David, D J; Tritschler, L; Guilloux, J-P; Gardier, A M; Sanchez, C; Gaillard, R
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
Buur, Jennifer L
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.
Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J.; Granero, Luis; Polache, Ana; Zornoza, Teodoro
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
González, José; Orero, Ana; Olmo, Vicente; Martínez, David; Prieto, José; Bahlsen, Jose Antonio; Zaragozá, Francisco; Honorato, Jesús
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.
Dobrovolskaia, Marina A
Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany pre-clinical development of nanotechnology-formulated drugs. Some of these challenges are not unique to nanotechnology and are common in the development of other pharmaceutical products. However, nanoparticle-formulated drugs are biochemically sophisticated, which causes their translation into the clinic to be particularly complex. An understanding of both the immune compatibility of nanoformulations and their effects on hematological parameters is now recognized as an important step in the (pre)clinical development of nanomedicines. An evaluation of nanoparticle immunotoxicity is usually performed as a part of a traditional toxicological assessment; however, it often requires additional in vitro and in vivo specialized immuno- and hematotoxicity tests. Herein, I review literature examples and share the experience with the NCI Nanotechnology Characterization Laboratory assay cascade used in the early (discovery-level) phase of pre-clinical development to summarize common challenges in the immunotoxicological assessment of nanomaterials, highlight considerations and discuss solutions to overcome problems that commonly slow or halt the translation of nanoparticle-formulated drugs toward clinical trials. Special attention will be paid to the grand-challenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge.
Simeon-Dubach, Daniel; Zeisberger, Steffen M.; Hoerstrup, Simon P.
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
Basner-Tschakarjan, Etiena; Bijjiga, Enoch; Martino, Ashley T
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
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
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.
Feig, Jonathan E.; Hewing, Bernd; Smith, Jonathan D.; Hazen, Stanley L.; Fisher, Edward A.
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
Fernandes, Ashley K; Borges, Nicole; Rodabaugh, Heather
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.
04-1-0594 TITLE: Pre-clinical and Clinical Evaluation of High Resolution, Mobile Gamma Camera and Positron Imaging Devices PRINCIPAL...2004 - 20 SEP 2010 4. TITLE AND SUBTITLE Pre-clinical and clinical evaluation of high resolution, mobile gamma camera and positron imaging devices...a compact and mobile gamma and positron imaging camera . This imaging device has several advantages over conventional systems: (1) greater
Khor, K H; Campbell, F E; Owen, H; Shiels, I A; Mills, P C
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.
Fuentealba, Carmen; Hecker, Kent G; Nelson, Phil D; Tegzes, John H; Waldhalm, Stephen J
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.
Lukman, H; Beevi, Z; Mohamadou, G; Yeap, R
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.
...: Pre- clinical Evaluation of Human Therapeutics Utilizing Ubiquitin Based Fusion Proteins With Apoptosis Modifying Proteins Such as BCL-XL AGENCY: National Institutes of Health, Public Health Service... an Extracellular BCL- x L Fusion Protein Inhibits Apoptosis'' (HHS Ref. No. E-073-...
Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.
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…
Michael, Joel A.; Rovick, Allen A.
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)
Park, S.-J.; Yu, A. R.; Kim, Y.-s.; Kang, W.-S.; Jin, S. S.; Kim, J.-S.; Son, T. J.; Kim, H.-J.
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
Trachtenberg, Jordan E.; Vo, Tiffany N.; Mikos, Antonios G.
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
Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.
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
Tillner, Falk; Thute, Prasad; Bütof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang
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.
Kaux, Jean-François; Drion, Pierre; Croisier, Jean-Louis; Crielaard, Jean-Michel
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
Lobo, D S S; Aleksandrova, L; Knight, J; Casey, D M; el-Guebaly, N; Nobrega, J N; Kennedy, J L
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.
Hayden, Kathleen M.; Kuchibhatla, Maragatha; Romero, Heather R.; Plassman, Brenda L.; Burke, James R.; Browndyke, Jeffrey N.; Welsh-Bohmer, Kathleen A.
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
Deane, Kevin D.; Norris, Jill M.; Holers, V. Michael
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
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
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
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.
Iglesias, Ainhoa; García-Nimo, Laura; Cocho de Juan, José A; Moreno, José C
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.
Flint, Katelyn M.; Weis, Jared A.; Yankeelov, Thomas E.; Miga, Michael I.
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.
Chawla, Surendra K; Shi, Weiwei; McIver, Bryant V; Vinten-Johansen, Jakob; Frater, Robert W M; Padala, Muralidhar
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.
Faggion, Clovis Mariano
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.
De Luca, Annamaria
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.
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
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
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.
Lagarce, L; Zenut, M; Lainé-Cessac, P
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.
Harris, Gerald R.
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.
Baker, Matthew P; Carr, Francis J
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.
Lee, Yueh Z.; Burk, Laurel; Wang, Ko-Han; Cao, Guohua; Lu, Jianping; Zhou, Otto
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.
O'Brien, Emma R.; Howarth, Clare; Sibson, Nicola R.
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
Rhéaume, Marc-André; Vavvas, Demetrios
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.
Foerster, M; Burdin, F; Seignon, F; Lambert, A; Vasquez, C; Charvet, G
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.
Zegarra-Moran, Olga; Galietta, Luis J V
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.
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.
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.
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…
Hutchinson, G; Neehall, J E; Simeon, D T; Littlewood, R
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.
Chiang, Po-Chang; Alsup, Jason W.; Lai, Yurong; Hu, Yiding; Heyde, Bruce R.; Tung, David
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.
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
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.
Tse, Gary; Liu, Tong; Li, Ka H. C.; Laxton, Victoria; Chan, Yin W. F.; Keung, Wendy; Li, Ronald A.; Yan, Bryan P.
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
Aron Badin, Romina; Vadori, Marta; Cozzi, Emanuele; Hantraye, Philippe
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.
Eslami, S.; Yang, Y.; Wong, J.; Patterson, M. S.; Iordachita, I.
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
Hothorn, Ludwig A; Sill, Martin; Schaarschmidt, Frank
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.
Meng Li; Xingchi He; Eslami, Sohrab; Ken Kang-Hsin Wang; Bin Zhang; Wong, John; Iordachita, Iulian
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%).
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.
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
Neuberger, Timothy; Burton, Bill; Clark, Heather; Van Goor, Fredrick
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.
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
Meyer, Amanda J; Stomski, Norman J; Innes, Stanley I; Armson, Anthony J
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.
Du, Louise Y.; Lee, Ting-Yim; Holdsworth, David W.
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.
Forte, Amalia; Rinaldi, Barbara; Berrino, Liberato; Rossi, Francesco; Galderisi, Umberto; Cipollaro, Marilena
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.
Brown, Kai M.; Xue, Aiqun; Mittal, Anubhav; Samra, Jaswinder S.; Smith, Ross; Hugh, Thomas J.
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
Botta, Cirino; Gullà, Annamaria; Correale, Pierpaolo; Tagliaferri, Pierosandro; Tassone, Pierfrancesco
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
Stegers-Jager, K M; Brommet, F N; Themmen, A P N
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.
Malloy, T R; Malkowicz, B
A discussion of the anatomy, neurophysiology, endocrinology, and organ pharmacology pertinent to erectile function is presented, highlighting recent innovations in the pharmacologic treatment of impotence. Both oral and intracorporal pharmacologic agents that affect erectile dysfunction are discussed.
Boran, Aislyn D. W.; Iyengar, Ravi
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
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.
Yost, Shawn E.; Pastorino, Sandra; Rozenzhak, Sophie; Smith, Erin N.; Chao, Ying S.; Jiang, Pengfei; Kesari, Santosh; Frazer, Kelly A.; Harismendy, Olivier
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
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.
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
Vazquez-Cintron, Edwin; Tenezaca, Luis; Angeles, Christopher; Syngkon, Aurelia; Liublinska, Victoria; Ichtchenko, Konstantin; Band, Philip
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.
Vazquez-Cintron, Edwin; Tenezaca, Luis; Angeles, Christopher; Syngkon, Aurelia; Liublinska, Victoria; Ichtchenko, Konstantin; Band, Philip
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
Toth, Linda A
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.
Waggoner, Darrel J; Martin, Christa Lese
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.
Background Convection-enhanced delivery (CED), a direct method for drug delivery to the brain through intraparenchymal microcatheters, is a promising strategy for intracerebral pharmacological therapy. By establishing a pressure gradient at the tip of the catheter, drugs can be delivered in uniform concentration throughout a large volume of interstitial fluid. However, the variables affecting perivascular distribution of drugs delivered by CED are not fully understood. The aim of this study was to determine whether the perivascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, by co-infusion of vasodilator, alteration of infusion rates or use of a ramping regime. We also wanted to make a preliminary comparison of the distribution of solutes with that of nanoparticles. Methods We analysed the perivascular distribution of 4, 10, 20, 70, 150 kDa fluorescein-labelled dextran and fluorescent nanoparticles at 10 min and 3 h following CED into rat striatum. We investigated the effect of local vasodilatation, slow infusion rates and ramping on the perivascular distribution of solutes. Co-localisation with perivascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by perivascular macrophages was quantified using stereological methods. Results Widespread perivascular distribution and macrophage uptake of fluorescein-labelled dextran was visible 10 min after cessation of CED irrespective of molecular weight. However, a significantly higher proportion of perivascular macrophages had taken up 4, 10 and 20 kDa fluorescein-labelled dextran than 150 kDa dextran (p < 0.05, ANOVA). Co-infusion with vasodilator, slow infusion rates and use of a ramping regime did not alter the perivascular distribution. CED of fluorescent nanoparticles indicated that particles co-localise with perivascular basement membranes throughout the striatum but
Yokozawa, Takako; Park, Chan Hum; Matsumoto, Kinzo
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.
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
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
Baker, David; Lidster, Katie; Sottomayor, Ana; Amor, Sandra
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.
Ruggeri, Bruce A; Camp, Faye; Miknyoczki, Sheila
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.
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...University of Health Sciences/The Chicago Medical School Department of 3333 Green Bay Road Telephone Pharmacology North Chicago, Illinois 60064...Region Bethesda, MD 20814-5044 • .RE: Annual Letter Report , ONR Contract #N00014-84-K-0562 " Pharmacology of Periodontal Disease" Dear Capt. Hancock
Maickel, R. P.
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.
Pugsley, M K; Authier, S; Curtis, M J
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.).
McNamara, B P; Cristofolini, L; Toni, A; Taylor, D
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
Pelayo, Rafael; Yuen, Kin
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.
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.…
Chemical and Engineering News, 1973
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)
Shaw, David H.; And Others
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)
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…
Buckingham, Julia C
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.
Commendador, Kathleen; Chi, Robert
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…
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...
Tosoni, Daniela; Pambianco, Sarah; Ekalle Soppo, Blanche; Zecchini, Silvia; Bertalot, Giovanni; Pruneri, Giancarlo; Viale, Giuseppe; Di Fiore, Pier Paolo; Pece, Salvatore
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.
de Laat, Melody A; Patterson-Kane, Janet C; Pollitt, Christopher C; Sillence, Martin N; McGowan, Catherine M
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.
Greene, LM; Butini, S; Campiani, G; Williams, DC; Zisterer, DM
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
Kennelly, Helen; Mahon, Bernard P.; English, Karen
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
Bourn, Rebecka; James, Judith A.
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
Narayan, Pritika; Dragunow, Mike
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
Waldman, S A; Terzic, A
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.
Byrne, Shaina L; Krishnamurthy, Divya; Wessling-Resnick, Marianne
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.
Byrne, Shaina L.; Krishnamurthy, Divya; Wessling-Resnick, Marianne
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
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.
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.
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
Chow, James C. L.
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.
Lofaso, Daryl P.; DeBlieux, Peter M.; DiCarlo, Richard P.; Hilton, Charles; Yang, Tong; Chauvin, Sheila W.
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
Madhavanprabhakaran, Girija; Al-Khasawneh, Esra; Wittmann, Lani
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
Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar
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
Hill, Melissa L.; Gorelikov, Ivan; Niroui, Farnaz; Levitin, Ronald B.; Mainprize, James G.; Yaffe, Martin J.; Rowlands, J. A.; Matsuura, Naomi
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.
Toren, Paul; Kim, Soojin; Johnson, Fraser; Zoubeidi, Amina
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
Passie, Torsten; Seifert, Juergen; Schneider, Udo; Emrich, Hinderk M
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.
Kouskoura, Thaleia; Katsaros, Christos; von Gunten, Stephan
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
Grant, Claire; Ewart, Lorna; Muthas, Daniel; Deavall, Damian; Smith, Simon A; Clack, Glen; Newham, Pete
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.
Yee, S; Wilson, G; Chavez, F
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.
Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L
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.
Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L
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
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…
Maiti, Rituparna; Alloza, José Luis
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.
Dajani, E Z; Shahwan, T G; Dajani, N E
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
Diaper, Alison M; Law, Fergus D; Melichar, Jan K
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
Diaper, Alison M; Law, Fergus D; Melichar, Jan K
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.
Vincent, John B
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.
Das, Tapas; Shinto, Ajit; Kamaleshwaran, Koramadai K; Sarma, Haladhar D; Mohammed, Sahiralam Khan; Mitra, Arpit; Lad, Sangita; Rajan, M G R; Banerjee, Sharmila
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.
Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis
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.
Maiti, Rituparna; Alloza, José Luis
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
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
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.
Kenakin, Terry; Christopoulos, Arthur
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.
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.
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.
Vakifahmetoglu-Norberg, Helin; Xia, Hong-guang; Yuan, Junying
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
Stefanska, Barbara; MacEwan, David J
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.
Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.
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
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
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
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
Even, Patrick C.; Blais, Anne
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
Kalra, Kiran; Franzese, Christopher J; Gesheff, Martin G; Lev, Eli I; Pandya, Shachi; Bliden, Kevin P; Tantry, Udaya S; Gurbel, Paul A
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.
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
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.
Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore
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.
Leoutsakos, Jeannie-Marie S.; Muthen, Bengt O.; Breitner, John C.S.; Lyketsos, Constantine G.
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
Mahmoudi, N; Eslahi, N; Mehdipour, A; Mohammadi, M; Akbari, M; Samadikuchaksaraei, A; Simchi, A
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.
Vlaar, A P; Straat, M; Juffermans, N P
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.
Jensen, Mette Munk; Kjaer, Andreas
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.
Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L
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.
Janda, Sue M; Fagan, Nancy L
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.
Ge, Jinwen; Wang, Dongsheng; He, Rong; Zhu, Huibin; Wang, Yuhong; He, Shilin
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.
Halford, J C; Blundell, J E
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
Hain, Timothy C; Uddin, Mohammed
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
Hapke, H J; Strathmann, W
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.
Oja, Simo S; Saransaari, Pirjo
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.
Dotta, Andrea; Braguglia, Annabella; Salvatori, Guglielmo
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.
Gomis Barbará, R
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.
Bolser, Donald C.
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
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.
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
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.
Hoppensteadt, D A; Fareed, J
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.
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.
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
Christ, George J; Saul, Justin M; Furth, Mark E; Andersson, Karl-Erik
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.
Hersh, Elliot V; Balasubramaniam, Ramesh; Pinto, Andres
Although there are theoretically numerous pharmacologic targets for relieving temporomandibular disorder (TMD)-associated pains, evidence-based literature clearly establishing the efficacy and safety of drugs in the TMD population is limited at best. This article reviews the pharmacology, toxicology, and research supporting the use of a host of pharmacologic agents that have been used in patients who have TMD, including nonsteroidal anti-inflammatory drugs, corticosteroids, benzodiazepines, nonbenzodiazepine sedative hypnotics, opioids, skeletal muscle relaxants, capsaicin, transdermal lidocaine, antidepressants, and anticonvulsants. Recommendations regarding the proper use of each drug class are also made.
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 . 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. . Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass . 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
Fajt, Virginia R; Brown, Dimitri; Scott, Maya M
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.
Siewerdsen, J H; Moseley, D J; Burch, S; Bisland, S K; Bogaards, A; Wilson, B C; Jaffray, D A
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
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)
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.
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.
Radu, A; Grosjean, P; Jaquet, Y; Pilloud, R; Wagnieres, G; van den Bergh, H; Monnier, Ph
Esophageal cancer, when detected at an early stage, has a very good probability of being eradicated by surgery or radiotherapy. However, less aggressive treatments also tend to provide high rates of cure without the side effects of radical surgery or radiotherapy. Among them, photodynamic therapy and endoscopic mucosal resection have been experienced as alternative techniques for mucosal ablation in patients with superficial squamous-cell carcinoma (SCC) of the esophagus, or high-grade dysplasia and early stage adenocarcinoma arising in Barrett's esophagus. We report on the results of our clinical experience with photodynamic therapy and discuss about its advantages and limitations. We also present a pre-clinical study, which had evaluated the feasibility, efficacy, and safety of a promising new method of endoscopic mucosal resection (EMR) based on the use of a modified rigid esophagoscope. The animal model chosen was the sheep because of its similarities with humans regarding the thickness and histologic structure of the esophagus. This new resection modality offers a promising approach in comparison with other options currently available, namely EMRs performed with flexible gastroscopes. It appears to be superior in terms of the size of the resected specimen, the precision and regularity of the resection depth, and the accuracy of histological diagnosis with safety margins.
Soto-Cerrato, Vanessa; Vitorino, Rui; Fardilha, Margarida; Pérez-Tomás, Ricardo
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
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. 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
Ashok, B T; Tadi, K; Banerjee, D; Konopa, J; Iatropoulos, M; Tiwari, R K
We have developed a group of 4-substituted-1-nitroacridines with potent anti-tumor activity against prostate cancer and less toxic than parent 1-nitroacridines. The most active 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748) was selected for pre-clinical studies. The current study was undertaken to evaluate clinical and/or morphological adverse effects of C-1748 as a single intravenous dose at concentrations ranging from 0.16 to 4.6 mg/kg administered to male Beagle dogs. The maximum tolerated dose was 1.5 mg/kg. Emesis was observed in all groups lasting an average of 30 min to 12 h post-dosing. At high dose, extreme aggression was observed in one dog followed by disorientation and depression lasting for 48 h a frequent observation with chemotherapy. Reductions in platelets and white blood cells were observed which was similar to that seen with other chemotherapeutic agents. A compensatory hyperplasia of lymph nodes and a transient and limited extravasation in the intestinal mucosa were also observed. Increases in aspartate aminotransferase, alkaline phosphatase and creatine phosphokinase were transient with normal levels restored by day 9. These enzyme increases were accompanied by epithelial hypertrophy of larger bile ductules in the periportal triads of the liver. The low toxicity profile and high tumor target activity make this novel class of drug a promising chemotherapeutic agent.
Solis-Najera, S.; Vazquez, F.; Hernandez, R.; Marrufo, O.; Rodriguez, A. O.
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.
Pagotto, Uberto; Vanuzzo, Diego; Vicennati, Valentina; Pasquali, Renato
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
Berger, Seth I.; Iyengar, Ravi
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: email@example.com PMID:19648136
Lowes, Lori E.; Goodale, David; Xia, Ying; Postenka, Carl; Piaseczny, Matthew M.; Paczkowski, Freeman; Allan, Alison L.
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
Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J
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.
Verheul, Ruurd C.; van Deutekom, Judith C. T.; Datson, Nicole A.
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
Martin, Pauline L
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.
Saul, Justin M.; Furth, Mark E.; Andersson, Karl-Erik
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
Rinchuse, D J; Rinchuse, D J; Sprecher, R
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.
Nahorski, Stefan R
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
Holzer, Peter; Izzo, Angelo A
This themed issue of the British Journal of Pharmacology contains review and research articles on recent advances in transient receptor potential (TRP) channel pharmacology. The review articles, written by a panel of distinguished experts, address the rapid progress in TRP channel research in fields as diverse as oncology, urology, dermatology, migraine, inflammation and pain. These reviews are complemented by original research reports focusing, among others, on the emerging roles of TRPV1 in osteoporosis and cystitis and on evodiamine as a lead structure for the development of potent TRPV1 agonists/desensitizers. Other papers highlight the differences in TRPV3 pharmacology between recombinant and native systems, the mechanisms of TRPM3 activation/inhibition and TRPP2 as a target of naringenin, a dietary flavonoid with anticancer actions. New therapeutic opportunities in pain may arise from the strategy to combine TRP channel and cell membrane impermeant sodium channel blockers to inhibit sensory nerve activity. LINKED ARTICLES This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:24773265
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
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.
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…
Maickel, Roger P.
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,…
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
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.
Cooper, David K C; Bottino, Rita; Gianello, Pierre; Graham, Melanie; Hawthorne, Wayne J; Kirk, Allan D; Korsgren, Olle; Park, Chung-Gyu; Weber, Collin
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.
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.
Kaddurah-Daouk, R; Weinshilboum, R M
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.
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.
Celardo, Ivana; Pedersen, Jens Z.; Traversa, Enrico; Ghibelli, Lina
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.
Upadhyay, Aparna; Singh, D K
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.
Gidday, Jeffrey M.
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
Medina, C; Santos-Martinez, M J; Radomski, A; Corrigan, O I; Radomski, M W
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
Groll, Andreas H; Gea-Banacloche, Juan C; Glasmacher, Axel; Just-Nuebling, Gudrun; Maschmeyer, Georg; Walsh, Thomas J
Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.
Mongardon, N.; Dyson, A.; Singer, M.
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
Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M
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
Goldenberg, David T; Trese, Michael T
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.
