify the plant metabolites, which confirmed the presence of ephedrinic skeleton alkaloids. The ethanol : acetone (1 : 1) extract exhibited dose-related antihistaminic, anti-inflammatory, antinociceptive, hypotensive, antioxidant and locomotor stimulant activity. The plant bears potential for further studies.

  3. Local Anesthetics: Review of Pharmacological Considerations

    PubMed Central

    Becker, Daniel E; Reed, Kenneth L

    2012-01-01

    Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article. PMID:22822998

  4. 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.

  5. Triethylenetetramine pharmacology and its clinical applications.

    PubMed

    Lu, Jun

    2010-09-01

    Triethylenetetramine (TETA), a Cu(II)-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.

  6. Pharmacological treatment of fibromyalgia syndrome: new developments.

    PubMed

    Staud, Roland

    2010-01-01

    Fibromyalgia is a chronic pain disorder characterized by widespread pain, stiffness, insomnia, fatigue and distress. Several randomized controlled trials (RCTs) have shown moderate effectiveness of pharmacological therapies for fibromyalgia pain. Evidence from these trials suggests that pharmacological therapy can not only improve pain but also fatigue, function and well-being in patients with fibromyalgia. Duloxetine and milnacipran, two highly selective serotonin-norepinephrine (noradrenaline) reuptake inhibitors, and the alpha(2)delta agonist pregabalin have been approved by the US FDA for the treatment of fibromyalgia symptoms. In general, about half of all treated patients seem to experience a 30% reduction of symptoms, suggesting that many patients with fibromyalgia will require additional therapies. Thus, other forms of treatment, including exercise, cognitive behavioural therapies and self-management strategies, may be necessary to achieve satisfactory treatment outcomes. Despite promising results of pilot trials, RCTs with dopamine receptor agonists and sodium channel antagonists have so far been disappointing for patients with fibromyalgia. However, new pharmacological approaches for the treatment of fibromyalgia pain and insomnia using sodium oxybate appear to be promising.

  7. Pharmacologic treatment of spasticity in children.

    PubMed

    Tilton, Ann; Vargus-Adams, Jilda; Delgado, Mauricio R

    2010-12-01

    Many clinicians frequently face the dilemma of whether and how to medically treat spasticity. When pharmacologic intervention is deemed appropriate, treatment decisions must first be based on accurate assessment using valid and reliable clinical instruments, and, importantly, specific, measurable, achievable, and realistic treatment goals should be delineated. For the treatment of localized or segmental spasticity, botulinum toxin (BoNT-A) is recommended as an effective and generally safe treatment. For more generalized spasticity, a number of useful oral agents and intrathecal baclofen are available, each with their positive and negative attributes. Fundamental knowledge of pharmacologic properties and toxicities of these medications is required for safe and appropriate use. To achieve optimum results, spasticity treatment should be part of an integrated therapeutic approach in which patients, caregivers, therapists, physicians, and surgeons have an open and clear communication about the overall rehabilitation process of the patient. This review summarizes the current pharmacologic approaches to spasticity treatment in children, critically evaluating published studies in the context of established evidence-based criteria. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. 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

  9. Teaching the Pharmacology of Antiarrhythmic Drugs

    PubMed Central

    Lynch, Launa M. J.

    2011-01-01

    Objective. To provide doctor of pharmacy (PharmD) students with highly integrated, comprehensive and up-to-date instruction related to the pharmacology of antiarrhythmic drugs. Design. 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. Assessment. 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. Conclusion. 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. PMID:21969725

  10. 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.

  11. 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

  12. Inflammation and pharmacological treatment in diabetic retinopathy.

    PubMed

    Kaštelan, Snježana; Tomić, Martina; Gverović Antunica, Antonela; Salopek Rabatić, Jasminka; Ljubić, Spomenka

    2013-01-01

    Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus, is estimated to be the leading cause of new blindness in the working population of developed countries. Primary interventions such as intensive glycemic control, strict blood pressure regulation, and lipid-modifying therapy as well as local ocular treatment (laser photocoagulation and pars plana vitrectomy) can significantly reduce the risk of retinopathy occurrence and progression. Considering the limitations of current DR treatments development of new therapeutic strategies, it becomes necessary to focus on pharmacological treatment. Currently, there is increasing evidence that inflammatory processes have a considerable role in the pathogenesis of DR with multiple studies showing an association of various systemic as well as local (vitreous and aqueous fluid) inflammatory factors and the progression of DR. Since inflammation is identified as a relevant mechanism, significant effort has been directed to the development of new concepts for the prevention and treatment of DR acting on the inflammatory processes and the use of pharmacological agents with anti-inflammatory effect. Inhibiting the inflammatory pathway could be an appealing treatment option for DR in future practices, and as further prospective randomized clinical trials accumulate data, the role and guidelines of anti-inflammatory pharmacologic treatments will become clearer.