Shah, Ankoor R; Trese, Michael T
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.
Pasternak, Gavril W
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.
Kochevar, Deborah T
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.
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
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
Santy, Patricia A.; Bungo, Michael W.
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.
Halstead, Mark E.
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
Trüeb, Ralph M
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
Fantegrossi, William E.; Murnane, Aeneas C.; Reissig, Chad J.
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
Ferner, R E
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
Fantegrossi, William E; Murnane, Kevin S; Reissig, Chad J
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.
Li, Gui-Rong; Dong, Ming-Qing
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.
Deinum, Jaap; Riksen, Niels P; Lenders, Jacques W M
Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.
Pugsley, Michael K; Curtis, Michael J
'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
Ramos Cordero, Primitivo; Yubero, Raquel
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.
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
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.
Camerino, Giulia Maria; Cannone, Maria; Giustino, Arcangela; Massari, Ada Maria; Capogrosso, Roberta Francesca; Cozzoli, Anna; De Luca, Annamaria
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.
El-Asrar, Ahmed M Abu; Al-Mezain, Hani S
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.
Racagni, Giorgio; Popoli, Maurizio
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.
Becker, Werner J
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.
Moroni, Rm; Vieira, Cs; Ferriani, Ra; Candido-Dos-Reis, Fj; Brito, Lgo
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.
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
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.
Graeff, F G; Parente, A; Del-Ben, C M; Guimarães, F S
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.
Hollingsworth, Michael; Markham, Anthony
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…
Brzeziński, M.; Bury, K.; Dąbrowski, L.; Holak, P.; Sejda, A.; Pawlak, M.; Jagielak, D.; Adamiak, Z.; Rogowski, J.
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
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
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
Ruge, Diane; Stephan, Klaas E.
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
Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo
Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation. PMID:26157557
Chan, Benjamin K; Abedon, Stephen T
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.
Clement, Pierre; Giuliano, François
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.
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.
Rolland, Yves; Onder, Graziano; Morley, John E; Gillette-Guyonet, Sophie; Abellan van Kan, Gabor; Vellas, Bruno
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.
Sassard, Jean; Hamon, Michel; Galibert, Francis
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.
Abubakar, S B; Abubakar, I S; Habib, A G; Nasidi, A; Durfa, N; Yusuf, P O; Larnyang, S; Garnvwa, J; Sokomba, E; Salako, L; Laing, G D; Theakston, R D G; Juszczak, E; Alder, N; Warrell, D A
The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED(50)) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8 mg (dry weight) of venom milked from captive E. ocellatus: 10 ml of MicroPharm "EchiTAb G" (ET-G) antivenom; 30 ml of Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50 ml of VacSera, Cairo "EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10 ml ET-G and 30 ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT.
Cazzola, Mario; Page, Clive P; Calzetta, Luigino; Matera, M Gabriella
regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.
Nixon, Gemma L; Moss, Darren M; Shone, Alison E; Lalloo, David G; Fisher, Nicholas; O'Neill, Paul M; Ward, Stephen A; Biagini, Giancarlo A
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.
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...
Vaiserman, Alexander M; Lushchak, Oleh V; Koliada, Alexander K
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.
Flute, P T
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.
Chen, Yuh F
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.
Waldman, S A; Terzic, A
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.
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
Cieslak, John A; Cullen, Joseph J
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.
Pugsley, M K; Curtis, M J
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.
Barkin, Robert L
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
Aronson, Jeffrey K
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
Aronson, Jeffrey K
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.
Kumar, Kuldip; Anand, Kuljeet Singh
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
Console-Bram, Linda; Marcu, Jahan; Abood, Mary E.
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
Schellekens, Reinout C A; Stellaard, Frans; Woerdenbag, Herman J; Frijlink, Henderik W; Kosterink, Jos G W
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
Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat
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.
Hotchandani, Tarun; Desgagne-Penix, Isabel
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.
Yadav, Kavita N.; Kadam, Prasad V.; Patel, Jigna A.; Patil, Manohar J.
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
Zhou, Yan-Xi; Xia, Wei; Yue, Wei; Peng, Cheng; Rahman, Khalid; Zhang, Hong
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
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.
Mendlewicz, J; Sevy, S
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.
Ring, Arne; Schall, Robert; Loke, Yoon K; Day, Simon
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.
Geerts, Bart F; Aarts, Leon P; Jansen, Jos R
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
McLean, Rebecca Jane; Gottlob, Irene
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.
Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K; Martin, Paul T
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.
Race, Amos; Miller, Mark A.; Mann, Kenneth A.
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
Damment, Stephen J P
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.
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.
Bass, Alan; Kinter, Lewis; Williams, Patricia
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.
Damment, Stephen JP
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
Reilly, James L.; Lencer, Rebekka; Bishop, Jeffrey R.; Keedy, Sarah; Sweeney, John A.
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…
Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge
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
Di Girolamo, G
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.
Austin, Vance L.
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…
Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge
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.
Kelmendi, Benjamin; Adams, Thomas G.; Yarnell, Stephanie; Southwick, Steven; Abdallah, Chadi G.; Krystal, John H.
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
Soeter, Marieke; Kindt, Merel
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…
Ramasamy, M Santhana; Manikandan, S
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.
Malone, Marvin H.; And Others
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…
Broadhurst, C; Wilson, K C M; Kinirons, M T; Wagg, A; Dhesi, J K
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
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
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)
Rickli, Anna; Kopf, Simone; Hoener, Marius C; Liechti, Matthias E
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
Csanádi, Zoltán; Fazekas, Tamás; Varró, András
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.
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.
El-Mas, Mahmoud M; El-Gowelli, Hanan M; Michel, Martin C
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.
Houts, Arthur C.; And Others
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…
Ravenscroft, Stephanie M.; Pointon, Amy; Williams, Awel W.; Cross, Michael J.; Sidaway, James E.
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
Prasanna, Ganesh; Li, Byron; Mogi, Muneto; Rice, Dennis S
Intraocular pressure (IOP) lowering drugs that are approved for the treatment of glaucoma and ocular hypertension have limited activity on increasing aqueous humor movement through the trabecular meshwork and Schlemm's canal (TM/SC). The TM/SC complex is considered the conventional outflow pathway and is a primary site of increased resistance to aqueous humor outflow in glaucoma. Novel mechanisms that enhance conventional outflow have shown promise in IOP reduction via modulation of several pathways including Rho kinase, nitric oxide/soluble guanylate cyclase/cGMP, adenosine A1, prostaglandin EP4/cAMP, and potassium channels. The clinical translatability of these pharmacological modulators based on pre-clinical efficacy models is currently being explored. In addition, identification of pathways from GWAS and other studies involving transgenic rodent models with elevated/reduced IOP phenotypes have begun to yield additional insights into IOP regulation and serve as a source for the next generation of IOP lowering targets. Lastly, improvements in drug delivery technologies to enable sustained IOP reduction are also discussed.
Edgar, Alan D; Levin, Robert; Constantinou, Christos E; Denis, Louis
Despite an unremitting increase in the number of patients presenting symptoms of benign prostate hyperplasia (BPH), the viable treatment options remain relatively limited when compared to other disorders of aging. This has spurred an interest in so-called alternative medicines, many of which continue to be used in spite of the more recent emergence of rationally targeted therapies. Nonetheless, in the case of plant extracts, the vast majority of these have not been subjected to the same rigorous pre-clinical pharmacological testing and large-scale clinical trials now required by health authorities. Furthermore, demonstration of their clinical efficacy in BPH has been hindered by trials of limited duration with a high placebo response. Beginning with a preliminary demonstration of in vitro inhibition of growth factor-mediated fibroblast proliferation with Pygeum africanum extract, a detailed series of in vitro and in vivo studies on prostate growth and bladder function were undertaken. These studies, reviewed herein, have permitted the identification of putative molecular targets of Pygeum africanum extract affecting both growth factor-mediated prostate growth as well as specific parameters of bladder function. These results, corroborated in part by short-term clinical efficacy, set the stage for a large-scale clinical trial to investigate the efficacy of Pygeum africanum extract in the treatment of lower urinary tract symptoms.
Pleticha, Josef; Heilmann, Lukas F; Evans, Christopher H; Asokan, Aravind; Samulski, Richard Jude; Beutler, Andreas S
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.
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
Dávalos, Alberto; Fernández-Hernando, Carlos
There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies.
[Effectiveness and difficulty of education on nosocomial infection control for pre-clinical practice in the clinic, so-called inclusive clinical practice phase I, for students in the Faculty of Dentistry, Tokyo Medical and Dental University].
Sunakawa, Mitsuhiro; Matsumoto, Hiroyuki
It has been planned to give pre-clinical practice in the clinic, so-called inclusive clinical practice phase I, for fifth-grade students in the School of Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, to give them the clinical training needed to perform dental practice and clinical practicum for comprehensive patient care, namely inclusive clinical practice phase II. This study analyzed the educative efficiency of the class on nosocomial infection control (NIC) by comparing achievements pre- and post-test, and discussed appropriate education planning on the NIC for dental students. Sixty-two fifth-grade students in the 2007 academic year sat the pre- and post-tests; the mean score and standard deviation of these tests were 5.30 +/- 1.26 (n = 56) and 8.59 +/- 1.18 (n = 59), respectively. There was a statistically significant difference between them (paired t-test, p < 0.01). Another finding was that students with high scores in the post-test did not necessarily achieve high ratings in the pre-test. It is suggested that the introduction of pre- and post-tests and the clarification of main points in the class as a theme of NIC could be a useful tool for increasing the comprehension of students on the theme. Since students at lower grades will attend clinical practice in the university hospital, it is thought that students should be given NIC training early in the clinical course, and the current curriculum should be improved to increase the opportunity for students to study this important issue.
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
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.
Waldman, S A; Terzic, A
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.
Kelmendi, Benjamin; Adams, Thomas G; Yarnell, Stephanie; Southwick, Steven; Abdallah, Chadi G; Krystal, John H
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.
Zhao, Liang; Ren, Tian-hua; Wang, Diane D
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
Zhang, Le-Le; Tian, Ke; Tang, Zheng-Hai; Chen, Xiao-Jia; Bian, Zhao-Xiang; Wang, Yi-Tao; Lu, Jin-Jian
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.
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
Lorberbaum, T; Nasir, M; Keiser, M J; Vilar, S; Hripcsak, G; Tatonetti, N P
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.
Palbag, Satadru; Dey, Bijay Kr; Singh, Narendra Kumar
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.
Łabuzek, Krzysztof; Sikorska, Patrycja; Szkudłapski, Dawid; Oleszczyk, Paulina; Juśko, Maciej; Kozłowski, Michał; Madej, Paweł; Okopień, Bogusław
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.
Yaksh, Ameeta; van der Does, Lisette JME; Lanters, Eva AH; de Groot, Natasja MS
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
Gourraud, Jean-Baptiste; Andrade, Jason G; Macle, Laurent
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
Di Sciascio, Guido; Riva, Marco Andrea
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
Peng, Fu; Du, Qiaohui; Peng, Cheng; Wang, Neng; Tang, Hailin; Xie, Xiaoming; Shen, Jiangang; Chen, Jianping
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.
Rudashevskaya, Elena L.; Stockner, Thomas; Trauner, Michael; Freissmuth, Michael; Chiba, Peter
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
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.
Easterling, Thomas R
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.
Bushra, Rabia; Aslam, Nousheen
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
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.
Pasternak, Gavril W.
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
Kilsby, Amanda J; Sayer, Avan A; Witham, Miles D
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.
Kaštelan, Snježana; Tomić, Martina; Gverović Antunica, Antonela; Salopek Rabatić, Jasminka; Ljubić, Spomenka
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.
Underhaug, Jarl; Aubi, Oscar; Martinez, Aurora
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.
Chesher, G B
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.
Abedon, Stephen T.
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
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.
Fryer, Ryan M.; Patel, Mita; Zhang, Xiaomei; Baum-Kroker, Katja S.; Muthukumarana, Akalushi; Linehan, Brian; Tseng, Yin-Chao
Establishing a wide therapeutic index (TI) for pre-clinical safety is important during lead optimization (LO) in research, prior to clinical development, although is often limited by a molecules physiochemical characteristics. Recent advances in the application of the innovative vibrating mesh spray-drying technology to prepare amorphous solid dispersions may offer an opportunity to achieve high plasma concentrations of poorly soluble NCEs to enable testing and establishment of a wide TI in safety pharmacology studies. While some of the amorphous solid dispersion carriers are generally recognized as safe for clinical use, whether they are sufficiently benign to enable in vivo pharmacology studies has not been sufficiently demonstrated. Thus, the physical properties, and effect in a battery of in vivo safety pharmacology models, were assessed in three classes of polymers employed as spray-dried dispersion carriers. The polymers (HPMC-AS, Eudragit, PVAP) displayed low affinity with acetone/methanol, suitable for solvent-based spray drying. The water sorption of the polymers was moderate, and the degree of hysteresis of HPMC-AS was smaller than Eudragit and PVAP indicating the intermolecular interaction of water-cellulose molecules is weaker than water-acrylate or water-polyvinyl molecules. The polymer particles were well-suspended without aggregation with a mean particle size less than 3 μm in an aqueous vehicle. When tested in conscious Wistar Han rats in safety pharmacology models (n = 6–8/dose/polymer) investigating effects on CNS, gastrointestinal, and cardiovascular function, no liabilities were identified at any dose tested (30–300 mg/kg PO, suspension). In brief, the polymers had no effect in a modified Irwin test that included observational and evoked endpoints related to stereotypies, excitation, sedation, pain/anesthesia, autonomic balance, reflexes, and others. No effect of the polymers on gastric emptying or intestinal transit was observed when
Fryer, Ryan M; Patel, Mita; Zhang, Xiaomei; Baum-Kroker, Katja S; Muthukumarana, Akalushi; Linehan, Brian; Tseng, Yin-Chao
Establishing a wide therapeutic index (TI) for pre-clinical safety is important during lead optimization (LO) in research, prior to clinical development, although is often limited by a molecules physiochemical characteristics. Recent advances in the application of the innovative vibrating mesh spray-drying technology to prepare amorphous solid dispersions may offer an opportunity to achieve high plasma concentrations of poorly soluble NCEs to enable testing and establishment of a wide TI in safety pharmacology studies. While some of the amorphous solid dispersion carriers are generally recognized as safe for clinical use, whether they are sufficiently benign to enable in vivo pharmacology studies has not been sufficiently demonstrated. Thus, the physical properties, and effect in a battery of in vivo safety pharmacology models, were assessed in three classes of polymers employed as spray-dried dispersion carriers. The polymers (HPMC-AS, Eudragit, PVAP) displayed low affinity with acetone/methanol, suitable for solvent-based spray drying. The water sorption of the polymers was moderate, and the degree of hysteresis of HPMC-AS was smaller than Eudragit and PVAP indicating the intermolecular interaction of water-cellulose molecules is weaker than water-acrylate or water-polyvinyl molecules. The polymer particles were well-suspended without aggregation with a mean particle size less than 3 μm in an aqueous vehicle. When tested in conscious Wistar Han rats in safety pharmacology models (n = 6-8/dose/polymer) investigating effects on CNS, gastrointestinal, and cardiovascular function, no liabilities were identified at any dose tested (30-300 mg/kg PO, suspension). In brief, the polymers had no effect in a modified Irwin test that included observational and evoked endpoints related to stereotypies, excitation, sedation, pain/anesthesia, autonomic balance, reflexes, and others. No effect of the polymers on gastric emptying or intestinal transit was observed when measured
Merlin, Jessica S; Bulls, Hailey W; Vucovich, Lee A; Edelman, E Jennifer; Starrels, Joanna L
Chronic pain occurs in as many as 85% of individuals with HIV and is associated with substantial functional impairment. Little guidance is available for HIV providers seeking to address their patients' chronic pain. We conducted a systematic review to identify clinical trials and observational studies that examined the impact of pharmacologic or non-pharmacologic interventions on pain and/or functional outcomes among HIV-infected individuals with chronic pain in high-development countries. Eleven studies met inclusion criteria and were mostly low or very low quality. Seven examined pharmacologic interventions (gabapentin, pregabalin, capsaicin, analgesics including opioids) and four examined non-pharmacologic interventions (cognitive behavioral therapy, self-hypnosis, smoked cannabis). The only controlled studies with positive results were of capsaicin and cannabis, and had short-term follow-up (≤12 weeks). Among the seven studies of pharmacologic interventions, five had substantial pharmaceutical industry sponsorship. These findings highlight several important gaps in the HIV/chronic pain literature that require further research.
Aim. To explore the pharmacological mechanism of Xiaoyao powder (XYP) on anovulatory infertility by a network pharmacology approach. Method. Collect XYP's active compounds by traditional Chinese medicine (TCM) databases, and input them into PharmMapper to get their targets. Then note these targets by Kyoto Encyclopedia of Genes and Genomes (KEGG) and filter out targets that can be noted by human signal pathway. Get the information of modern pharmacology of active compounds and recipe's traditional effects through databases. Acquire infertility targets by Therapeutic Target Database (TTD). Collect the interactions of all the targets and other human proteins via String and INACT. Put all the targets into the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to do GO enrichment analysis. Finally, draw the network by Cytoscape by the information above. Result. Six network pictures and two GO enrichment analysis pictures are visualized. Conclusion. According to this network pharmacology approach some signal pathways of XYP acting on infertility are found for the first time. Some biological processes can also be identified as XYP's effects on anovulatory infertility. We believe that evaluating the efficacy of TCM recipes and uncovering the pharmacological mechanism on a systematic level will be a significant method for future studies. PMID:28074099
Briansó, Ferran; Carrascosa, Maria C.; Oprea, Tudor I.; Mestres, Jordi
The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish themselves from the rest of the members in the family by their remarkably high levels of pharmacological similarity among them. Clusters of non-GPCR targets related by cross-pharmacology with particular GPCRs are identified and the implications for unwanted side-effects, as well as for repurposing opportunities, discussed. PMID:21851335
Lötsch, Jörn; Ultsch, Alfred
A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks.
Tramutola, Antonella; Triplett, Judy C; Di Domenico, Fabio; Niedowicz, Dana M; Murphy, Michael P; Coccia, Raffaella; Perluigi, Marzia; Butterfield, D Allan
The clinical symptoms of Alzheimer disease (AD) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. At the molecular level, AD subjects present overt amyloid β (Aβ) production and tau hyperphosphorylation. Aβ species have been proposed to overactivate the phosphoinositide3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis, which plays a central role in proteostasis. The current study investigated the status of the PI3K/Akt/mTOR pathway in post-mortem tissue from the inferior parietal lobule (IPL) at three different stages of AD: late AD, amnestic mild cognitive impairment (MCI) and pre-clinical AD (PCAD). Our findings suggest that the alteration of mTOR signaling and autophagy occurs at early stages of AD. We found a significant increase in Aβ (1-42) levels, associated with reduction in autophagy (Beclin-1 and LC-3) observed in PCAD, MCI, and AD subjects. Related to the autophagy impairment, we found a hyperactivation of PI3K/Akt/mTOR pathway in IPL of MCI and AD subjects, but not in PCAD, along with a significant decrease in phosphatase and tensin homolog. An increase in two mTOR downstream targets, p70S6K and 4EBP1, occurred in AD and MCI subjects. Both AD and MCI subjects showed increased, insulin receptor substrate 1, a candidate biomarker of brain insulin resistance, and GSK-3β, a kinase targeting tau phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical groups. The results hint at a link between Aβ and the PI3K/Akt/mTOR axis and provide further insights into the relationship between AD pathology and insulin resistance. In addition, we speculate that the alteration of mTOR signaling in the IPL of AD and MCI subjects, but not in PCAD, is due to the lack of substantial increase in oxidative stress. The figure represents the three different stages of Alzheimer Disease: Preclinical Alzheimer Disease (PCAD), Mild cognitive impairment (MCI
Wiebe, V J; Sipila, P E
The use of antineoplastic agents in pregnant women poses obvious risks to both the patient and the developing fetus, particularly during organogenesis. While the use of antineoplastics during pregnancy is often unavoidable, the physician may limit the risks by having a clear knowledge of the pharmacology and teratogenic potential of individual agents. Specific physiologic changes in the pregnant patient, such as enhanced renal excretion of drugs, increased or decreased hepatic function, altered gastrointestinal absorption and enterohepatic circulation, altered plasma protein binding, an increase in plasma volume (50%), and creation of a fluid filled 3rd compartment (amniotic fluid) for water soluble drugs may all significantly influence the pharmacology of antineoplastic agents. These physiological changes may effect the pregnant patients ability to absorb orally administered drugs, metabolize drugs to either active or inactive metabolites, and eliminate cytotoxically active drugs. A resulting reduction in concentration x time (C x T) for drug exposure to the maternal system may reduce the efficacy of the antineoplastic agents, while an increase in C x T may expose the patient and her fetus to undue toxicity. The timing of drug administration to gestational age is also a critical factor for some drugs. While many drugs result in adverse effects on the fetus regardless of gestational age, others appear to pose less of a threat if administered beyond the first trimester. This review addresses the pharmacology, pharmacokinetics and the teratogenic potential of individual antineoplastic agents that are commonly used in pregnant patients. The aim of this review is to help the physician select, on a patient specific basis, antineoplastic agents that avoid at least some of the fetal risk involved while maintaining efficacy in the treatment of the patient.
Liktor, Balázs; Szekanecz, Zoltán; Batta, Tamás József; Sziklai, István; Karosi, Tamás
To review our current knowledge of the pathologic bone metabolism in otosclerosis and to discuss the possibilities of non-surgical, pharmacological intervention. Otosclerosis has been suspected to be associated with defective measles virus infection, local inflammation and consecutive bone deterioration in the human otic capsule. In the early stages of otosclerosis, different pharmacological agents may delay the progression or prevent further deterioration of the disease and consecutive hearing loss. Although effective anti-osteoporotic drugs have become available, the use of sodium fluoride and bisphosphonates in otosclerosis has not yet been successful. Bioflavonoids may relieve tinnitus due to otosclerosis, but there is no data available on long-term application and effects on sensorineural hearing loss. In the initial inflammatory phase, corticosteroids or non-steroidal anti-inflammatory drugs may be effective; however, extended systemic application may lead to serious side effects. Vitamin D administration may have effects on the pathological bone loss, as well as on inflammation. No information has been reported on the use of immunosuppressive drugs. Anti-cytokine targeted biological therapy, however, may be feasible. Indeed, one study on the local administration of infliximab has been reported. Potential targets of future therapy may include osteoprotegerin, RANK ligand, cathepsins and also the Wnt-β-catenin pathway. Finally, anti-measles vaccination may delay the progression of the disease and potentially decrease the number of new cases. In conclusion, stapes surgery remains to be widely accepted treatment of conductive hearing loss due to otosclerosis. Due to lack of solid evidence, the place of pharmacological treatment targeting inflammation and bone metabolism needs to be determined by future studies.
Martin, G. F.
The author of this article reviews the pharmacology of nasal medication, focusing on the indications and side-effects. The newer group of non-sedating antihistamines proves to be a useful supplement to disodium cromoglycate and the traditional antihistamines in the treatment of allergic rhinitis. The topical steroids (flunisolide and beclomethasone dipropionate) did not produce a significant incidence of adrenal suppression, mucosal atrophy, or nasal candidiasis. The anticholinergic ipatropium bromide shows promise in the treatment of rhinorrhea. The author also reviews the use of decongestants and emollients and remarks on the factors that affect patient compliance when nasal medications are prescribed. PMID:20469495
Omar, Syed Haris
Olive from Olea europaea is native to the Mediterranean region and, both the oil and the fruit are some of the main components of the Mediterranean diet. The main active constituents of olive oil include oleic acid, phenolic constituents, and squalene. The main phenolic compounds, hydroxytyrosol and oleuropein, give extra-virgin olive oil its bitter, pungent taste. The present review focuses on recent works that have analyzed the relationship between the major phenolic compound oleuropein and its pharmacological activities including antioxidant, anti-inflammatory, anti-atherogenic, anti-cancer activities, antimicrobial activity, antiviral activity, hypolipidemic and hypoglycemic effect. PMID:21179340
Undem, Bradley J; Carr, Michael J
Afferent nerves in the airways serve to regulate breathing pattern, cough, and airway autonomic neural tone. Pharmacologic agents that influence afferent nerve activity can be subclassified into compounds that modulate activity by indirect means (e.g. bronchial smooth muscle spasmogens) and those that act directly on the nerves. Directly acting agents affect afferent nerve activity by interacting with various ion channels and receptors within the membrane of the afferent terminals. Whether by direct or indirect means, most compounds that enter the airspace will modify afferent nerve activity, and through this action alter airway physiology. PMID:11686889
Leader, Benjamin; Baca, Quentin J; Golan, David E
Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.
Sromek, Anna W; Provencher, Brian A; Russell, Shayla; Chartoff, Elena; Knapp, Brian I; Bidlack, Jean M; Neumeyer, John L
A series of levo- and dextromorphinan pairs have been synthesized and evaluated for their affinities to the mu, kappa, and delta opioid receptors, the N-methyl-D-aspartate (NMDA) channel, and sigma 1 and 2 receptors. It was found that levo isomers tended to have higher affinities at the opioid receptors and moderate to high affinities to the NMDA and sigma receptors, while dextro isomers tended to have lower affinities to the opioid receptors but comparatively higher affinities to the NMDA and sigma receptors. This series of compounds have interesting and complex pharmacological profiles, and merit further investigation as potential therapies for drug abuse treatment.
Pittenger, Christopher; Bloch, Michael H
Obsessive-compulsive disorder (OCD) affects up to 2.5% of the population of the course of a lifetime and produces substantial morbidity. Approximately 70% of patients can experience significant symptomatic relief with appropriate pharmacotherapy. Selective serotonin reuptake inhibitors are the mainstay of pharmacological treatment. These drugs are typically used at higher doses and for longer periods than in depression. Proven second-line treatments include the tricyclic clomipramine and the addition of low-dose neuroleptic medications. OCD refractory to available treatments remains a profound clinical challenge.
Secades, J J
This review is based on the previous one published in 2006 -Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56-, incorporating the new references until now, having all the information available to facilitate the access to the informacion in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
Nair, Girish B; Ilowite, Jonathan S
There are no approved pharmacologic agents to enhance mucus clearance in non-cystic fibrosis (CF) bronchiectasis. Evidence supports the use of hyperosmolar agents in CF, and studies with inhaled mannitol and hypertonic saline are ongoing in bronchiectasis. N-acetylcysteine may act more as an antioxidant than a mucolytic in other lung diseases. Dornase α is beneficial to patients with CF, but is not useful in patients with non-CF bronchiectasis. Mucokinetic agents such as β-agonists have the potential to improve mucociliary clearance in normals and many disease states, but have not been adequately studied in patients with bronchiectasis.
Omar, Syed Haris
Olive from Olea europaea is native to the Mediterranean region and, both the oil and the fruit are some of the main components of the Mediterranean diet. The main active constituents of olive oil include oleic acid, phenolic constituents, and squalene. The main phenolic compounds, hydroxytyrosol and oleuropein, give extra-virgin olive oil its bitter, pungent taste. The present review focuses on recent works that have analyzed the relationship between the major phenolic compound oleuropein and its pharmacological activities including antioxidant, anti-inflammatory, anti-atherogenic, anti-cancer activities, antimicrobial activity, antiviral activity, hypolipidemic and hypoglycemic effect.
Favela-Hernández, Juan Manuel J; González-Santiago, Omar; Ramírez-Cabrera, Mónica A; Esquivel-Ferriño, Patricia C; Camacho-Corona, María del Rayo
Presently the search for new drugs from natural resources is of growing interest to the pharmaceutical industry. Natural products have been the source of new drugs since ancient times. Plants are a good source of secondary metabolites which have been found to have beneficial properties. The present study is a review of the chemistry and pharmacology of Citrus sinensis. This review reveals the therapeutic potential of C. sinensis as a source of natural compounds with important activities that are beneficial for human health that could be used to develop new drugs.
The aim of this paper is to provide an overview of the management of neuropathic pain associated with cancer and to provide helpful clinical advice for nurses working with patients who may have neuropathic pain. While cancer pain is a mixed-mechanism pain, this article will focus only on neuropathic pain management. The impact of neuropathic pain on patients' quality of life is great and while many patients recover from their cancer, a significant number continue to suffer from a neuropathic pain syndrome. Management of neuropathic pain is significantly different from management of nociceptive pain with respect to pharmacological and non-pharmacological strategies. Neuropathic pain is complex, and as such requires complex management using pharmacological as well as non-pharmacological approaches. Specific drugs for neuropathic pain may be effective for some patients, but not all; therefore, ongoing and comprehensive assessment and management are required. Furthermore, these patients may require trials of several drugs before they find one that works for them. It is important for nurses to understand neuropathic pain, its manifestation, impact on quality of life and management when nursing patients with neuropathic pain associated with cancer.
Nagarajan, M.; Kuruvilla, Gina R.; Kumar, K. Subrahmanya; Venkatasubramanian, Padma
The Ayurvedic literature during the medieval period suggests the use of Musta (Cyperus rotundus), a common weed, as a pratinidhi dravya (substitute) for Ativisha (Aconitum heterophyllum), an endangered species. Contemporary Ayurvedic practice also uses Cryptocoryne spiralis, (known as Naattu Atividayam in South India) and Nagaramusta (Cyperus scariosus) as substitutes for Ativisha and Musta, respectively. This article reviews published literature on the pharmacology of the above four species. Both A. heterophyllum and C. rotundus are reported to possess antiinflammatory, antipyretic, antibacterial and antidiarrhoeal properties, while antiinflammatory and antibacterial activities are attributed to C. scariosus. No reports exist on the bioactivity of Cryptocoryne spiralis. It is interesting to note that other than the veerya which is different, the biological properties of Ativisha and Musta are similar according to Ayurvedic classification of dravyaguna. This is also supported by modern pharmacological studies, which show that, both A. heterophyllum and C. rotundus have antidiarrheal, antipyretic, antiinflammatory, antihyperlipidemic and hypoglycemic activities. However, the similarities between the discussed species cannot be attributed to their phytochemical composition or taxonomical classification as these are quite distinct. The dravyaguna method of classifying materials, which we are calling as “pharmaco-taxonomy”, offers a unique way of classifying those plant materials which lack similarity at the botanical or chemical level, but are similar at the level of biological functions. PMID:26167002
Tetrandrine, dauricine, daurisoline and neferine are bisbenzylisoquinoline alkaloid derivatives isolated from Chinese traditional medicine and herbs. The cardiovascular pharmacological effects and the mechanism of actions of these compounds were reviewed. Tetrandrine isolated from Stephania tetrandra S Moore possesses antihypertensive and antiarrhythmic effects. The antihypertensive effects of tetrandrine have been demonstrated in experimental hypertensive animals and in hypertensive patients. Recent studies showed that in addition to its calcium antagonistic effect, tetrandrine interacted with M receptors. Modulation by M receptor is one of the pharmacological mechanisms of cardiovascular effects of tetrandrine. Dauricine and daurisoloine were isolated from Menispermum dauricum DC. The antiarrhythmic effects of dauricine have been verified in different experimental arrhythmic models and in cardiac arrhythmic patients. Dauricine blocked the cardiac transmembrane Na+,K+ and Ca2+ ion currents. Differing from quinidine and sotalol, which exhibited reverse use-dependent effect, dauricine prolonged APD in a normal use-dependent manner in experimental studies. The antiarrhythmic effect of daurisoline and neferine which is an alkaloid isolated from Nelumbo nucifera Gaertn, and their mechanisms of actions have also been studied. The antiarrhythmic effect of daurisoline is more potent than that of dauricine.
Sanodiya, Bhagwan S; Thakur, Gulab Singh; Baghel, Rakesh K; Prasad, G B K S; Bisen, P S
Ganoderma lucidum (Ling Zhi) is a basidiomycete white rot macrofungus which has been used extensively as "the mushroom of immortality" in China, Japan, Korea and other Asian countries for 2000 years. A great deal of work has been carried out on therapeutic potential of Ganoderma lucidum. The basidiocarp, mycelia and spores of Ganoderma lucidum contain approximately 400 different bioactive compounds, which mainly include triterpenoids, polysaccharides, nucleotides, sterols, steroids, fatty acids, proteins/peptides and trace elements which has been reported to have a number of pharmacological effects including immunomodulation, anti-atherosclerotic, anti-inflammatory, analgesic, chemo-preventive, antitumor, chemo and radio protective, sleep promoting, antibacterial, antiviral (including anti-HIV), hypolipidemic, anti-fibrotic, hepatoprotective, anti-diabetic, anti-androgenic, anti-angiogenic, anti-herpetic, antioxidative and radical-scavenging, anti-aging, hypoglycemic, estrogenic activity and anti-ulcer properties. Ganoderma lucidum has now become recognized as an alternative adjuvant in the treatment of leukemia, carcinoma, hepatitis and diabetes. The macrofungus is very rare in nature rather not sufficient for commercial exploitation for vital therapeutic emergencies, therefore, the cultivation on solid substrates, stationary liquid medium or by submerged cultivation has become an essential aspect to meet the driving force towards the increasing demands in the international market. Present review focuses on the pharmacological aspects, cultivation methods and bioactive metabolites playing a significant role in various therapeutic applications.
Mali, Prashant Y.
Premna integrifolia Linn. (Verbenaceae) is an important constituent of the formulation of ten roots of herbs known as Daśamūla and is widely used for treating various ailments in the Indian system of medicine. Aim of this review is to provide comprehensive information on the pharmacological activities of various parts of P. integrifolia. All the relevant universally accepted electronic databases were searched with respect to the terms “Agnimanthā”, “Headache tree”, “Premna integrifolia”, “Premna obtusifolia”, “Premna serratifolia” including Indian classical texts, pharmacopoeias, Ayurvedic books, journals, etc., for information without specific timeline. Complete information of the plant has been collected manually since the year 1964 and has been arranged chronologically. The collected data reflects that many ethno-medicinal claims have been confirmed through the modern in-vitro and in-vivo pharmacological studies using different extracts and their isolates of P. integrifolia. The isolation of active constituents, their biological actions, clinical safety and validation of traditional uses of P. integrifolia could provide leads for further scientific research. The information collected here will be useful to set-up research protocols for modern drugs and Ayurvedic formulation development. PMID:27143797
Chekman, I S
Literary data and results of own investigations about pharmacological and pharmaceutical grounds of nanodrugs are analyzed in the article. Main requirements to nanodrugs are summarized. (1) To have much more expressed effect in comparison with drugs used in a medicinal practice. (2) New nanodrug mustn't have adverse reactions. (3) Nanodrugs must decrease adverse effects of other drugs. (4) Nanodrugs mustn't negatively influence on clinic-pharmacological properties of drugs used in medicinal practice forthe treatment of different disorders. (5) One of the requirements to nanodrugs is positive pharmacoeconomic parameters. (6) Medicinal form of nanodrug must be usable for different ways of drug administration. (7) Technology of drug production should be inexpensive, without negative influence on ecology. Comprehensive experimental researches of nanoparticle pharmacodynamics and pharmacokinetics in the human body and its influence on environment should be done. A new technology of obtaining nanoparticles of iron oxide, silver, copper and their composites has been developed in the laboratory of electron-beam nanotechnology of nonorganic materials for medicine. It was shown, that nanoparticles of iron and silver oxide have more significant antimicrobial activity than oxides of these metals in normal size.
Macias, Rocio I. R.
Cholangiocarcinoma (CCA), or tumor of the biliary tree, is a rare and heterogeneous group of malignancies associated with a very poor prognosis. Depending on their localization along the biliary tree, CCAs are classified as intrahepatic, perihilar, and distal, and these subtypes are now considered different entities that differ in tumor biology, the staging system, management, and prognosis. When diagnosed, an evaluation by a multidisciplinary team is essential; the team must decide on the best therapeutic option. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although this is only achieved in less than 50% of cases. Five-year survival rates have increased in the recent past owing to improvements in imaging techniques, which permits resectability to be predicted more accurately, and in surgery. Chemotherapy and radiotherapy are relatively ineffective in treating nonoperable tumors and the resistance of CCA to these therapies is a major problem. Although the combination of gemcitabine plus platinum derivatives is the pharmacological treatment most widely used, to date there is no standard chemotherapy, and new combinations with targeted drugs are currently being tested in ongoing clinical trials. This review summarizes the biology, clinical management, and pharmacological perspectives of these complex tumors. PMID:27335842
Simmler, LD; Buser, TA; Donzelli, M; Schramm, Y; Dieu, L-H; Huwyler, J; Chaboz, S; Hoener, MC; Liechti, ME
Background and Purpose Designer β-keto amphetamines (e.g. cathinones, ‘bath salts’ and ‘research chemicals’) have become popular recreational drugs, but their pharmacology is poorly characterized. Experimental Approach We determined the potencies of cathinones to inhibit DA, NA and 5-HT transport into transporter-transfected HEK 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. Key Results Mephedrone, methylone, ethylone, butylone and naphyrone acted as non-selective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced the release of 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone and flephedrone, similar to amphetamine and methamphetamine, acted as preferential DA and NA uptake inhibitors and induced the release of DA. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) were highly potent and selective DA and NA transporter inhibitors but unlike amphetamines did not evoke the release of monoamines. The non-β-keto amphetamines are trace amine-associated receptor 1 ligands, whereas the cathinones are not. All the cathinones showed high blood–brain barrier permeability in an in vitro model; mephedrone and MDPV exhibited particularly high permeability. Conclusions and Implications Cathinones have considerable pharmacological differences that form the basis of their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is probably associated with a considerable risk of addiction. PMID:22897747
Prajapati, Rakesh P; Kalariya, Manisha; Parmar, Sachin K; Sheth, Navin R
Lagenaria siceraria (Molina) standley (LS) (Family: Cucurbitaceae) is an annual herbaceous climbing plant with a long history of traditional medicinal uses in many countries, especially in tropical and subtropical regions. Since ancient times the climber has been known for its curative properties, and has been utilized for treatment of various ailments, including jaundice, diabetes, ulcer, piles, colitis, insanity, hypertension, congestive cardiac failure (CCF), and skin diseases. Its fruit pulp is used both as an emetic and purgative, and for its cooling, diuretic, antibilious, and pectoral properties. Boiled in oil this pulp is used to treat rheumatism and insomnia. A wide range of chemical compounds including sterols, terpenoids, flavonoids, and saponins have been isolated from the species. Its extracts have been found to possess various pharmacological activities. Below, we give a comprehensive review of its ethnomedical uses, chemical constituents, and pharmacological profile as a medicinal plant. Particular attention is given to its analgesic, anti-inflammatory, antihyperlipidemic, diuretic, hepatoprotective, anthelmintic, and antibacterial effects so that its potential uses in pharmaceutics can be better evaluated.
Prajapati, Rakesh P.; Kalariya, Manisha; Parmar, Sachin K.; Sheth, Navin R.
Lagenaria siceraria (Molina) standley (LS) (Family: Cucurbitaceae) is an annual herbaceous climbing plant with a long history of traditional medicinal uses in many countries, especially in tropical and subtropical regions. Since ancient times the climber has been known for its curative properties, and has been utilized for treatment of various ailments, including jaundice, diabetes, ulcer, piles, colitis, insanity, hypertension, congestive cardiac failure (CCF), and skin diseases. Its fruit pulp is used both as an emetic and purgative, and for its cooling, diuretic, antibilious, and pectoral properties. Boiled in oil this pulp is used to treat rheumatism and insomnia. A wide range of chemical compounds including sterols, terpenoids, flavonoids, and saponins have been isolated from the species. Its extracts have been found to possess various pharmacological activities. Below, we give a comprehensive review of its ethnomedical uses, chemical constituents, and pharmacological profile as a medicinal plant. Particular attention is given to its analgesic, anti-inflammatory, antihyperlipidemic, diuretic, hepatoprotective, anthelmintic, and antibacterial effects so that its potential uses in pharmaceutics can be better evaluated. PMID:21731373
Schroeder, Megan J; Hoffman, Allison C
Objective To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. Methods Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. Results Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products’ ability to support and maintain nicotine dependence. Conclusions Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products’ impact on public health. PMID:24732160
Zídek, Z; Anzenbacher, P; Kmoníčková, E
The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions. PMID:19371342
Xie, Lei; Draizen, Eli J; Bourne, Philip E
Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.
la Paz, Sergio Montserrat-de; Bermudez, Beatriz; Naranjo, M Carmen; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G
The well-known changes in modern lifestyle habits including over nutrition and physical inactivity have led to striking adverse effects on public health (e.g., obesity, diabetes, and metabolic syndrome) over recent decades. One noticeable consequence is exaggerated and prolonged state of postprandial hyperlipemia due to the ingestion of multiple fat-enriched meals during the course of a day. Postprandial (non-fasting) hyperlipemia is characterized by increased blood levels of exogenous triglycerides (TG) in the form of apolipoprotein (apo) B48-containing TG-rich lipoproteins (TRL), which have a causal role in the pathogenesis and progression of cardiovascular disease (CVD). The cardiovascular benefits of lifestyle modification (healthy diet and exercise) and conventional lipid-lowering therapies (e.g., statins, fibrates, and niacin) could involve their favourable effects on postprandial metabolism. Pharmacologically, niacin has been used as an athero-protective drug for five decades. Studies have since shown that niacin may decrease fasting levels of plasma verylow- density lipoproteins (VLDL), low-density lipoprotein cholesterol (LDL-C), and lipoprotein [a] (Lp[a]), while may increase high-density lipoprotein cholesterol (HDL-C). Herein, the purpose of this review was to provide an update on effects and mechanisms related to the pharmacological actions of niacin on acute hyperlipemia.
Simply put, there is no cure for obesity. Pharmaceuticals that induce weight loss of extent of at least 5% from baseline are applied and tested as the weight loosing drugs. Available guidelines include recommendations that pharmacologic treatment of obesity may be offered to patients with BMI > 30 kg/m2; or BMI >27 kg/m2 and obesity related comorbidity. Both categories cumulatively include essential boundary condition of failing to achieve clinically significant weight loss through diet and exercise alone. In despite the exceedingly growing number of investigations and approaches, overall achievements in pharmacological treatments of obesity are limited. Antiobesity drugs are typically burdened with issues concerning the sustainability of lost weight, besides limitations in short term efficiency. Another important problem lays in the fact that the drug induced weight loss could be annihilated or reversed if patient does not adhere to personal lifestyle changes. Later include adjustments in behaviour sphere, dietary habits and physical activity. Recently, focus of clinical interests came to prevention of obesity epidemic through optimization of chronic pharmacotherapies, especially ones associated with weight gain side-effect. This review presents the most important representatives of antiobesity drugs and essential principles that ought to be taken in to count in order to treat obesity more successfully.