  13. Phenylalanine hydroxylase misfolding and pharmacological chaperones.

    PubMed

    Underhaug, Jarl; Aubi, Oscar; Martinez, Aurora

    2012-01-01

    Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH(4)) cofactor as query structure for shape-focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH(4). Furthermore, PAH shares a number of ligands, such as BH(4), amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH-chaperoning compounds represent novel possibilities in the treatment of PKU.

  14. 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.

  15. Improving pharmacological targeting of AKT in melanoma.

    PubMed

    Kuzu, Omer F; Gowda, Raghavendra; Sharma, Arati; Noory, Mohammad A; Dinavahi, Saketh S; Kardos, Gregory; Drabick, Joseph J; Robertson, Gavin P

    2017-09-28

    Targeting AKT with pharmacological agents inhibiting this protein in the melanoma clinic is ineffective. This is a major contradiction considering the substantial preclinical data suggesting AKT as an effective target. Various approaches have been undertaken to unravel this contradiction and drug combinations sought that could resolve this concern. We have shown that genetic targeting AKT3 or WEE1 can be effective for inhibiting tumor growth in preclinical animal models. However, no one has examined whether combining pharmacological agents targeting each of these enzymes could be more effective than inhibiting each alone and enhance the efficacy of targeting AKT in melanoma. This report shows that combining the AKT inhibitors (AZD5363 or MK1775) with the WEE1 inhibitor, AZD5363, can synergistically kill cultured melanoma cells and decrease melanoma tumor growth by greater than 90%. Co-targeting AKT and WEE1 led to enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating the transcription factors p53 and FOXM1, as well as the proteins whose expression is regulated by these two proteins. Thus, this study identifies a unique combination of pharmacological agents and the ratio needed for efficacy that could be used to potentially improve the therapeutic effectiveness of targeting AKT in the clinic. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Selecting Potential Pharmacological Interventions in Sarcopenia.

    PubMed

    Kilsby, Amanda J; Sayer, Avan A; Witham, Miles D

    2017-04-01

    Sarcopenia of age is prevalent and costly and proven pharmacological interventions are currently lacking. The pathophysiology of sarcopenia is incompletely understood but appears to involve multiple pathways, including inflammation, hormonal dysregulation, impaired regeneration, mitochondrial dysfunction and denervation. There are several ways in which we might select potential pharmacological interventions for testing in clinical trials. These include a 'bottom-up' approach using basic science to elucidate the molecular processes involved and identify potential targets from this knowledge-a strategy that has led to the development of myostatin inhibitors. A 'top-down' approach might use observational data to examine the association between physical function and use of certain medications, such as the association between angiotensin-converting enzyme inhibitors with slower decline in physical function. Once a pharmacological intervention has been proposed, efficacy must be demonstrated in this complex multi-morbid population. Both muscle mass and muscle function need to be measured as outcomes, but these outcomes require large sample sizes and sufficient follow-up to detect change. Biomarkers that can predict the response of sarcopenia to intervention after a short time would greatly assist our ability to select candidate interventions in short proof-of-concept trials. Further development of trial methods is required to accelerate progress in this important area of medicine for older people.

  17. Pharmacological enhancement of fear reduction: preclinical models

    PubMed Central

    Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

    2011-01-01

    Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

  18. Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues

    PubMed Central

    Ravenscroft, Stephanie M.; Pointon, Amy; Williams, Awel W.; Cross, Michael J.; Sidaway, James E.

    2016-01-01

    The immature phenotype of stem cell derived cardiomyocytes is a significant barrier to their use in translational medicine and pre-clinical in vitro drug toxicity and pharmacological analysis. Here we have assessed the contribution of non-myocyte cells on the contractile function of co-cultured human embryonic stem cell derived cardiomyocytes (hESC-CMs) in spheroid microtissue format. Microtissues were formed using a scaffold free 96-well cell suspension method from hESC-CM cultured alone (CM microtissues) or in combination with human primary cardiac microvascular endothelial cells and cardiac fibroblasts (CMEF microtissues). Contractility was characterized with fluorescence and video-based edge detection. CMEF microtissues displayed greater Ca2+ transient amplitudes, enhanced spontaneous contraction rate and remarkably enhanced contractile function in response to both positive and negative inotropic drugs, suggesting a more mature contractile phenotype than CM microtissues. In addition, for several drugs the enhanced contractile response was not apparent when endothelial cell or fibroblasts from a non-cardiac tissue were used as the ancillary cells. Further evidence of maturity for CMEF microtissues was shown with increased expression of genes that encode proteins critical in cardiac Ca2+ handling (S100A1), sarcomere assembly (telethonin/TCAP) and β-adrenergic receptor signalling. Our data shows that compared with single cell-type cardiomyocyte in vitro models, CMEF microtissues are superior at predicting the inotropic effects of drugs, demonstrating the critical contribution of cardiac non-myocyte cells in mediating functional cardiotoxicity. PMID:27125969

  19. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs.

    PubMed

    Pleticha, Josef; Heilmann, Lukas F; Evans, Christopher H; Asokan, Aravind; Samulski, Richard Jude; Beutler, Andreas S

    2014-09-02

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.

  20. Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs

    PubMed Central

    2014-01-01

    Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting. PMID:25183392