Ruzza, Chiara; Rizzi, Anna; Malfacini, Davide; Cerlesi, Maria Camilla; Ferrari, Federica; Marzola, Erika; Ambrosio, Caterina; Gro, Cristina; Severo, Salvadori; Costa, Tommaso; Calo, Girolamo; Guerrini, Remo
Background and Purpose Peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity and reproducibility. Using this technique, we have synthesized and pharmacologically characterized the tetrabranched derivatives of the tachykinins, substance P (SP), neurokinin A (NKA) and B (NKB). Experimental Approach The following in vitro assays were used: calcium mobilization in cells expressing human recombinant NK receptors, BRET studies of G-protein – NK1 receptor interaction, guinea pig ileum and rat urinary bladder bioassays. Nociceptive behavioural response experiments were performed in mice following intrathecal injection of PWT2-SP. Key Results In calcium mobilization studies, PWT tachykinin derivatives behaved as full agonists at NK receptors with a selectivity profile similar to that of the natural peptides. NK receptor antagonists display similar potency values when tested against PWT2 derivatives and natural peptides. In BRET and bioassay experiments PWT2-SP mimicked the effects of SP with similar potency, maximal effects and sensitivity to aprepitant. After intrathecal administration in mice, PWT2-SP mimicked the nociceptive effects of SP, but with higher potency and a longer-lasting action. Aprepitant counteracted the effects of PWT2-SP in vivo. Conclusions and Implications The present study has shown that the PWT technology can be successfully applied to the peptide sequence of tachykinins to generate tetrabranched derivatives characterized with a pharmacological profile similar to the native peptides. In vivo, PWT2-SP displayed higher potency and a marked prolongation of action, compared with SP. PMID:24758475
Bergel, Riki; Hadar, Eran; Toledano, Yoel; Hod, Moshe
Gestational diabetes mellitus (GDM) is one of the most common morbidities complicating pregnancy, with short- and long-term consequences to the mothers, fetuses, and newborns. Management and treatment are aimed to achieve best possible glycemic control, while avoiding hypoglycemia and ensuring maternal and fetal safety. It involves behavioral modifications, nutrition and medications, if needed; concurrent with maternal and fetal surveillance for possible adverse outcomes. This review aims to elaborate on the pharmacological options for GDM therapy. We performed an extensive literature review of different available studies, published during the last 50 years, concerning pharmacological therapy for GDM, dealing with safety and efficacy, for both fetal and maternal morbidity consequences; as well as failure and success in establishing appropriate metabolic and glucose control. Oral medication therapy is a safe and effective treatment modality for GDM and in some circumstances may serve as first-line therapy when nutritional modifications fail. When oral agents fail to establish glucose control then insulin injections should be added. Determining the best oral therapy in inconclusive, although it seems that metformin is slightly superior to glyburide, in some aspects. As for parenteral therapy, all insulins listed in this article are considered both safe and effective for treatment of hyperglycemia during pregnancy. Importantly, a better safety profile, with similar efficacy is documented for most analogues. As GDM prevalence rises, there is a need for successful monitoring and treatment for patients. Caregivers should know the possible and available therapeutic options.
González-Castro, Paloma; Cueli, Marisol; Rodríguez, Celestino; García, Trinidad; Álvarez, Luis
Behavioral training in neurofeedback has proven to be an essential complement to generalize the effects of pharmacological support in subjects who have attention deficit with hyperactivity disorder (ADHD). Therefore, this investigation attempts to analyze the efficacy of neurofeedback compared with pharmacological support and the combination of both. Participants were 131 students, classified into four groups: control (did not receive neurofeedback or pharmacological support), neurofeedback group, pharmacological support group, and combined group (neurofeedback + pharmacological support). Participants' executive control and cortical activation were assessed before and after treatment. Results indicate that the combined group obtained more benefits and that the neurofeedback group improved to a greater extent in executive control than the pharmacological support group. It is concluded that this kind of training may be an alternative to stimulate activation in subjects with ADHD.
Teichert, Russell W; Schmidt, Eric W; Olivera, Baldomero M
Constellation pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (constellations) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the ongoing development of constellation pharmacology, there is a positive feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As constellation pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform.
Lathers, C. M.; Charles, J. B.; Bungo, M. W.
In this second article in the two-part series on pharmacology in space, Claire Lathers and colleagues discuss the pharmacology of drugs used to control motion sickness in space and note that the pharmacology of the 'ideal' agent has yet to be worked out. That motion sickness may impair the pharmacological action of a drug by interfering with its absorption and distribution because of alteration of physiology is a problem unique to pharmacology in space. The authors comment on the problem of designing suitable ground-based studies to evaluate the pharmacological effect of drugs to be used in space and discuss the use of salivary samples collected during space flight to allow pharmacokinetic evaluations necessary for non-invasive clinical drug monitoring.
The field of bioinformatics has allowed the interpretation of massive amounts of biological data, ushering in the era of 'omics' to biomedical research. Its potential impact on pharmacology research is enormous and it has shown some emerging successes. A full realization of this potential, however, requires standardized data annotation for large health record databases and molecular data resources. Improved standardization will further stimulate the development of system pharmacology models, using translational bioinformatics methods. This new translational bioinformatics paradigm is highly complementary to current pharmacological research fields, such as personalized medicine, pharmacoepidemiology and drug discovery. In this review, I illustrate the application of transformational bioinformatics to research in numerous pharmacology subdisciplines.
Hugger, Alfons; Schindler, Hans J; Türp, Jens C; Hugger, Sybille
Pharmacological interventions in temporomandibular joint (TMJ) pain differ from corresponding therapeutic interventions of jaw muscle (myofascial) pain. An actual systematic literature search lists and evaluates available articles on randomised controlled trials for treatment of arthralgia of the TMJ. On the basis of the few available trial reports, non-steroidal anti-inflammatory drugs (NSAIDs) seem to be effective, but side effects and drug interactions need to be considered. In relation to other therapeutic modalities, the rapidity of the onset of action of NSAIDs seems to be different, and the extension of side effects can be varied or reduced by changing the application route (oral versus topical). Palmitoylethanolamide (PEA) as dietary supplement for special medical purposes can apparently evoke positive therapeutic effects in TMJ arthralgia which need to be analysed in further studies.
Andrzejowski, Paul; Carroll, Will
Codeine is a drug that until recently was widely used in children. It was endorsed by the WHO as the second step on the analgesic ladder for cancer pain and has been used routinely for postoperative and breakthrough pain. Recently, its safety and efficacy have been called into question, following deaths after adenotonsillectomy was associated with its use. This has led to regulation by the US Food and Drug Administration, European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency to place significant restrictions on its use, and some centres have stopped using it altogether.In this article, we discuss the developmental pharmacology underpinning its action, reviewing what is known about the pharmacokinetics, pharmacodynamics and pharmacogenetics in children, how this relates to prescribing, as well as the practical issues and the recent regulatory framework surrounding its use.
Current day's research has been focusing much on the potential pharmacological or nutraceutical agents of selective health benefits with less toxicity. As a consequence of increased demand of nutritional supplements of great medicinal values, development of therapeutic agents from natural sources, in particular, marine environment are being considered much important. A diverse array of marine natural products containing medicinally useful nutritional substances, i.e., marine nutraceuticals have been focused to the benefit of mankind. Carbohydrates, by being constituted in considerable amount of many marine organisms display several nutraceutical and pharmaceutical behavior to defend from various diseases. Moreover, the carbohydrates from algae as well as from shellfish wastes, like chitosan and its derivatives, showed tremendous applications in biology and biomedicine. In the current chapter, several of marine carbohydrates from various marine flora and fauna have been covered with their applications and prospects in the development of nutraceuticals and pharmaceuticals.
Collins, Angela S; Graves, Barbara A; Gullette, Donna; Edwards, Rebecca
Pharmacology decision making requires clinical judgment. The authors created interactive microsimulation applying drug information to varying patients' situations. The theory-based microsimulation requires situational analysis for each scenario. The microsimulation uses an interactive format that allows the participant to navigate through three separate virtual clients' situations. Correct clinical decisions are rewarded by sounds and by video footage of the patient improving. Conversely, incorrect choices show video footage of the patient decompensating. This micro-simulation was developed to help students learn from the consequences of incorrect medication decision making in the virtual world without harming patients. The feedback of watching an incorrect decision on a patient helps students associate cause and effect on patient outcomes. The microsimulation reinforces the ease with which medication errors can occur and the extent of possible sequalae. The development process used to incorporate the technology in the nursing curriculum is discussed.
Nishie, K; Norred, W P; Swain, A P
The pharmacological responses produced by alpha chaconine and tomatine on guinea pig ileum, on the isolated electrically stimulated frog ventricle, and recordings of EEG, ECG, respiration and blood pressure in the rabbit showed no essential differences from those produced by alpha solanine. The LD50 values of chaconine and solanine in the mouse and rabbit are also similar and suggest that compounds other than these are probably responsible for the predominant toxic effects of certain hybrid potatoes in man and animals. The failure of the three glycoalkaloids to produce a significant teratological effect in the chick embryo lends no support to the hypothesis that they may be the teratogens responsible for certain congenital malformations in man.
Silverstone, T; Goodall, E
One way of gaining a greater understanding of the central mechanisms underlying hunger and the regulation of feeding behaviour in humans is to examine the actions and interactions on hunger and food intake of drugs with known or presumed pharmacological modes of action. To this end we have undertaken a number of studies which fall into three main categories: the mechanisms by which amphetamine anorexia is induced; the possible role of endogenous opioids in feeding; the action of amino acids thought to be involved in the regulation of feeding. In this field the potential for cross-fertilization between basic scientists working with laboratory animals and clinical scientists working with human subjects exists. For example, the clinical pharmacologist has been able to test out hypotheses on human subjects which could only have been developed using laboratory animals. Furthermore, using human subjects it is possible to extend the field of inquiry into an exploration of the subjective dimensions of appetite and hunger.
Lim, K-S; Kam, P C A
Chlorhexidine is a widely used skin antisepsis preparation and is an ingredient in toothpaste and mouthwash. It is an especially effective antiseptic when combined with alcohol. Its antimicrobial effects persist because it is binds strongly to proteins in the skin and mucosa, making it an effective antiseptic ingredient for handwashing, skin preparation for surgery and the placement of intravascular access. Catheters impregnated with chlorhexidine and antimicrobial agents can reduce the incidence of catheter-related bloodstream infections. Contact dermatitis related to chlorhexidine is not common in health care workers. The incidence of contact dermatitis to chlorhexidine in atopic patients is approximately 2.5 to 5.4%. Acute hypersensitivity reactions to chlorhexidine are often not recognised and therefore may be underreported. This review discusses the pharmacology, microbiology, clinical applications and adverse effects of chlorhexidine.
Mullane, Kevin; Winquist, Raymond J; Williams, Michael
The translational sciences represent the core element in enabling and utilizing the output from the biomedical sciences and to improving drug discovery metrics by reducing the attrition rate as compounds move from preclinical research to clinical proof of concept. Key to understanding the basis of disease causality and to developing therapeutics is an ability to accurately diagnose the disease and to identify and develop safe and effective therapeutics for its treatment. The former requires validated biomarkers and the latter, qualified targets. Progress has been hampered by semantic issues, specifically those that define the end product, and by scientific issues that include data reliability, an overt reductionistic cultural focus and a lack of hierarchically integrated data gathering and systematic analysis. A necessary framework for these activities is represented by the discipline of pharmacology, efforts and training in which require recognition and revitalization.
Forman, Stuart A.
This review focuses on the unique clinical and molecular pharmacology of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single bolus administration. It also produces a unique toxicity among anesthetic drugs-- inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis. PMID:21263301
Nitroimidazoles are being studied extensively as hypoxic cell radiosensitizers. Besides their ability to selectively sensitize hypoxic cells to radiation, which depends on the parent compound, nitroimidazoles have a variety of other effects in vitro, in vivo and clinically which appear to require reductive metabolism. As a first step to suggesting possible mechanisms for these other biological effects, a summary has been made of the known oxidative and reductive products of the two most widely studied radiosensitizers, metronidazole and misonidazole. As a second step to suggesting possible mechanisms for these biological effects, it is important to view the problem in terms of the in vivo situation where distribution and sites of metabolism of the drug and its reduction products will be important factors. Combining basic information about the reduction chemistry of nitroimidazoles with knowledge about the pharmacology of drugs and their reduced products should allow a better assessment of mechanism of action as well as a better implementation of these drugs clinically.
Reyes-Escogido, Maria de Lourdes; Gonzalez-Mondragon, Edith G; Vazquez-Tzompantzi, Erika
Capsaicin is a unique alkaloid found primarily in the fruit of the Capsicum genus and is what provides its spicy flavor. Generally extracted directly from fruit, high demand has driven the use of established methods to increase production through extraction and characterization. Over time these methods have improved, usually be applying existing techniques in conjunction. An increasingly wide range of potential applications has increased interest in capsaicin. Especially compelling are the promising results of medical studies showing possible beneficial effects in many diseases. Capsaicin's pungency has limited its use in clinical trials to support its biological activity. Characterization and extraction/ synthesis of non-pungent analogues is in progress. A review is made of capsaicin research focusing mainly on its production, synthesis, characterization and pharmacology, including some of its main potential clinical uses in humans.
Hamdam, Junnat; Sethu, Swaminathan; Smith, Trevor; Alfirevic, Ana; Alhaidari, Mohammad; Atkinson, Jeffrey; Ayala, Mimieveshiofuo; Box, Helen; Cross, Michael; Delaunois, Annie; Dermody, Ailsa; Govindappa, Karthik; Guillon, Jean-Michel; Jenkins, Rosalind; Kenna, Gerry; Lemmer, Björn; Meecham, Ken; Olayanju, Adedamola; Pestel, Sabine; Rothfuss, Andreas; Sidaway, James; Sison-Young, Rowena; Smith, Emma; Stebbings, Richard; Tingle, Yulia; Valentin, Jean-Pierre; Williams, Awel; Williams, Dominic; Park, Kevin; Goldring, Christopher
Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.
Baron, J M; Merk, H F; Heise, R
Because of their variable application, microarrays are currently used in different areas of research and development, such as skin pharmacology and allergology. Microarrays are plane carriers, on whose surface a variety of known DNA-molecules and proteins were immobilised. Transcripts can be detected by cDNA- and oligonucleotid-arrays and proteins of activated genes can be discovered using antibody microarrays. Detection of allergen-specific IgE from human serum can be performed using allergen chips. Since many details of the molecular mechanism and pathogenesis of skin cancer and inflammatory skin diseases and the effect of xenobiotics on cells of the human skin are still not known, array-technologies are a powerful tool to identify novel marker genes and offer the possibility of develop new therapeutic strategies as well as prognosis- and diagnosis-systems.
Morris, Jonathan C.; Oltean, Sebastian; Donaldson, Lucy F.
More than 95% of genes in the human genome are alternatively spliced to form multiple transcripts, often encoding proteins with differing or opposing function. The control of alternative splicing is now being elucidated, and with this comes the opportunity to develop modulators of alternative splicing that can control cellular function. A number of approaches have been taken to develop compounds that can experimentally, and sometimes clinically, affect splicing control, resulting in potential novel therapeutics. Here we develop the concepts that targeting alternative splicing can result in relatively specific pathway inhibitors/activators that result in dampening down of physiologic or pathologic processes, from changes in muscle physiology to altering angiogenesis or pain. The targets and pharmacology of some of the current inhibitors/activators of alternative splicing are demonstrated and future directions discussed. PMID:28034912
Deshmukh, Aparna; Radha, S.; Khan, Y.; Tilak, Priya
Nanoparticles are being explored in the targeted drug delivery of pharmacological agents : angiogenesis being one such novel application which involves formation of new blood vessels or branching of existing ones. The present study involves the use of ferrite nanoparticles for precise therapeutic modulation of angiogenesis. The ferrite nanoparticles synthesized by co-precipitation of ferrous and ferric salts by a suitable base, were found to be 10-20 nm from X-ray diffraction and TEM measurements. The magnetization measurements showed superparamagnetic behavior of the uncoated nanoparticles. These ferrite nanoparticles were found to be bio-compatible with lymphocytes and neural cell lines from the biochemical assays. The chick chorioallantoic membrane(CAM) from the shell of fertile white Leghorn eggs was chosen as a model to study angiogenic activity. An enhancement in the angiogenic activity in the CAM due to addition of uncoated ferrite nanoparticles was observed.
Hodgson, W C
1. Australia has some of the most venomous fauna in the world. Although humans are not usually perceived as being predators against these animals they are often envenomated, accidentally or otherwise. This has led to the development of antivenoms against some of the potentially lethal venoms. However, further understanding of the mechanism(s) of action of these and other venoms is important, not only for developing new treatment strategies but also in the search for novel research tools. 2. The present review discusses the pharmacology of some of the components found in venoms and outlines the research undertaken on some of Australia's venomous animals, with the exception of snakes. 3. Biogenic amines, peptides and enzymes are common venom components and produce a wide range of effects in envenomated humans. For example, respiratory failure observed after envenomation by the box jellyfish (Chirnex fleckeri) and Sydney funnel-web spider (Atrax robustus) is most likely due to potent neurotoxins in the venoms. Stonefish (Synanceja trachynis) and platypus (Ornithorhynchus anatinus) venoms, although not considered lethal, cause severe pain. However, the components responsible for these effects have not been isolated. Venom components, as yet unidentified, may be responsible for the cutaneous necrotic lesions that have been reported after some spider bites (e.g. Lampona cylindrata). Other venoms, such as those of the jumper ant (Myrmecia pilosula) and bull ant (M. pyriformis), may produce only mild skin irritation to the majority of humans but a severe anaphylactic response in sensitized victims. 4. While there has been a renewed interest in toxinology, further research is required to fully elucidate the pharmacological action of many of these venoms.
Gross, M.; Bürli, R.; Jones, P.; Garcia, M.; Batiste, B.; Kaizerman, J.; Moser, H.; Jiang, V.; Hoch, U.; Duan, J.-X.; Tanaka, R.; Johnson, K. W.
Heteroaromatic polycycle (HARP) compounds are a novel class of small (Mw, 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics. PMID:14576101
Mace, O J; Tehan, B; Marshall, F
Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of
Krafte, D S; Davison, K; Dugrenier, N; Estep, K; Josef, K; Barchi, R L; Kallen, R G; Silver, P J; Ezrin, A M
Pharmacological modulation of human sodium current was examined in Xenopus oocytes expressing human heart Na+ channels. Na+ currents activated near -50 mV with maximum current amplitudes observed at -20 mV. Steady-state inactivation was characterized by a V1/2 value of -57 +/- 0.5 mV and a slope factor (k) of 7.3 +/- 0.3 mV. Sodium currents were blocked by tetrodotoxin with an IC50 value of 1.8 microM. These properties are consistent with those of Na+ channels expressed in mammalian myocardial cells. We have investigated the effects of several pharmacological agents which, with the exception of lidocaine, have not been characterized against cRNA-derived Na+ channels expressed in Xenopus oocytes. Lidocaine, quinidine and flecainide blocked resting Na+ channels with IC50 values of 521 microM, 198 microM, and 41 microM, respectively. Use-dependent block was also observed for all three agents, but concentrations necessary to induce block were higher than expected for quinidine and flecainide. This may reflect differences arising due to expression in the Xenopus oocyte system or could be a true difference in the interaction between human cardiac Na+ channels and these drugs compared to other mammalian Na+ channels. Importantly, however, this result would not have been predicted based upon previous studies of mammalian cardiac Na+ channels. The effects of DPI 201-106, RWJ 24517, and BDF 9148 were also tested and all three agents slowed and/or removed Na+ current inactivation, reduced peak current amplitudes, and induced use-dependent block. These data suggest that the alpha-subunit is the site of interaction between cardiac Na+ channels and Class I antiarrhythmic drugs as well as inactivation modifiers such as DPI 201-106.
Melas, Ioannis N; Kretsos, Kosmas; Alexopoulos, Leonidas G
Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the late-stage clinical trials. The different questions addressed during each stage of drug R&D has led to the emergence of different modeling methodologies. In the research phase, systems biology couples experimental data with elaborate computational modeling techniques to capture lifecycle and effector cellular functions (e.g. metabolism, signaling, transcription regulation, protein synthesis and interaction) and integrates them in quantitative models. These models are subsequently used in various ways, i.e. to identify new targets, generate testable hypotheses, gain insights on the drug's mode of action (MOA), translate preclinical findings, and assess the potential of clinical drug efficacy and toxicity. In the development phase, pharmacokinetic/pharmacodynamic (PK/PD) modeling is the established way to determine safe and efficacious doses for testing at increasingly larger, and more pertinent to the target indication, cohorts of subjects. First, the relationship between drug input and its concentration in plasma is established. Second, the relationship between this concentration and desired or undesired PD responses is ascertained. Recognizing that the interface of systems biology with PK/PD will facilitate drug development, systems pharmacology came into existence, combining methods from PK/PD modeling and systems engineering explicitly to account for the implicated mechanisms of the target system in the study of drug–target interactions. Herein, a number of popular system biology methodologies are discussed, which could be leveraged within a systems pharmacology framework to address major issues in drug development. PMID:23983165
Kanabus, M; Heales, S J; Rahman, S
Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24116962
Ali, B H; Blunden, Gerald
The seeds of Nigella sativa Linn. (Ranunculaceae), commonly known as black seed or black cumin, are used in folk (herbal) medicine all over the world for the treatment and prevention of a number of diseases and conditions that include asthma, diarrhoea and dyslipidaemia. This article reviews the main reports of the pharmacological and toxicological properties of N. sativa and its constituents. The seeds contain both fixed and essential oils, proteins, alkaloids and saponin. Much of the biological activity of the seeds has been shown to be due to thymoquinone, the major component of the essential oil, but which is also present in the fi ed oil. The pharmacological actions of the crude extracts of the seeds (and some of its active constituents, e.g. volatile oil and thymoquinone) that have been reported include protection against nephrotoxicity and hepatotoxicity induced by either disease or chemicals. The seeds/oil have antiinflammatory, analgesic, antipyretic, antimicrobial and antineoplastic activity. The oil decreases blood pressure and increases respiration. Treatment of rats with the seed extract for up to 12 weeks has been reported to induce changes in the haemogram that include an increase in both the packed cell volume (PCV) and haemoglobin (Hb), and a decrease in plasma concentrations of cholesterol, triglycerides and glucose. The seeds are characterized by a very low degree of toxicity. Two cases of contact dermatitis in two individuals have been reported following topical use. Administration of either the seed extract or its oil has been shown not to induce significant adverse effects on liver or kidney functions. It would appear that the beneficial effects of the use of the seeds and thymoquinone might be related to their cytoprotective and antioxidant actions, and to their effect on some mediators of inflammation.
Grigoriou, Stefania S.; Karatzaferi, Christina; Sakkas, Giorgos K.
Depression is a mental disorder with a high prevalence among patients with end stage renal disease (ESRD). It is reported that depression afflicts approximately 20-30% of this patient population, being associated, amongst other, with high mortality rate, low adherence to medication and low perceived quality of life. There is a variety of medications known to be effective for the treatment of depression but due to poor adherence to treatment as well as due to the high need for medications addressing other ESRD comorbidities, depression often remains untreated. According to the literature, depression is under-diagnosed and undertreated in the majority of the patients with chronic kidney disease. In the current review the main pharmacological and non-pharmacological approaches and research outcomes for the management of depressive symptoms in hemodialysis patients are discussed. PMID:26973957
A novel functional‐genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in “big data” providing comprehensive information about the drugs’ targets and their functional genomics is proposed. In “process pharmacology”, drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high‐dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. PMID:27069773
Dutra, Rafael C; Campos, Maria M; Santos, Adair R S; Calixto, João B
This review article focuses on pre-clinical and clinical studies with some selected Brazilian medicinal plants in different areas of interest, conducted by research groups in Brazil and abroad. It also highlights the Brazilian market of herbal products and the efforts of Brazilian scientists to develop new phytomedicines. This review is divided into three sections. The section I describes the Brazilian large biodiversity and some attempts of Brazilian scientists to assess the pharmacological profile of most plant extracts or isolated active principles. Of note, Brazilian scientists have made a great effort to study the Brazilian biodiversity, especially among the higher plants. In fact, more than 10,000 papers were published on plants in international scientific journals between 2011 and 2013. This first part also discussed the main efforts to develop new medicines from plants, highlighting the Brazilian phytomedicines market. Despite the large Brazilian biodiversity, notably with the higher plants, which comprise over 45,000 species (20-22% of the total worldwide), and the substantial number of scientific publications on medicinal plants, only one phytomedicine is found in the top 20 market products. Indeed, this market is still only worth about 261 million American dollars. This represents less than 5% of the global Brazilian medicine market. The section II of this review focus on the use of Brazilian plant extract and/or active principles for some selected diseases, namely: central nervous systems disorders, pain, immune response and inflammation, respiratory diseases, gastrointestinal tract and metabolic diseases. Finally, section III discusses in more details some selected Brazilian medicinal plants including: Cordia verbenacea, Euphorbia tirucalli, Mandevilla velutina, Phyllanthus spp., Euterpe oleracea, Vitis labrusca, Hypericum caprifoliatum and Hypericum polyanthemum, Maytenus ilicifolia, Protium kleinii and Protium heptaphylium and Trichilia catigua. Most
Heart failure is one of the most common diagnoses and reason for hospitalization in the United States. Ace inhibitors, diuretics, beta-blockers and digitalis are the leading agents in pharmacologic management of heart failure. In order to improve patient outcomes, adult-health nurses need to understand the diagnosis, pathophysiology, nursing interventions, and pharmacologic treatment of this common disorder.
Seen as daunting and stressful, pharmacology is often rejected by student nurses. This discipline requires and draws on multiple skills. When future nurses realise that their prescribing role goes beyond simple execution, they are able to appreciate the full scope of pharmacology.
Robertson, Lee T.
A survey of 51 of the 53 dental schools in the continental United States investigated pharmacology curriculum content and time allocation. Found that most schools offered a traditional didactic course in basic pharmacology, with half of the medical school-based and three-fourths of the dental school-based programs providing additional pharmacology…
Csaky, T. Z.
Rudolf Buchheim's thesis on why and how to teach pharmacology to medical students is reexamined in view of the so-called identity crisis. It is suggested that the crisis is not one of identity but one of acceptance of medical school pharmacology by clinical colleagues and professional educators. (LBH)
Talbert, Robert L.; Walton, Charles A.
The impact of the clinical faculty on the content of the pharmacology course is described in a discussion of trends in pharmacology instruction. Interfaculty communication and development of course objectives are reviewed, and descriptions of two baccalaureate courses at the University of Texas College of Pharmacy are appended. (LBH)
Branch, Marc N.
Behavioral pharmacology is a maturing science that has made significant contributions to the study of drug effects on behavior, especially in the domain of drug-behavior interactions. Less appreciated is that research in behavioral pharmacology can have, and has had, implications for the experimental analysis of behavior, especially its…
Carey, Erin T; Till, Sara R; As-Sanie, Sawsan
Chronic pelvic pain (CPP) is a multifaceted condition that often has both peripheral and central generators of pain. An understanding of neurobiology and neuropsychology of CPP should guide management. Successful treatment of CPP is typically multimodal, and pharmacologic treatment strategies include analgesics, hormonal suppression, anesthetics, antidepressants, membrane stabilizers, and anxiolytics. Evidence for these and other emerging pharmacologic therapies is presented in this article.
Kumar, R N; Chambers, W A; Pertwee, R G
This review highlights the pharmacology, pharmacokinetics, pharmacological actions, therapeutic uses and adverse effects of cannabinoids. The effect of cannabinoids on anaesthesia is mentioned briefly. Important advances have taken place in cannabinoid research over the last few years and have led to the discovery of novel ligands. The possible clinical applications of these ligands and the direction of future research are discussed.
MacDonald, Ewen; Saarti, Jarmo
In 2005, we were able to digitally record the so-called pharmacology songbook; a set of songs with lyrics devoted to pharmacological topics. A CD was prepared entitled The Beta-blocker Blues and its contents are now all freely available in mp3 format from our web page (Ewen MacDonald & friends, 2005). The web page also contains the lyrics and…
Wu, Yan-Qing; Zhou, Ying-Wu; Qin, Xiu-de; Hua, Sheng-Yu; Zhang, Yu-Lian; Kang, Li-Yuan
Despite many successful applications of Chinese herbal medicine (CHM) in the treatment and prevention of neurological diseases (ND), the fully scientific understanding of CHM's action mechanisms had been hampered for lack of appropriate methods to explore the combinatorial rules, the synergistic mechanisms, and the molecular basis of CHM. As an improved pharmacology approach, cerebrospinal fluid pharmacology (CSFP), based on the fact that cerebrospinal fluid plays an important role in the health maintenance of specific survival environment for neurons and glial cells, has been constructed and applied to CHM research for treating ND. In the present review, the concept and advantages of CSFP are briefly introduced. The approaches and key technologies of CSFP in CHM research are also collated and analyzed. Furthermore, the developing tendency of CSFP is summarized, and its framework in CHM research is also proposed. In summary, CSFP provides a new strategy not only to eliminate some barriers of CHM research for treating ND, but also to broaden the pharmacology research for bridging the gap between CHM and modern medicine. Moreover, the advancements in CSFP will bring about a conceptual move in active ingredients discovery of CHM and make a significant contribution to CHM modernization and globalization.
Carnevali, Luca; Rivara, Silvia; Nalivaiko, Eugene; Thayer, Julian F; Vacondio, Federica; Mor, Marco; Sgoifo, Andrea
Numerous studies have documented a link between psychological disorders and cardiac disease. Yet, no systematic attempts have been made to develop pharmacological approaches for mood and anxiety disorders that could also be beneficial for cardiac health. The endocannabinoid system has been implicated in the regulation of stress, emotional behavior and cardiovascular function. General preclinical findings indicate that the endocannabinoid anandamide modulates physiological and behavioral stress responses and may also protect the heart from arrhythmias. Moreover, recent experimental studies suggest that pharmacological enhancement of anandamide signaling via inhibition of its degrading enzyme fatty acid amide hydrolase (FAAH) exerts anxiolytic- and antidepressive-like effects and improves cardiac autonomic function and the electrical stability of the myocardium in rodent models that reproduce aspects of human psychological/cardiac comorbidity. Here we summarize and discuss such experimental findings, which might guide future preclinical studies towards a systematic evaluation of the therapeutic potential of pharmacological approaches that target FAAH activity for the treatment of the comorbidity between psychological disorders and cardiac disease.
Over the years, multiple forms and doses of pharmacologic agents have been used for cervical ripening and labor induction. This chapter will review potential criteria and article situations for choosing a particular pharmacologic agent. The discussion in this chapter will be limited to comparisons between pharmacologic agents; direct comparisons between mechanical agents and pharmacologic agents will largely be reviewed in the accompanying article: Methods of cervical ripening and labor induction: mechanical. For the purposes of this discussion, the term labor induction will be limited to patients with a "favorable cervix" by Bishop's score <6, whereas the term cervical ripening will be limited to patients with an unfavorable cervix and includes subsequent induction or augmentation of labor. Although the pharmacologic agent used for the initial cervical ripening process is the focus of this discussion, subsequent treatment with oxytocin may or may not be required for delivery.
Hassett, Afton L; Williams, David A
Individuals with chronic widespread pain, including those with fibromyalgia, pose a particular challenge to treatment, given the modest effectiveness of pharmacological agents for this condition. The growing consensus indicates that the best approach to treatment involves the combination of pharmacological and non-pharmacological interventions. Several non-pharmacological interventions, particularly exercise and cognitive-behavioural therapy (CBT), have garnered good evidence of effectiveness as stand-alone, adjunctive treatments for patients with chronic pain. In this article, evidenced-based, non-pharmacological management techniques for chronic widespread pain are described by using two broad categories, exercise and CBT. The evidence for decreasing pain, improving functioning and changing secondary symptoms is highlighted. Lastly, the methods by which exercise and CBT can be combined for a multi-component approach, which is consistent with the current evidence-based guidelines of several American and European medical societies, are addressed.
Dávalos, Alberto; Fernández-Hernando, Carlos
There has been strong evolutionary pressure to ensure that an animal cell maintain levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies. PMID:23435093
Furlong, Michael T; Ouyang, Zheng; Wu, Steven; Tamura, James; Olah, Timothy; Tymiak, Adrienne; Jemal, Mohammed
For the development of human antibody Fc (fraction crystallizable) region-containing therapeutic protein candidates, which can be either monoclonal antibodies (mAbs) or pharmacologically active proteins/peptides fused to the Fc region of human Immunoglobulin G (IgG), reliable quantification of these proteins in animal pharmacokinetic study plasma samples is critical. LC-MS/MS has emerged as a promising assay platform for this purpose. LC-MS/MS assays used for bioanalysis of human antibody Fc region-containing therapeutic protein candidates frequently rely upon quantification of a 'signature' surrogate peptide whose sequence is unique to the protein analyte of interest. One drawback of the signature peptide approach is that a new LC-MS/MS assay must be developed for each new human Fc region-containing therapeutic protein. To address this issue, we propose an alternative 'universal surrogate peptide' approach for the quantification of human antibody Fc region-containing therapeutic protein candidates in plasma samples from all nonclinical species. A single surrogate tryptic peptide was identified in the Fc region of most human antibody Fc-containing therapeutic protein candidates. An LC-MS-MS method based upon this peptide was shown to be capable of supporting bioanalysis of a diversity of human Fc region-containing therapeutic protein candidates in plasma samples of all commonly used animal species.
Schwarz, Adam J; Danckaert, Anne; Reese, Torsten; Gozzi, Alessandro; Paxinos, George; Watson, Charles; Merlo-Pich, Emilio V; Bifone, Angelo
We describe a stereotaxic rat brain MRI template set with a co-registered digital anatomical atlas and illustrate its application to the analysis of a pharmacological MRI (phMRI) study of apomorphine. The template set includes anatomical images and tissue class probability maps for brain parenchyma and cerebrospinal fluid (CSF). These facilitate the use of standard fMRI software for spatial normalisation and tissue segmentation of rat brain data. A volumetric reconstruction of the Paxinos and Watson rat brain atlas is also co-localised with the template, enabling the atlas structure and stereotaxic coordinates corresponding to a feature within a statistical map to be interactively reported, facilitating the localisation of functional effects. Moreover, voxels falling within selected brain structures can be combined to define anatomically based 3D volumes of interest (VOIs), free of operator bias. As many atlas structures are small relative to the typical resolution of phMRI studies, a mechanism for defining composite structures as agglomerations of individual atlas structures is also described. This provides a simple and robust means of interrogating structures that are otherwise difficult to delineate and an objective framework for comparing and classifying compounds based on an anatomical profile of their activity. These developments allow a closer alignment of pre-clinical and clinical analysis techniques.
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Siasios, Ioannis; Kapsalaki, Eftychia Z; Fountas, Kostas N
Aneurysmal subarachnoid hemorrhage- (aSAH-) associated vasospasm constitutes a clinicopathological entity, in which reversible vasculopathy, impaired autoregulatory function, and hypovolemia take place, and lead to the reduction of cerebral perfusion and finally ischemia. Cerebral vasospasm begins most often on the third day after the ictal event and reaches the maximum on the 5th-7th postictal days. Several therapeutic modalities have been employed for preventing or reversing cerebral vasospasm. Triple "H" therapy, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators, administration of substances like magnesium sulfate, statins, fasudil hydrochloride, erythropoietin, endothelin-1 antagonists, nitric oxide progenitors, and sildenafil, are some of the therapeutic protocols, which are currently employed for managing patients with aSAH. Intense pathophysiological mechanism research has led to the identification of various mediators of cerebral vasospasm, such as endothelium-derived, vascular smooth muscle-derived, proinflammatory mediators, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Oral, intravenous, or intra-arterial administration of antagonists of these mediators has been suggested for treating patients suffering a-SAH vasospam. In our current study, we attempt to summate all the available pharmacological treatment modalities for managing vasospasm.
Siasios, Ioannis; Kapsalaki, Eftychia Z.; Fountas, Kostas N.
Aneurysmal subarachnoid hemorrhage- (aSAH-) associated vasospasm constitutes a clinicopathological entity, in which reversible vasculopathy, impaired autoregulatory function, and hypovolemia take place, and lead to the reduction of cerebral perfusion and finally ischemia. Cerebral vasospasm begins most often on the third day after the ictal event and reaches the maximum on the 5th–7th postictal days. Several therapeutic modalities have been employed for preventing or reversing cerebral vasospasm. Triple “H” therapy, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators, administration of substances like magnesium sulfate, statins, fasudil hydrochloride, erythropoietin, endothelin-1 antagonists, nitric oxide progenitors, and sildenafil, are some of the therapeutic protocols, which are currently employed for managing patients with aSAH. Intense pathophysiological mechanism research has led to the identification of various mediators of cerebral vasospasm, such as endothelium-derived, vascular smooth muscle-derived, proinflammatory mediators, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Oral, intravenous, or intra-arterial administration of antagonists of these mediators has been suggested for treating patients suffering a-SAH vasospam. In our current study, we attempt to summate all the available pharmacological treatment modalities for managing vasospasm. PMID:23431440
Domínguez-Clavé, Elisabet; Soler, Joaquim; Elices, Matilde; Pascual, Juan C; Álvarez, Enrique; de la Fuente Revenga, Mario; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi
Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders.
Guastella, Virginie; Mick, Gérard; Laurent, Bernard
Nondrug treatments of neuropathic pain should always begin at the same time as pharmacologic treatment. There are three types of nondrug treatment for neuropathic pain: physical, surgical, and "psychocorporal" and psychotherapeutic treatment. Transcutaneous electrical nerve stimulation (TENS) is a simple physical treatment that strengthens local inhibitory controls and is indicated in focal neuropathic pain when upstream stimulation is possible for a superficial sensitive nerve trunk. Destructive surgery is represented today by "DREZotomy", destruction of nociceptive fibers and their dorsal root entry zones. It is indicated essentially in intractable pain due to plexus avulsion. Functional surgery is implanted electric stimulation--either spinal or central (encephalic)--of structures that exert inhibitory control on the pain pathways. Spinal stimulation is performed at the level of the posterior spinal cord and is indicated essentially in segmental mononeuropathies refractory to drug treatment. Central stimulation is performed at the motor cortex and is indicated for refractory central pain. "Psychocorporal" techniques (relaxation, sophrology, hypnosis) are useful to reduce anxiety and neurovegetative hypertonicity, both factors that aggravate neuropathic pain.
Jadhav, Amol D.; Wei, Li; Shi, Peng
Dissociated primary neuronal cell culture remains an indispensable approach for neurobiology research in order to investigate basic mechanisms underlying diverse neuronal functions, drug screening and pharmacological investigation. Compartmentalization, a widely adopted technique since its emergence in 1970s enables spatial segregation of neuronal segments and detailed investigation that is otherwise limited with traditional culture methods. Although these compartmental chambers (e.g. Campenot chamber) have been proven valuable for the investigation of Peripheral Nervous System (PNS) neurons and to some extent within Central Nervous System (CNS) neurons, their utility has remained limited given the arduous manufacturing process, incompatibility with high-resolution optical imaging and limited throughput. The development in the area of microfabrication and microfluidics has enabled creation of next generation compartmentalized devices that are cheap, easy to manufacture, require reduced sample volumes, enable precise control over the cellular microenvironment both spatially as well as temporally, and permit highthroughput testing. In this review we briefly evaluate the various compartmentalization tools used for neurobiological research, and highlight application of the emerging microfluidic platforms towards in vitro single cell neurobiology. PMID:26813122
Ramalingam, Mahesh; Kim, Sung-Jin
Liriopogons (Liriope and Opiopogon) species are used as a main medicinal ingredient in several Asian countries. The Liriopes Radix (tuber, root of Liriope platyphylla) has to be a promising candidate due to their source of phytochemicals. Steroidal saponins and their glycosides, phenolic compounds, secondary metabolites are considered of active constituents in Liriopes Radix. Spicatoside A, a steroidal saponin, could be more efficacious drug candidate in future. In this review, we summarized the available knowledge on phytochemical and pharmacological activities for spicatoside A. It significantly suppressed the level of NF-κB, NO, iNOS, Cox-2, IL-1β, IL-6 and MAPKs in LPS-stimulated inflammation. The production of MUC5AC mucin was increased. MMP-13 expression was down-regulated in IL-1β-treated cells and reduced glycosaminoglycan release from IL-1α-treated cells. The neurite outgrowth activity, PI3K, Akt, ERK1/2, TrkA and CREB phosphorylation and neurotropic factors such as NGF and BDNF were upregulated with increased latency time. It also showed cell growth inhibitory activity on various carcinoma cells. From this, spicatoside A exerts anti-inflammation, anti-asthma, anti-osteoclastogenesis, neurite outgrowth, memory consolidation and anticancer activities. Further studies are needed on spicatoside A in order to understand mechanisms of action to treat various human diseases. PMID:27169821
Scriabine, A.; Anderson, C.L.; Janis, R.A.; Kojima, K.; Rasmussen, H.; Lee, S.; Michal, U.
The available evidence indicates that nitrendipine and other dihydropyridines with a similar pharmacological action exert their therapeutic effects by inhibiting Ca/sup 2 +/ channels. In recent experiments, nitrendipine was shown to block K+-stimulated /sup 45/Ca/sup 2 +/ uptake and K+-induced contractions of isolated rabbit aortic rings. Its IC/sub 50/ were 4.7 and 8.9 nM for inhibition of Ca/sup 2 +/ uptake and of contractions, respectively. At higher concentrations, nitrendipine also reduced norepinephrine-induced /sup 45/Ca/sup 2 +/ uptake and norepinephrine-induced contractions of rabbit aortic strips. The norepinephrine-induced contractions were only slightly (21%) reduced by nitrendipine at 10 microM. Nitrendipine at 10 nM and higher concentrations inhibited K+- or angiotensin-II-(AII) induced release of aldosterone from isolated bovine adrenal glomerulosa cells. Dantrolene, 25 microM, enhanced the inhibitory activity of nitrendipine on AII-stimulated aldosterone release. Acute renal failure produced by either glycerol or gentamicin in rats was antagonized by nitrendipine at oral doses of 15-25 mg/kg/day. The studies confirmed previously reported observations that the usefulness of nitrendipine in the treatment of hypertension may be determined not only by its vasodilator action.
Collado, Antonio; Conesa, Arantxa
Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients.
Jadhav, Amol D; Wei, Li; Shi, Peng
Dissociated primary neuronal cell culture remains an indispensable approach for neurobiology research in order to investigate basic mechanisms underlying diverse neuronal functions, drug screening and pharmacological investigation. Compartmentalization, a widely adopted technique since its emergence in 1970s enables spatial segregation of neuronal segments and detailed investigation that is otherwise limited with traditional culture methods. Although these compartmental chambers (e.g. Campenot chamber) have been proven valuable for the investigation of Peripheral Nervous System (PNS) neurons and to some extent within Central Nervous System (CNS) neurons, their utility has remained limited given the arduous manufacturing process, incompatibility with high-resolution optical imaging and limited throughput. The development in the area of microfabrication and microfluidics has enabled creation of next generation compartmentalized devices that are cheap, easy to manufacture, require reduced sample volumes, enable precise control over the cellular microenvironment both spatially as well as temporally, and permit highthroughput testing. In this review we briefly evaluate the various compartmentalization tools used for neurobiological research, and highlight application of the emerging microfluidic platforms towards in vitro single cell neurobiology.
Mauri, M.C.; Paletta, S.; Maffini, M.; Colasanti, A.; Dragogna, F.; Di Pace, C.; Altamura, A.C.
This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects. PMID:26417330
Mohammadi, Hakimeh; Bienzle, Dorothee
Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses and causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Due to marked similarity in genomic organization, virus structure, virus replication and disease pathogenesis of FIV and HIV, infection of cats with FIV is a useful tool to study and develop novel drugs and vaccines for HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: (1) inhibition of virus entry into susceptible cells at the level of attachment to host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus membrane with the cell membrane; (3) blockade of reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and viral DNA integration into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy slowing disease progression in people, similar therapy has not been thoroughly investigated in cats. In this article we review current pharmacological approaches and novel targets for anti-lentiviral therapy, and critically assess potentially suitable applications against FIV infection in cats. PMID:22754645
Mackenzie, A H
The pharmacokinetics, physiologic effects, and the metabolization of chloroquine and hydroxychloroquine are all similar. Their concentrations in plasma and tissue are directly related to daily dosing. The highest concentrations are found in melanin-containing tissues, particularly the choroid and ciliary body of the eye. The pharmacologic effects of 4-aminoquinoline compounds are reviewed in detail. It is likely that the rheumatologic effectiveness of these agents is primarily related to lysosomal actions. The drug-induced lysosomal abnormalities include diminished vesicle fusion, diminished exocytosis, and reversible "lysosomal storage disease." It is likely that the retinal toxicity of these drugs is one manifestation of the altered lysosomal physiology involving the retinal pigmented epithelium. Tissue of retinal pigmented epithelium is similar to that of the bone-marrow-derived macrophage. Depression of extra-oculogram is an early sign of excessive dosage and can be used to measure potential toxicity during therapy with 4-aminoquinolines. Dosages ranging from 3.5 to 4.0 mg/kg per day for chloroquine and 6.0 to 6.5 mg/kg per day for hydroxychloroquine are clinically safe.
Hunter, Robert P; Isaza, Ramiro
Lack of approved pharmaceutical agents and/or pharmacokinetic data in the literature for exotic, wildlife, and zoo species is a major issue for veterinarians. These practitioners must take approved agents (veterinary or human) and extrapolate their use to non-approved species with little or no scientific basis to support this decision. There is little information concerning pharmacokinetic parameters for drugs in non-domestic species. Zoo veterinarians often have to formulate the medication(s) into a meal, hoping that the animal will ingest it. Due to lack of patient compliance, the veterinarian may have to resort to other means of drug administration. Additionally, due to the value of these animals, the traditional method of 'trial and error' for treatment selection and resulting compliance is often inappropriate, and lends itself to a mentality where no zoo veterinarian wants to be the first to administer an agent/formulation in an untested species. This review intends to present the current state of zoological pharmacology and the direction it may be heading.
al-Zuhair, H; el-Sayeh, B; Ameen, H A; al-Shoora, H
Cardamom seeds are widely used for flavouring purposes in food and as carminative. Little information has been reported on their pharmacological and toxicological properties or, for their volatile oil which constitutes about 5% of the seed's total weight. A comparative study of the anti-inflammatory activity of the oil extracted from commercial Elettaria cardamomum seeds, in doses of 175 and 280 microliters/kg and indomethacin in a dose of 30 mg/kg against acute carrageenan-induced planter oedema in male albino rats was performed, which proved to be marked. Moreover, investigation of the analgesic activity using p-benzoquinone as a chemical stimulus proved that a dose of 233 microliters/kg of the oil produced 50% protection against the writhing (stretching syndrome) induced by intraperitoneal administration of a 0.02% solution of p-benzoquinone in mice. In addition the antispasmodic activity was determined on a rabbit intestine preparation using acetylcholine as agonist, the results proving that cardamom oil exerts its antispasmodic action through muscarinic receptor blockage.
Halford, Jason C G; Cooper, Gillian D; Dovey, Terence M
The discovery of the adiposity signal leptin a decade ago revolutionised our understanding of the hypothalamic mechanisms underpinning the central control of ingestive behaviour. Subsequently, the structure and function of various hypothalamic peptide systems (Neuropeptide Y (NPY), Orexins, Melanocortins, Cocaine and Amphetamine Regulating Transcript (CART), Galanin/Galanin Like Peptides (GALP) and endocannabinoids) have been characterised in detail in rodent models. The therapeutic benefit of targeting these systems remains to be discovered. More is becoming known about the pharmacological potential of peripheral, meal-induced, episodic endogenous peptides. Hormones such as Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Glucagon-Like Peptide I (GLP-1) Enterostatin, Amylin, Peptide YY (PYY) and Ghrelin are released prior to, during and/or after a meal, controlling intake and subjective feelings of appetite (hunger and satiety). In addition, there is an expanding body of literature detailing the effects of a wide variety of drugs on human appetite and food intake. Some of these drugs act upon CNS monoamine systems such as Serotonin (5-HT). Dopamine (DA) and Noradrenaline (NA), have long been implicated in appetite regulation. Detailed examination of both the effect of agonising endogenous gut peptide systems and the effect of various monoaminergic drugs on the expression of human appetite can provide a greater understanding of mechanisms underpinning normal appetite regulation. However, such an understanding must be based on knowledge of the effect of the treatment on meal size, eating rate, meal pattern, food choice and the subjective experience of appetite flux (hunger and satiety), and notjust food intake.
Hamdam, Junnat; Sethu, Swaminathan; Smith, Trevor; Alfirevic, Ana; Alhaidari, Mohammad; Atkinson, Jeffrey; Ayala, Mimieveshiofuo; Box, Helen; Cross, Michael; Delaunois, Annie; Dermody, Ailsa; Govindappa, Karthik; Guillon, Jean-Michel; Jenkins, Rosalind; Kenna, Gerry; Lemmer, Björn; Meecham, Ken; Olayanju, Adedamola; Pestel, Sabine; Rothfuss, Andreas; and others
Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. - Highlights: • SP — mandatory non-clinical risk assessments performed during drug development. • SP organ system studies ensure the safety of clinical participants in FiH trials. • Frontloading in SP facilitates lead candidate drug selection. • Emerging trends: integrating SP-Toxicological endpoints; combined core battery tests.
Cotelli, Maria; Manenti, Rosa; Zanetti, Orazio; Miniussi, Carlo
Non-pharmacological intervention of memory difficulties in healthy older adults, as well as those with brain damage and neurodegenerative disorders, has gained much attention in recent years. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human central nervous and the discovery that during aging, the connections in the brain are not fixed but retain the capacity to change with learning. Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation [i.e., repetitive transcranial magnetic stimulation and transcranial direct current stimulation to specific cortical areas]. The present review provides an overview of memory rehabilitation in individuals with mild cognitive impairment and in patients with Alzheimer's disease with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits, memory intervention therapy could lead to performance improvements in memory, nevertheless further studies need to be conducted in order to establish the real value of this approach.
Gurevich, E V; Gurevich, V V
Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder.
Elgoyhen, Ana B.; Langguth, Berthold; Vanneste, Sven; De Ridder, Dirk
Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for one in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single Food and Drug Administration (FDA)-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system (CNS) disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in CNS pathologies is changing from that of “magic bullets” that target individual chemoreceptors or “disease-causing genes” into that of “magic shotguns,” “promiscuous” or “dirty drugs” that target “disease-causing networks,” also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy. PMID:22291622
Rang, H P
Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs. Receptors, therefore, lie at the heart of pharmacology. This article describes the way in which the receptor concept originated early in the 20th century, and evolved through a highly innovative stage of quantitative theory based on chemical kinetics, to the point where receptors were first isolated and later cloned, until we now have a virtually complete catalogue of all the receptors present in the genome. Studies on signal transduction are revealing great complexity in the events linking ligand binding to the physiological or therapeutic response. Though some simple quantitative rules of ‘receptor theory' are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of ‘receptor theory'. PMID:16402126
Aronson, Jeffrey K
A thorough analysis of a case that involves a medication that may have caused or contributed to an adverse outcome, or a comparison of two compounds in a patent dispute, requires consideration of many processes that affect the clinical effects of a medication. These include its chemical structure, its pharmacological actions (pharmacodynamics), the pharmaceutical formulation, and its absorption, distribution, metabolism, and excretion (pharmacokinetics). They also include analysis of clinical details, including the diagnosis, the quality of the prescribing decisions, the accuracy of the prescription, dispensing, and administration of medications, and how appropriately the case was managed, including monitoring. A causality assessment should be attempted for both the general case and the particular case. Knowledge of the systems that describe a medication's mechanisms of action (EIDOS) and the dose-relationships and time-courses of adverse outcomes and individual susceptibilities to them (DoTS) can inform several aspects of the analysis. Reports should be written in clear English and should not contain statements that rely on expertise that the expert does not possess.
Chronic insomnia, i. e. complaints about prolonged sleep onset, difficulties in maintaining sleep, early morning awakening and associated impairments of daytime functioning afflicts approximately 10 % of the population in most Western industrialized countries. Chronic insomnia can be due to somatic disorders, mental disorders, intake of medications, legal or illicit drugs. One third of all patients with chronic insomnias suffers from primary insomnia, a diagnosis which is given when none of the above mentioned factors can be identified as a causal factor. In medical practice, insomnia usually is treated with hypnotic drugs or other sedative drugs such as antidepressants. In the last 20 years it was shown that cognitive-behavioral therapy for insomnia can be applied successfully independent of causal factors. Cognitive-behavioral treatment for insomnia (CBT-I) encompasses psychoeducation about sleep and sleep hygiene, relaxation techniques, i. e. progressive muscle relaxation, specific behavioral techniques like stimulus control or sleep restriction and cognitive techniques to reduce nocturnal ruminations. Several published meta-analyses from the last two decades showed that these techniques, especially in their combined form, can be considered as evidence-based. It was shown that they are as effective as pharmacological therapy in the short-term and in the long-run even superior to pharmacotherapy. Cognitive-behavioral techniques for the therapy of insomnia can be used very successfully by trained physicians and psychotherapists.
Sánchez Cisneros, Noé
The term acute coronary syndromes includes a phantom of symptomatic clinical pictures that represent the acute occlusion of the coronary arteries by diverse degrees of plate of cholesterol, clot and spasm. They are divided in acute coronary ischemic syndromes without elevation of the ST (instable angina). And with elevation of the ST (acute infarct to the myocardium). The pharmacologic therapy includes a treatment in common for the syndromes before diagnosing the tipe of syndrome, this called therapy attached treatment includes the administration of oxygen, morphine, aspirin, nitrates, betablock, astatines and laxatives. The treatment for the acute coronary ischemic syndromes without elevation of the ST is with a preservative strategy where plaquetary antithrombotic drugs are used, while in the treatment of the acute coronary ischemic syndromes with elevation of the ST the strategy is of repercussion with the fibrinolytic drugs use like streptokinase anda rt-PA. The participation of infirmary is essential during the evolution and treatment of the individual dividing in four sections its interventions according to the clinical situation and time of intervention.
Srivastava, Shalini; Chandra, Deepak
In the last few years there has been an exponential growth in the field of herbal medicine, and these drugs are gaining popularity in both developing and developed countries because of their natural origin and lesser side effects. Syzygium cumini (syn. Eugenia jambolana, Syzygium jambolana, Eugenia cumini, Syzygium jambos), commonly known as jamun in India, is an evergreen tree distributed throughout the Indian subcontinent, Southeast Asia and East Africa. It is mainly utilised as a fruit producer and for its timber. Medicinally, the fruit is reported to have antidiabetic, antihyperlipidaemic, antioxidant, antiulcer, hepatoprotective, antiallergic, antiarthritic, antimicrobial, anti-inflammatory, antifertility, antipyretic, antiplaque, radioprotective, neuropsychopharmacological, nephroprotective and antidiarrhoeal activities. Among these beneficial physiological effects, the antidiabetic property of S. cumini has the most promising nutraceutical value. The health-beneficial effects of S. cumini are mainly attributed to various phytoconstituents such as tannins, alkaloids, steroids, flavonoids, terpenoids, fatty acids, phenols, minerals, carbohydrates and vitamins present in the fruit. This review paper presents an overview of experimental evidence for the pharmacological potential of S. cumini.
van Gool, J D; Vijverberg, M A; Messer, A P; Elzinga-Plomp, A; de Jong, T P
In children with 'functional incontinence', defined as any form of (daytime) wetting caused by non-neuropathic bladder/sphincter dysfunction, most signs and symptoms are rooted in habitual non-physiological responses to signals from bladder and urethra. These responses develop at toddler age, when children learn how to remain dry. Once they have become a habit, incomplete bladder emptying and recurrent urinary tract infections come into play, reiterating the non-physiological responses into fixed patterns of bladder/sphincter dysfunction with functional incontinence as the leading symptom. Non-pharmacological treatment of functional incontinence implies relearning and training the normal responses to signals from bladder and urethra: a cognitive process, with perception of the signals reinforced by biofeedback. This type of treatment is best combined with long-term chemoprophylaxis. Severe cases will benefit from anticholinergic drugs, as adjuvants to the training programme. Urodynamics play a crucial role in documenting the specific patterns of incontinence and in providing biofeedback. For a successful programme, psychological screening of the children is indispensable.
Memantine is a relatively new drug specially developed for use in moderate-to-severe dementia. It is an uncompetitive N-methyl-D-aspartate receptor antagonist and reduces glutamatergic excitotoxicity. Though Alzheimer's disease (AD) is the commonest cause of dementia in the world, there is no "cure" available for the same. Cholinesterase inhibitors such as donepezil and rivastigmine have been shown to provide symptomatic relief in patients with AD but have no effect on disease progression or survival. Moreover, they are not helpful in more severe stages of dementia. Memantine has been shown to cause modest improvement in clinical symptoms in severe stages of AD and may retard the disease progression. Moreover, it has been shown to be useful in various forms of dementia including AD, vascular dementia and Wernicke-Korsakoff psychosis. It is also the first drug to cause complete disappearance of pendular nystagmus due to multiple sclerosis. The current review focuses on the pharmacological properties of memantine and examines the recent evidence in favor of memantine.
Shoskes, Jennifer J.; Wilson, Meghan K.
The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs). Currently the routes of delivery approved for use by the United States Food and Drug Administration encompasses buccal, nasal, subdermal, transdermal, and intramuscular (IM). Many factors must be considered when a clinician is choosing the most correct formulation for a patient. As this decision depends highly on the patient, active patient participation is important for effective selection. The aim of this review is to describe and compare all testosterone preparations currently available and approved by the United States Food and Drug Administration. Areas of focus will include pharmacology, PKs, adverse effects, and specifics related to individual delivery routes. PMID:28078214
Monoamine agonists and antagonists were applied to the lobster cardiac ganglion in an attempt to clarify the different actions of 5-hydroxytryptamine (5HT) and dopamine (DA) on this rhythmic pattern generator. Experiments were designed to determine whether the similar responses to 5HT and DA applied to the anterior region of the ganglion could be separated by pharmacological approaches, and whether the different responses to 5HT applied to the anterior and posterior regions of the ganglion could be attributed to mediation by different receptors. A small number of the 5HT agonists which were tested mimic the effects of 5HT, in that they increase the frequency of bursting and decrease burst duration when applied to the whole ganglion, but decrease burst frequency and increase burst duration when applied only to the posterior half. Other 5HT agonists decrease frequency and prolong bursts when applied to the whole ganglion. Of the DA agonists tested, none acts as DA itself does. Rather, they mimic the effects of 5HT applied to the posterior ganglion, by slowing bursting and prolonging bursts. The actions of agonists do not correspond in any clear way to the receptor specificities as defined in vertebrates. Most antagonists tested do not show similar specificities to their effects in vertebrates. In particular, most of the DA antagonists tested are more effective in blocking exogenous 5HT than DA. One monoamine agonist directly alters the properties of endogenous burst-organizing potentials (driver potentials) in the motorneurons of the ganglion.
Varamini, Pegah; Blanchfield, Joanne T; Toth, Istvan
Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment of severe pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratory depression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathic pain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, native endomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins suffer from poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier. Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesized with the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation. In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associated with endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in addition to application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approaches that resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effects are also discussed giving an insight into the development of opioid peptides with an improved side effect profile.
More, Sandeep Vasant; Choi, Dong-Kug
Parkinson's disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT-1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD. In this review, we discuss various emerging preclinical pharmacological targets that may serve as a new promising neuroprotective strategy that could actually help alleviate PD and its symptoms. PMID:26988916
Manayi, Azadeh; Vazirian, Mahdi; Saeidnia, Soodabeh
Echinacea purpurea (Asteraceae) is a perennial medicinal herb with important immunostimulatory and anti-inflammatory properties, especially the alleviation of cold symptoms. The plant also attracted scientists’ attention to assess other aspects of its beneficial effects. For instance, antianxiety, antidepression, cytotoxicity, and antimutagenicity as induced by the plant have been revealed in various studies. The findings of the clinical trials are controversial in terms of side effects. While some studies revealed the beneficial effects of the plant on the patients and no severe adverse effects, some others have reported serious side effects including abdominal pain, angioedema, dyspnea, nausea, pruritus, rash, erythema, and urticaria. Other biological activities of the plant such as antioxidant, antibacterial, antiviral, and larvicidal activities have been reported in previous experimental studies. Different classes of secondary metabolites of the plant such as alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins are believed to be biologically and pharmacologically active. Actually, concurrent determination and single analysis of cichoric acid and alkamides have been successfully developed mainly by using high-performance liquid chromatography (HPLC) coupled with different detectors including UV spectrophotometric, coulometric electrochemical, and electrospray ionization mass spectrometric detectors. The results of the studies which were controversial revealed that in spite of major experiments successfully accomplished using E. purpurea, many questions remain unanswered and future investigations may aim for complete recognition of the plant's mechanism of action using new, complementary methods. PMID:26009695
Zagorodnikova Goryachkina, Ksenia; Burbello, Aleksandra; Sychev, Dmitry; Frolov, Maxim; Kukes, Vladimir; Petrov, Vladimir
Clinical pharmacology in Russia has long history and is currently active, but rather unrecognized internationally. It is governmentally approved as a teaching/scientific specialty since 1983 and as a medical specialty since 1997. Courses of clinical pharmacology are included in the undergraduate curricula in the 5th and/or 6th year of education at all medical schools in the Russian Federation. Postgraduate education includes initial specialization in internal medicine with further residency in clinical pharmacology. Governmental legislation recommends that every healthcare institution has either a department or a single position of clinical pharmacologist. Major routine duties include information about and monitoring of medication use, consultations in difficult clinical situations, pharmacogenetic counseling, therapeutic drug monitoring, pharmacovigilance, and participation in drug and therapeutics (formulary) committees. There are official experts in clinical pharmacology in Russia responsible for coordinating relevant legislative issues. The chief expert clinical pharmacologist represents the discipline directly at the Ministry of Health. Research in clinical pharmacology in Russia is extensive and variable, but only some of it is published internationally. Russia is a participant of international societies of clinical pharmacology and therapeutics and collaboration is actively ongoing. There are still certain problems related to the development of the discipline in Russia-some healthcare institutions do not see the need for clinical pharmacology. However, the number of clinical pharmacologists in Russia is increasing as well as their role in physicians' education, national healthcare, and research.
Aronson, Jeffrey K
1 This is a manifesto for UK clinical pharmacology. 2 A clinical pharmacologist is a medically qualified practitioner who teaches, does research, frames policy, and gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice. Those without medical qualifications who practise some aspect of clinical pharmacology could be described as, say, ‘applied pharmacologists’. 3 Clinical pharmacology is operationally defined as a translational discipline in terms of the basic tools of human pharmacology (e.g. receptor pharmacology) and applied pharmacology (e.g. pharmacokinetics) and how they are used in drug discovery and development and in solving practical therapeutic problems in individuals and populations. 4 Clinical pharmacologists are employed by universities, health-care services, private organizations (such as drug companies), and regulatory agencies. They are • mentors and teachers, teaching laboratory science, clinical science, and all aspects of practical drug therapy as underpinned by the science of pharmacology; they write and edit didactic and reference texts; • researchers, covering research described by the operational definition; • clinicians, practising general medicine, clinical toxicology, other medical specialties, and general practice; • policy makers, framing local, national, and international medicines policy, including formularies, licensing of medicines and prescribing policies. 5 The future of clinical pharmacology depends on the expansion and maintenance of a central core of practitioners (employed by universities or health-care services), training clinical pharmacologists to practise in universities, health-care services, private organizations, and regulatory agencies, and training other clinicians in the principles and practice of clinical pharmacology. PMID:20642541
Branch, Marc N
Behavioral pharmacology is a maturing science that has made significant contributions to the study of drug effects on behavior, especially in the domain of drug-behavior interactions. Less appreciated is that research in behavioral pharmacology can have, and has had, implications for the experimental analysis of behavior, especially its conceptualizations and theory. In this article, I outline three general strategies in behavioral pharmacology research that have been employed to increase understanding of behavioral processes. Examples are provided of the general characteristics of the strategies and of implications of previous research for behavior theory. Behavior analysis will advance as its theories are challenged.
Chhangani, Bantu; Greydanus, Donald E; Patel, Dilip R; Feucht, Cynthia
There is a high prevalence of sleep disorders in children and an apparent increasing need for pharmacologic management. However, because of the paucity of data available with regards to dosing, efficacy, tolerability, and safety profiles of medications as well as a lack of adequate well-designed clinical trials, medications are currently not approved for the pediatric population by the US Food and Drug Administration. There are no pharmacologic guidelines for the specific sleep disorders or the different pediatric age ranges. Additional research is needed for evidence-based pediatric sleep pharmacotherapy. This article reviews pediatric sleep disorders and the pharmacologic therapeutic options.
Xu, Hai-Yu; Yang, Hong-Jun
Chinese medicinal formulae( CMF) were often used in the clinics of traditional Chinese medicine (TCM) which were critical for modernization of Chinese medicine to shed light on the interaction between CMF and biological organisms. In current studies, correlation between system and part, macroscopic actions and microcosmic mechanism, ADME process and pharmacologic actions were often neglected. Thus, we put forward integrative pharmacology, which could integrate the correlation between CMF and biological organisms from multi-levels and multi-dimensional views. Integrative pharmacology would reveal the molecular mechanism of CMF for ailments treatment and screen out effective material systematically, which would be the new paradigm of TCM research.
Grillo, Joseph A; Huang, Shiew Mei
This paper focuses on the role of clinical and translational pharmacology in the drug development and the regulatory process. Contemporary regulatory issues faced by FDA's Office of Clinical Pharmacology (OCP) in fulfilling its mission to advance the science of drug response and translate patient diversity into optimal drug therapy are discussed. Specifically current focus of the following key aspects of the drug development and regulatory science processes are discussed: the OCP vision and mission, two key OCP initiatives (i.e. guidance modernization, labeling and health communications), and translational and clinical pharmacology related regulatory science issues in (i.e. uncertainty, breakthrough therapies, individualization).
Montastruc, J L; Bagheri, H; Lapeyre-Mestre, M; Senard, J M
It is now well established that only clinical trials performed before drug approval are not sufficient for a full modern pharmacological evaluation of drugs and treatments. The need of both pharmacovigilance and pharmacoepidemiology is underlined in order to evaluate drugs under real conditions. After a summary of methods used in pharmacoepidemiological trials (spontaneous reports, imputability assessment, cohorts, case control studies etc.), recent pharmacoepidemiological data useful for the neurologist are summarized: side effects of tacrine and vaccines, serotoninergic syndrome and side effects of new antiepileptic drugs.
... Pharmacology; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice... Science and Clinical Pharmacology. General Function of the Committee: To provide advice...
... Pharmacology; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice... Science and Clinical Pharmacology. General Function of the Committee: To provide advice...
... Pharmacology; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice... Science and Clinical Pharmacology. General Function of the Committee: To provide advice...
Secades, Julio J; Lorenzo, José Luis
Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head
The keynote presentation of the Safety Pharmacology (SP) Society 9th Annual Meeting addressed the urgency, for pharmaceutical organizations, to implement strategies for effectively communicating drug risks to all concerned stakeholders and, in particular, the general public. The application of chronobiology to SP investigational protocols can improve the search of drug-induced adverse effects. The Distinguished Service Award Lecture reviewed a life-long journey through trials and tribulations in the quest of the ever-distant scientific truth. The revision process of Directive 86/609/EC for improving animal welfare should be conducted with the purpose of maintaining a fair balance among animal protection, human health and research imperatives in order to prevent the migration of pharmaceutical activities outside Europe. Additional topics of interest were the behavioral, metabolic and cardiovascular problems experienced by small animals housed at the standard laboratory temperature. A technology for the automated collection of blood and urine samples in rats implanted with telemetry sensors was presented. Non-clinical, clinical, regulatory and legal aspects of abuse liability were expertly reviewed. The 'degradability' of pharmaceuticals into environment-friendly chemicals should be an actively searched and optimized feature of future pharmaceuticals in order to prevent drug pollution of ecosystems. Transgenic and diseased animal models should be selected whenever they can facilitate the determination of drug-induced adverse effects. SP strategies to investigate the safety of drug combination products were exemplified and analyzed in depth. The future of SP was proposed to lie not in the performance of regulatory studies of pharmacodynamic nature but in developing and early applying an array of screening assays for clearing clinical candidates against known drug-induced organ function injuries. In conclusion, the 2009 SP Society annual meeting offered a wealth of
Foerster, Florian; Braig, Simone; Chen, Tao; Altmann, Karl-Heinz; Vollmar, Angelika M
Natural compounds offer a broad spectrum of potential drug candidates against human malignancies. Several cytostatic drugs, which are in clinical use for decades, derive directly from natural sources or are synthetically optimized derivatives of natural lead structures. An eukaryote target molecule to which many natural derived anti-cancer drugs bind to is the microtubule network. Of similar importance for the cell is the actin cytoskeleton, responsible for cell movements, migration of cells and cytokinesis. Nature provides also a broad range of compounds directed against actin as intracellular target, but none of these actin-targeting compounds has ever been brought to clinical trials. One reason why actin-binding compounds have not yet been considered for further clinical investigations is that little is known about their pharmacological properties in cancer cells. Herein, we focused on the closer characterization of doliculide, an actin binding natural compound of marine origin in the breast cancer cell lines MCF7 and MDA-MB-231. We used fluorescence-recovery-after-photobleaching (FRAP) analysis to determine doliculide's early effects on the actin cytoskeleton and rhodamin-phalloidin staining for long-term effects on the actin CSK. After validating the disruption of the actin network, we further investigated the functional effects of doliculide. Doliculide treatment leads to inhibition of proliferation and impairs the migratory potential. Finally, we could also show that doliculide leads to the induction of apoptosis in both cell lines. Our data for the first time provide a closer characterization of doliculide in breast cancer cells and propagate doliculide for further investigations as lead structure and potential therapeutic option as actin-targeting compound.
Álvarez-Castro, Paula; Pena, Lara; Cordido, Fernando
The aim of this review is to summarize the physiological and pharmacological aspects of ghrelin. Obesity can be defined as an excess of body fat and is associated with significant disturbances in metabolic and endocrine function. Obesity has become a worldwide epidemic. In obesity there is a decreased growth hormone (GH) secretion, and the altered somatotroph secretion in obesity is functional. Ghrelin is a peptide that has a unique structure with 28 amino-acids and an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. The pathophysiological mechanism responsible for GH hyposecretion in obesity is probably multifactorial, and there is probably a defect in ghrelin secretion. Ghrelin is the only known circulating orexigenic factor, and has been found to be reduced in obese humans. Ghrelin levels in blood decrease during periods of feeding. Due to its orexigenic and metabolic effects, ghrelin has a potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal and cardiac disease, and age-related frailty. Theoretically ghrelin receptor antagonists could be employed as anti-obesity drugs, blocking the orexigenic signal. By blocking the constitutive receptor activity, inverse agonists of the ghrelin receptor may lower the set-point for hunger, and could be used for the treatment of obesity. In summary, ghrelin secretion is reduced in obesity, and could be partly responsible for GH hyposecretion in obesity, ghrelin antagonist or partial inverse agonists should be considered for the treatment of obesity.
West, D P; Worobec, S; Solomon, L M
Cutaneous metabolism and pharmacology have been the focus of increased scientific inquiry in the past 2 decades. However, in the past few years, attention has been focused specifically on the effects of topically applied drugs in infants as different qualitatively or quantitatively from their effects in adults. Prior to 1972, it was known that brain damage occurred in animals with prolonged blood levels of 2 microgram/ml hexachlorophene, and that washing newborn babies with a standard 3% hexachlorophene liquid soap for 3-5 days resulted in significant blood levels of the compound. However, this knowledge was not disseminated widely enough to prevent the tragic deaths of infants after the use of baby powder contaminated with 6.6% hexachlorophene . This incident highlighted the need for increased understanding of drug effects not only from the viewpoint of the skin as a target organ, but also of percutaneous penetration and resultant blood levels; the affinity of other body tissues for drugs and their metabolites, metabolites which may result from the effect of the skin itself acting on the drug; and the infant's much greater ratio of surface area to body weight, allowing the infant to percutaneously absorb proportionately greater quantities of topical medication than an adult. Although tissue distribution of most drugs has not been studied in infants, it is known that such distribution often depends on age. For example, in infants and children with a given plasma level, of drugs such as barbiturates, morphine and tetracycline, the brain tissue level may exceed that of the adult. Thus, drugs and chemicals that penetrate infant skin may produce effects different than those penetrating adult skin.
Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.
Bolser, Donald C.
Background Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis. Methods Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.” Results Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further. Conclusions These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants. PMID:16428717
Kamato, Danielle; Mitra, Partha; Davis, Felicity; Osman, Narin; Chaplin, Rebecca; Cabot, Peter J; Afroz, Rizwana; Thomas, Walter; Zheng, Wenhua; Kaur, Harveen; Brimble, Margaret; Little, Peter J
Seven transmembrane G protein-coupled receptors (GPCRs) have gained much interest in recent years as it is the largest class among cell surface receptors. G proteins lie in the heart of GPCRs signalling and therefore can be therapeutically targeted to overcome complexities in GPCR responses and signalling. G proteins are classified into four families (Gi, Gs, G12/13 and Gq); Gq is further subdivided into four classes. Among them Gαq and Gαq/11 isoforms are most crucial and ubiquitously expressed; these isoforms are almost 88% similar at their amino acid sequence but may exhibit functional divergences. However, uncertainties often arise about Gαq and Gαq/11 inhibitors, these G proteins might also have suitability to the invention of novel-specific inhibitors for each isoforms. YM-254890 and UBO-QIC are discovered as potent inhibitors of Gαq functions and also investigated in thrombin protease-activated receptor (PAR)-1 inhibitors and platelet aggregation inhibition. The most likely G protein involved in PAR-1 stimulates responses is one of the Gαq family isoforms. In this review, we highlight the molecular structures and pharmacological responses of Gαq family which may reflect the biochemical and molecular role of Gαq and Gαq/11. The advanced understanding of Gαq and Gαq/11 role in GPCR signalling may shed light on our understanding on cell biology, cellular physiology and pathophysiology and also lead to the development of novel therapeutic agents for a number of diseases.
For people seeking treatment, the course of heroin addiction tends to be chronic and relapsing, and longer duration of treatment is associated with better outcomes. Heroin addiction is strongly associated with deviant behaviour and crime, and the objectives in treating heroin addiction have been a blend of humane support, rehabilitation, public health intervention and crime control. Reduction in street heroin use is the foundation on which all these outcomes are based. The pharmacological basis of maintenance treatment of dependent individuals is to minimize withdrawal symptoms and attenuate the reinforcing effects of street heroin, leading to reduction or cessation of street heroin use. Opioid maintenance treatment can be moderately effective in suppressing heroin use, although deviations from evidence-based approaches, particularly the use of suboptimal doses, have meant that treatment as delivered in practice may have resulted in poorer outcomes than predicted by research. Methadone treatment has been ‘programmatic’, with a one-size-fits-all approach that in part reflects the perceived need to impose discipline on deviant individuals. However, differences in pharmacokinetics and in side-effects mean that many patients do not respond optimally to methadone. Injectable diamorphine (heroin) provides a more reinforcing medication for some ‘nonresponders’ and can be a valuable option in the rehabilitation of demoralized, socially excluded individuals. Buprenorphine, a partial agonist, is a less reinforcing medication with different side-effects and less risk of overdose. Not only is it a different medication, but also it can be used in a different paradigm of treatment, office-based opioid treatment, with less structure and offering greater patient autonomy. PMID:23210630
The existence of three types of opioid receptors - ..mu.., kappa, and sigma - was postulated to explain the effects of different opioids in the chronic spinal dog. Sigma receptors, named for the prototypic agonist SKF 10,047 (N-allylnormetazocine), were suggested to mediate the psychotomimetic-like effects of SKF 10,047 in the dog. 3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist. However, the drug specificity of (+)(/sup 3/H)3-PPP binding in brain is identical to that of sigma receptor binding sites which may mediate psychotomimetic effects of some opioids. Pharmacological and autoradiographic analyses reveal that (+)(/sup 3/H)SKF 10,047, the prototypic sigma agonist, labels two sites in brain. The drug specificity of the high affinity site for (+)(/sup 3/H)SKF 10,047 resembles that of putative sigma receptors labeled with (+)(/sup 3/H)3-PPP, being potently inhibited by (+)3-PPP, haloperidol, and (+/-)pentazocine, and demonstrating stereoselectivity for the (+) isomer of SKF 10,047. Autoradiographic localizations of high affinity (+)(/sup 3/H)SKF 10,047 binding sites closely resemble those of (+)(/sup 3/H)3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, and pontine and cranial nerve nuclei. Thus, putative sigma receptors and PCP receptors represent distinct receptor populations in brain. This proposal is supported by the presence of sigma binding sites - and absence of PCP receptors - on NCB-20 cell membranes, a hybrid neurotumor cell line that provides a model system for the physiological and biochemical study of sigma receptors.
For people seeking treatment, the course of heroin addiction tends to be chronic and relapsing, and longer duration of treatment is associated with better outcomes. Heroin addiction is strongly associated with deviant behaviour and crime, and the objectives in treating heroin addiction have been a blend of humane support, rehabilitation, public health intervention and crime control. Reduction in street heroin use is the foundation on which all these outcomes are based. The pharmacological basis of maintenance treatment of dependent individuals is to minimize withdrawal symptoms and attenuate the reinforcing effects of street heroin, leading to reduction or cessation of street heroin use. Opioid maintenance treatment can be moderately effective in suppressing heroin use, although deviations from evidence-based approaches, particularly the use of suboptimal doses, have meant that treatment as delivered in practice may have resulted in poorer outcomes than predicted by research. Methadone treatment has been 'programmatic', with a one-size-fits-all approach that in part reflects the perceived need to impose discipline on deviant individuals. However, differences in pharmacokinetics and in side-effects mean that many patients do not respond optimally to methadone. Injectable diamorphine (heroin) provides a more reinforcing medication for some 'nonresponders' and can be a valuable option in the rehabilitation of demoralized, socially excluded individuals. Buprenorphine, a partial agonist, is a less reinforcing medication with different side-effects and less risk of overdose. Not only is it a different medication, but also it can be used in a different paradigm of treatment, office-based opioid treatment, with less structure and offering greater patient autonomy.
Pieramico, Valentina; Esposito, Roberto; Cesinaro, Stefano; Frazzini, Valerio; Sensi, Stefano L.
Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia. PMID:25228860
Sharma, Arun Kumar; Rani, Ekta; Waheed, Abdul; Rajput, Satyendra K.
Uncontrolled seizure or epilepsy is intricately related with an increase risk of pharmacoresistant epilepsy. The failure to achieve seizure control with the first or second drug trial of an anticonvulsant medication given at the appropriate daily dosage is termed as pharmacoresistance, despite the fact that these drugs possess different modes of action. It is one of the devastating neurological disorders act as major culprit of mortality in developed as well as developing countries with towering prevalence. Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc. But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario. Hence, utility of alternative strategies in management of resistance epilepsy is increased which further possible by continuing developing of promising therapeutic interventions to manage this insidious condition adequately. Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results. In this review we will shed light on the current pharmacological and non pharmacological mediator with their potential pleiotropic action on pharmacoresistant epilepsy. PMID:26157666
Im, Dong-soon; Nah, Seung-yeol
Ginseng, the root of Panax ginseng, has been used in traditional Chinese medicine as a tonic herb that provides many beneficial effects. Pharmacologic studies in the last decades have shown that ginsenosides (ginseng saponins) are primarily responsible for the actions of ginseng. However, the effects of ginseng are not fully explained by ginsenosides. Recently, another class of active ingredients called gintonin was identified. Gintonin is a complex of glycosylated ginseng proteins containing lysophosphatidic acids (LPAs) that are the intracellular lipid mitogenic mediator. Gintonin specifically and potently activates the G protein-coupled receptors (GPCRs) for LPA. Thus, the actions of ginseng are now also linked to LPA and its GPCRs. This linkage opens new dimensions for ginseng pharmacology and LPA therapeutics. In the present review, we evaluate the pharmacology of ginseng with the traditional viewpoint of Yin and Yang components. Furthermore, we will compare ginsenoside and gintonin based on the modern view of molecular pharmacology in terms of ion channels and GPCRs.
Shen, Liang; Ji, Hong-Fang
The natural product curcumin has gained considerable attention in recent years for its multiple pharmacological activities, but more efforts are needed to understand how curcumin can have these pharmacological effects considering its low bioavailability. In addition, it is unclear how curcumin exerts inhibitory effects against numerous enzymes, especially those that cannot accommodate curcumin within recognized binding pockets. By analyzing the similarities between the biological activities of curcumin and its degradation products against diseases such as Alzheimer's disease and cancer, as well as the preferential inhibition of some enzymes by degradation products, it appears that the bioactive degradation products may contribute to the pharmacological effects of curcumin. This possibility should be given full attention when elucidating the pharmacology of this promising natural product for various diseases.
Chernow, B. )
This book contains papers addressing the pharmacologic approach to the critically ill patient. Chapter topics include: Radiation injury; Red cell substitutes: a current appraisal; and Psychopharmacology in the ICU.
Bai, Yu; Fan, Xue-mei; Sun, Han; Wang, Yi-ming; Liang, Qiong-lin; Luo, Guo-an
Applications of network pharmacology are increasingly widespread and methods abound in the field of drug development and pharmacological research. In this study, we choose rosiglitazone compound as the object to predict the targets and to discuss the mechanism based on three kinds of prediction methods of network pharmacology. Comparison of the prediction result has identified that the three kinds of prediction methods had their own characteristics: targets and pathways predicted were not in accordance with each other. However, the calcium signaling pathway could be predicted in the three kinds of methods, which associated with diabetes and cognitive impairment caused by diabetes by bioinformatics analysis. The above conclusion indicates that the calcium signaling pathway is important in signal pathway regulation of rosiglitazone compound, which provides a clue to further explain the mechanism of the compound and also provides a reference for the selection and application of methods of network pharmacology in the actual research.
Aulakh, G S; Narayanan, S; Mahadevan, G
Pharmacognosy, Pharmacology, Clinical studies and photochemistry of the four plants, viz., Convolvulus pluricaulis, Evolvulus alsinoides, Canscora decussate and Clitoria ternatea commonly used as the drug Shankapushphi have been reviewed here.
Laties, Victor G.
Psychologists, particularly those influenced by the work of B. F. Skinner, played a major part in the development of behavioral pharmacology in the 1950s and 1960s. Revolutionary changes in pharmacology and psychiatry, including the discovery of powerful therapeutic agents such as chlorpromazine and reserpine, had produced a surge of interest in drug research. Pharmaceutical companies began hiring psychologists with operant conditioning backgrounds so as to compete successfully in the search for new drugs. Psychologists, most of whom were skilled in the behavior-analytic approach, started to assume prominent positions as authors and editors for the Journal of Pharmacology and Experimental Therapeutics as its emphasis on behavior increased. This also proved true with the other publications founded to deal with the popularity of behavioral pharmacology. Especially important were contributions by B. F. Skinner, Peter B. Dews, and Joseph V. Brady. PMID:22478405
Liu, Lu; Cao, Jian-Xin; Yao, Yuan-Cheng; Xu, Sheng-Ping
Alkaloid was a kind of biological active ingredient. There were various types of alkaloids in Apocynaceae. This paper reviewed the progress on alkaloids from Apocynaceae, which contained origin, structure, and pharmacological activity.
Mitchell, Gary; Agnelli, Joanne
Distress is one of the most common clinical manifestations associated with dementia. Pharmacological intervention may be appropriate in managing distress in some people. However, best practice guidelines advocate non-pharmacological interventions as the preferred first-line treatment. The use of non-pharmacological interventions encourages healthcare professionals to be more person-centred in their approach, while considering the causes of distress. This article provides healthcare professionals with an overview of some of the non-pharmacological approaches that can assist in alleviating distress for people living with dementia including: reminiscence therapy, reality orientation, validation therapy, music therapy, horticultural therapy, doll therapy and pet therapy. It provides a summary of their use in clinical practice and links to the relevant literature.
Laties, Victor G
Psychologists, particularly those influenced by the work of B. F. Skinner, played a major part in the development of behavioral pharmacology in the 1950s and 1960s. Revolutionary changes in pharmacology and psychiatry, including the discovery of powerful therapeutic agents such as chlorpromazine and reserpine, had produced a surge of interest in drug research. Pharmaceutical companies began hiring psychologists with operant conditioning backgrounds so as to compete successfully in the search for new drugs. Psychologists, most of whom were skilled in the behavior-analytic approach, started to assume prominent positions as authors and editors for the Journal of Pharmacology and Experimental Therapeutics as its emphasis on behavior increased. This also proved true with the other publications founded to deal with the popularity of behavioral pharmacology. Especially important were contributions by B. F. Skinner, Peter B. Dews, and Joseph V. Brady.
Taylor, W A; Gold, M S
When pharmacologic agents are considered in the treatment of cocaine addiction, the objective of such treatment--sustained abstinence--must be considered. Medication and medical approaches have been disappointing in the treatment of cocaine overdose. The central neurobiologic mechanism(s) involved in cocaine toxicity are poorly understood. Without a cocaine antagonist, pharmacologic approaches have been less than promising in preventing relapse. Various psychoactive medications have been tried in early cocaine abstinence, with some success. PMID:1971975
Vlak, Tonko; Aljinović, Jure
Non-pharmacological treatment of osteoporosis is a mandatory part of all algorithms and recommendations for dealing with this disease. However, the belief that pharmacological therapy is much more superior to treating osteoporosis than non-pharmacological treatment is still common in the medical community. The probable reason is that pharmacological treatment can be measured and statistically analyzed, and that's why the abundance of data from controlled randomized trials, meta-analyses and systematic reviews are available. Non-pharmacological treatment of osteoporosis is not so much represented in evidence based medicine (EBM) because there are a lot of different exercise protocols, different machines with different setups for applying the same models of physical therapy. So the main problem are inclusion criteria in meta-analyses or systematic reviews of patients whose data is collected using different protocols. Non-pharmacological treatment ofosteoporosis: myth or reality? Maybe we did not answer this question in fullness, but by analyzing data from the scientifically relevant data bases we can conclude that non-pharmacological treatment is an important factor in prevention of osteoporosis and part of all treatment protocols available today--almost as equally significant as pharmacological treatment. Cochrane library database and PEDro database provide EBM information that can help to identify the best types of ex- ercises and physical procedures for bone mineral density and prevention of falls. The best result in non-pharmaco- logical treatment of osteoporosis showed a combination of exercise programs that include muscle strengthening exercises, aerobic exercises, exercises with progressive resistance increase, and high-impact exercises. As for individual exercises, a non-weight-bearing high force exercise showed small but statistically significant increase in bone mineral density in femoral neck, in some scientific papers. Exercises for balance and
Ngo, Tony; Ilatovskiy, Andrey V; Stewart, Alastair G; Coleman, James L J; McRobb, Fiona M; Riek, R Peter; Graham, Robert M; Abagyan, Ruben; Kufareva, Irina; Smith, Nicola J
Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.
Jallad, N S
The discipline of Clinical Pharmacology serves many purposes and plays a critical role in therapeutic education, especially in a medical school. An effective program bridges the gap between basic pharmacology and clinical practice. A clinical pharmacology program must provide the student with the necessary information to employ the basic pharmacology knowledge gained in formatting a successful therapeutic plan. The program is built around the student and brings together the best to be offered in 2 or more disciplines; it requires diverse disciplines to work together in a variety of departments and centers which cut across disciplinary lines. In order to facilitate this interaction, the Division of Clinical Pharmacology at the University of Miami embarked on establishing a Ph.D. program with an emphasis on Clinical Pharmacology utilizing an already established unique program referred to as "Interdepartmental Graduate Studies". To enter the structured Ph.D. program the students must be among the fellowship awardees of the Interdepartment Graduate Studies Program, which is administered by social committees with specific roles, directions and guidelines. The students follow the general requirements of the Ph.D. degree set forth by the graduate school. Students attend formal classes tailored to their program of interest based on the committee's recommendations in the respective departments involved. The significance of this program is that it can be tailored to fit individual areas of interest leading to a well-developed researcher who is neither overspecialized nor undereducated and able to make rational decisions in an age of multiple therapies.
Hao, Da Cheng; Xiao, Pei Gen
Network pharmacology, based on the theory of systems biology, is a new discipline that analyzes the biological network and screens out the nodes of particular interest, with the aim of designing poly-target drug molecule. It emphasizes maximizing drug efficacy and minimizing adverse effect via the multiple regulation of the signaling pathway. Coincidentally, almost all traditional Chinese medicine (TCM) and worldwide ethnomedicine exert therapeutic effect by targeting multiple molecules of the human body. In this overview, we offer a critique on the present perception of TCM and network pharmacology; illustrate the utility of network pharmacology in the study of single herb, medicine pair, and TCM formula; and summarize the recent progress of TCM-based drug discovery inspired by network pharmacology. Network pharmacology could be of great help in decreasing drug attrition rate and thus is essential in rational and cost-effective drug development. We also pinpoint the current TCM issues that could be tackled by the flexible combined use of network pharmacology and relevant disciplines.
Caviola, Lucius; Faber, Nadira S.
We review work on the effectiveness of different forms of cognitive enhancement, both pharmacological and non-pharmacological. We consider caffeine, methylphenidate, and modafinil for pharmacological cognitive enhancement (PCE) and computer training, physical exercise, and sleep for non-pharmacological cognitive enhancement (NPCE). We find that all of the techniques described can produce significant beneficial effects on cognitive performance. However, effect sizes are moderate, and consistently dependent on individual and situational factors as well as the cognitive domain in question. Although meta-analyses allowing a quantitative comparison of effectiveness across techniques are lacking to date, we can conclude that PCE is not more effective than NPCE. We discuss the physiological reasons for this limited effectiveness. We then propose that even though their actual effectiveness seems similar, in the general public PCE is perceived as fundamentally different from NPCE, in terms of effectiveness, but also in terms of acceptability. We illustrate the potential consequences such a misperception of PCE can have. PMID:26696922
Caviola, Lucius; Faber, Nadira S
We review work on the effectiveness of different forms of cognitive enhancement, both pharmacological and non-pharmacological. We consider caffeine, methylphenidate, and modafinil for pharmacological cognitive enhancement (PCE) and computer training, physical exercise, and sleep for non-pharmacological cognitive enhancement (NPCE). We find that all of the techniques described can produce significant beneficial effects on cognitive performance. However, effect sizes are moderate, and consistently dependent on individual and situational factors as well as the cognitive domain in question. Although meta-analyses allowing a quantitative comparison of effectiveness across techniques are lacking to date, we can conclude that PCE is not more effective than NPCE. We discuss the physiological reasons for this limited effectiveness. We then propose that even though their actual effectiveness seems similar, in the general public PCE is perceived as fundamentally different from NPCE, in terms of effectiveness, but also in terms of acceptability. We illustrate the potential consequences such a misperception of PCE can have.
Bradley, Eamonn; Fedigan, Stephen; Webb, Timothy; Hollywood, Mark A; Thornbury, Keith D; McHale, Noel G; Sergeant, Gerard P
Recent studies have shown that transmembrane protein 16 A (TMEM16A) is a subunit of calcium-activated chloride channels (CACCs). Pharmacological agents have been used to probe the functional role of CACCs, however their effect on TMEM16A currents has not been systematically investigated. In the present study, we characterized the voltage and concentration-dependent effects of 2 traditional CACC inhibitors (niflumic acid and anthracene-9-carboxcylic acid) and 2 novel CACC / TMEM16A inhibitors (CACC(inh)A01 and T16A(inh)A01) on TMEM16A currents. The whole cell patch clamp technique was used to record TMEM16A currents from HE K 293 cells that stably expressed human TMEM16A. Niflumic acid, A-9-C, CACC(inh)A01 and T16A(inh)A01 inhibited TMEM16A currents with IC50 values of 12, 58, 1.7 and 1.5 μM, respectively, however, A-9-C and niflumic acid were less efficacious at negative membrane potentials. A-9-C and niflumic acid reduced the rate of TMEM16A tail current deactivation at negative membrane potentials and A-9-C (1 mM) enhanced peak TMEM16A tail current amplitude. In contrast, the inhibitory effects of CACC(inh)A01 and T16A(inh)A01 were independent of voltage and they did not prolong the rate of TMEM16A tail current deactivation. The effects of niflumic acid and A-9-C on TMEM16A currents were similar to previous observations on CACCs in vascular smooth muscle, strengthening the hypothesis that they are encoded by TMEM16A. However, CACC(inh)A01 and T16A(inh)A01 were more potent inhibitors of TMEM16A channels and their effects were not diminished at negative membrane potentials making them attractive candidates to interrogate the functional role of TMEM16A channels in future studies.
A brief account is given of the scientific career of Walter Ernest Dixon, and of the importance of his work and his influence for the development of Pharmacology in England. It is suggested that the Memorial Lecture may appropriately deal with some matter of new interest, from one of the fields of research in which Dixon himself was active. Special mention is made of his work with Brodie on the physiology and pharmacology of the bronchioles and the pulmonary blood-vessels, as probably showing the beginning of Dixon's interest in the actions of the alkaloids and organic bases which reproduce the effects of autonomic nerves.An account is given of Dixon's early interest in the suggestion, first made by Elliott, that autonomic nerves transmit their effects by releasing, at their endings, specific substances, which reproduce their actions; and of his attempt to obtain experimental support for this conception. After the War it was established by the experiments of O. Loewi; and it is now generally recognized that parasympathetic effects are so transmitted by release of acetylcholine, sympathetic effects by that of a substance related to adrenaline.Very recent evidence indicates that acetylcholine, by virtue of its other ("nicotine-like") action, also acts as transmitter of activity at synapses in autonomic ganglia, and from motor nerve to voluntary muscle.The terms "cholinergic" and "adrenergic" have been introduced to describe nerve-fibres which transmit their actions by the release at their endings of acetylcholine, and of a substance related to adrenaline, respectively. It is shown that Langley and Anderson's evidence, long available, as to the kinds of peripheral efferent fibres which can replace one another in regeneration, can be summarized by the statement, that cholinergic can replace cholinergic fibres, and that adrenergic can replace adrenergic fibres; but that fibres of different chemical function cannot replace one another. The bearing of this new evidence on
Lewis, L D; Nierenberg, D W
Currently, the training and education of young clinical pharmacologist who represent the future of our discipline rest almost entirely on institutions/organizations with established and productive fellowship training programs. Here, we discuss the role of the American Board of Clinical Pharmacology (ABCP) in accrediting fellowship training programs and certifying individual clinical pharmacologists. We also explore how ABCP certification adds value to both individual trainees and the discipline in the evolving world of clinical therapeutics and research in human pharmacology.
Frankland, Paul W; Ohno, Masuo; Takahashi, Eiki; Chen, Adele R; Costa, Rui M; Kushner, Steven A; Silva, Alcino J
Mouse transgenic and knock-out approaches have made fundamental contributions to our understanding of the molecular and cellular bases of learning and memory. These approaches have successfully identified a large number of molecules with either a central or modulatory role in learning and memory. However, there are limitations associated with first-generation mutant mice, which include, for example, the lack of temporal control over the mutation. Recent technical developments have started to address some of these shortcomings. Here, the authors review a newly developed inducible approach that takes advantage of synergistic interactions between subthreshold genetic and pharmacological manipulations. This approach is easily set up and can be used to study the functional interactions between molecules in signaling pathways.
Pugsley, Michael K; Authier, Simon; Stonerook, Michael; Curtis, Michael J
The relative importance of the discipline of safety pharmacology (which integrates physiology, pharmacologyand toxicology) has evolved since the incorporation of the Safety Pharmacology Society (SPS) as an entity on August 10, 2000. Safety pharmacology (SP), as a synthesis of these other fields of knowledge, is concerned with characterizing the safety profile (or potential undesirable pharmacodynamic effects) of new chemical entities (NCEs) and biologicals. Initially focused on the issue of drug-induced QT prolongation it has developed into an important discipline over the past 15years with expertise beyond its initial focus on torsades de pointes (TdP). It has become a repository for interrogation of models for drug safety studies and innovative non-clinical model development, validation and implementation. Thus, while safety pharmacology consists of the triumvirate obligatory cardiovascular, central nervous system (CNS) and respiratory system core battery studies it also involves assessing drug effects on numerous other physiological systems (e.g., ocular, auditory, renal, gastrointestinal, blood, immune) leveraging emerging new technologies in a wide range of non-clinical drug safety testing models. As with previous editorials that preface the themed issue on safety pharmacology methods published in the Journal of Pharmacological and Toxicological Methods (JPTM), we highlight here the content derived from the most recent (2014) SPS meeting held in Washington, DC. The dynamics of the discipline remain fervent and method development, extension and refinement are reflected in the content. This issue of the JPTM continues the tradition of providing a publication summary of articles (reviews, commentaries and methods) with impact on the discipline of safety pharmacology.
Du, Juan; Wagner, Brett A; Buettner, Garry R; Cullen, Joseph J
Pharmacological ascorbate has been shown to induce toxicity in a wide range of cancer cell lines. Pharmacological ascorbate in animal models has shown promise for use in cancer treatment. At pharmacological concentrations the oxidation of ascorbate produces a high flux of H2O2 via the formation of ascorbate radical (Asc(•-)). The rate of oxidation of ascorbate is principally a function of the level of catalytically active metals. Iron in cell culture media contributes significantly to the rate of H2O2 generation. We hypothesized that increasing intracellular iron would enhance ascorbate-induced cytotoxicity and that iron chelators could modulate the catalytic efficiency with respect to ascorbate oxidation. Treatment of cells with the iron-chelators deferoxamine (DFO) or dipyridyl (DPD) in the presence of 2mM ascorbate decreased the flux of H2O2 generated by pharmacological ascorbate and reversed ascorbate-induced toxicity. Conversely, increasing the level of intracellular iron by preincubating cells with Fe-hydroxyquinoline (HQ) increased ascorbate toxicity and decreased clonogenic survival. These findings indicate that redox metal metals, e.g., Fe(3+)/Fe(2+), have an important role in ascorbate-induced cytotoxicity. Approaches that increase catalytic iron could potentially enhance the cytotoxicity of pharmacological ascorbate in vivo.
Wu, Jiaqi; Peng, Wei; Qin, Rongxin; Zhou, Hong
Crataegus pinnatifida (Hawthorn) is widely distributed in China and has a long history of use as a traditional medicine. The fruit of C. pinnatifida has been used for the treatment of cardiodynia, hernia, dyspepsia, postpartum blood stasis, and hemafecia and thus increasing interest in this plant has emerged in recent years. Between 1966 and 2013, numerous articles have been published on the chemical constituents, pharmacology or pharmacologic effects and toxicology of C. pinnatifida. To review the pharmacologic advances and to discuss the potential perspective for future investigation, we have summarized the main literature findings of these publications. So far, over 150 compounds including flavonoids, triterpenoids, steroids, monoterpenoids, sesquiterpenoids, lignans, hydroxycinnamic acids, organic acids and nitrogen-containing compounds have been isolated and identified from C. pinnatifida. It has been found that these constituents and extracts of C. pinnatifida have broad pharmacological effects with low toxicity on, for example, the cardiovascular, digestive, and endocrine systems, and pathogenic microorganisms, supporting the view that C. pinnatifida has favorable therapeutic effects. Thus, although C. pinnatifida has already been widely used as pharmacological therapy, due to its various active compounds, further research is warranted to develop new drugs.
Li, Shao; Zhang, Bo
Traditional Chinese medicine (TCM) has a long history of viewing an individual or patient as a system with different statuses, and has accumulated numerous herbal formulae. The holistic philosophy of TCM shares much with the key ideas of emerging network pharmacology and network biology, and meets the requirements of overcoming complex diseases, such as cancer, in a systematic manner. To discover TCM from a systems perspective and at the molecular level, a novel TCM network pharmacology approach was established by updating the research paradigm from the current "one target, one drug" mode to a new "network target, multi-components" mode. Subsequently, a set of TCM network pharmacology methods were created to prioritize disease-associated genes, to predict the target profiles and pharmacological actions of herbal compounds, to reveal drug-gene-disease co-module associations, to screen synergistic multi-compounds from herbal formulae in a high-throughput manner, and to interpret the combinatorial rules and network regulation effects of herbal formulae. The effectiveness of the network-based methods was demonstrated for the discovery of bioactive compounds and for the elucidation of the mechanisms of action of herbal formulae, such as Qing-Luo-Yin and the Liu-Wei-Di-Huang pill. The studies suggest that the TCM network pharmacology approach provides a new research paradigm for translating TCM from an experience-based medicine to an evidence-based medicine system, which will accelerate TCM drug discovery, and also improve current drug discovery strategies.
Alexander, Stephen Ph; Kelly, Eamonn; Marrion, Neil; Peters, John A; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Southan, Christopher; Buneman, O Peter; Catterall, William A; Cidlowski, John A; Davenport, Anthony P; Fabbro, Doriano; Fan, Grace; McGrath, John C; Spedding, Michael; Davies, Jamie A
The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.
Prasad, A; Datta, P P; Pattanayak, C; Panda, P
Pharmacology is a subject taught in the medical curriculum in India over a period of one and half years along with pathology, microbiology and forensic medicine. The present study was planned to know the opinion of medical students regarding pharmacology and to assess the proposed teaching schedule and methods of teaching pharmacology. The study was conducted in a private medical college in eastern India among the medical undergraduate students in 5th semester. Total 74 students participated in the study. A pre-designed, pre-tested, semi-structured questionnaire was given to the students and data was collected after one hour. Collected data was compiled, tabulated and analyzed in SPSS (version 16.0). The subject was perceived as interesting and useful by majority of students and most of them were in opinion to integrate pharmacology with the clinical subjects. Lecture in whole class was the most preferred teaching method according to the students and teaching with chalk and board they preferred most. Rational use of medicine, clinical trial, pediatric and geriatric pharmacology are the important topics the students felt to be included in the curriculum. Regular assessment of teaching methods by the students and taking suggestions from the students about improving the teaching method and redesigning the curriculum can help a lot in improving the learning capacity of the medical students and that will give benefit for the society as a whole.
The environment on the International Space Station (ISS) includes a variety of potential stressors including the absence of Earth's gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. The effects of this extreme environment on pharmacokinetics, pharmacodynamics, and even on stored medication doses, are not yet understood. Dr. Wotring will discuss recent analyses of medication doses that experienced long duration storage on the ISS and a recent retrospective examination of medication use during long-duration spaceflights. She will also describe new pharmacology experiments that are scheduled for upcoming ISS missions. Dr. Virginia E. Wotring is a Senior Scientist in the Division of Space Life Sciences in the Universities Space Research Association, and Pharmacology Discipline Lead at NASA's Johnson Space Center, Human Heath and Countermeasures Division. She received her doctorate in Pharmacological and Physiological Science from Saint Louis University after earning a B.S. in Chemistry at Florida State University. She has published multiple studies on ligand gated ion channels in the brain and spinal cord. Her research experience includes drug mechanisms of action, drug receptor structure/function relationships and gene & protein expression. She joined USRA (and spaceflight research) in 2009. In 2012, her book reviewing pharmacology in spaceflight was published by Springer: Space Pharmacology, Space Development Series.
Curtice, Kigen J.; Leavitt, Lee S.; Chase, Kevin; Raghuraman, Shrinivasan; Horvath, Martin P.; Olivera, Baldomero M.
A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation-pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of α-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain. PMID:26581874
Soares, Célia; Fernandes, Natália; Morgado, Pedro
At present, no treatment recommendations can be made for compulsive buying disorder. Recent studies have found evidence for the efficacy of psychotherapeutic options, but less is known regarding the best pharmacologic treatment. The purpose of this review is to present and analyze the available published evidence on the pharmacological treatment of compulsive buying disorder. To achieve this, we conducted a review of studies focusing on the pharmacological treatment of compulsive buying by searching the PubMed/MEDLINE database. Selection criteria were applied, and 21 studies were identified. Pharmacological classes reported included antidepressants, mood stabilizers, opioid antagonists, second-generation antipsychotics, and N-methyl-D-aspartate receptor antagonists. We found only placebo-controlled trials for fluvoxamine; none showed effectiveness against placebo. Three open-label trials reported clinical improvement with citalopram; one was followed by a double-blind discontinuation. Escitalopram was effective in an open-label trial but did not show efficacy in the double-blind phase. Memantine was identified as effective in a pilot open-label study. Fluoxetine, bupropion, nortriptyline, clomipramine, topiramate and naltrexone were only reported to be effective in clinical cases. According to the available literature, there is no evidence to propose a specific pharmacologic agent for compulsive buying disorder. Future research is required for a better understanding of both pathogenesis and treatment of this disorder.
Zahorodnyĭ, M I; Nebesna, T Iu; Kazakova, O O; Horchakova, N O; Svintsits'kyĭ, A S; Chekman, I S
Quantum pharmacology allows to study the mechanisms of action of cardiovascular drugs, to predict pharmacological activity and identify the most pronounced pharmacodynamic efficacy and therapeutic activity of new compounds. Calculation of quantum-pharmacological parameters for molecules of beta-blockers (propranolol, atenolol, metoprolol, carvedilol) in aqueous media, research its hydrophobic interaction with receptors allow to form a theoretical basis for the development of new generations of more effective and safe medicines for hypertension treatment. Increased hydrophobicity leads to poor solubility of carvedilol in water and high--in the lipids. The clinical pharmacology of the drug is shown by such indicators as the therapeutic dose, half-life and degree of metabolism in the liver. Due to enhanced interaction with adrenergic receptor effective dose of carvedilol is an order of magnitude lower than other beta-blockers, even with the relatively low bioavailability. Reduced bioavailability of carvedilol versus atenolol, metoprolol and propranolol is caused by elevated metabolism during the first pass through the liver, which is also due to the hydrophobicity of the drug. High solubility in lipids appears to extend the half-life of carvedilol. QSAR studies make an important contribution to the study of the properties of chemical compounds and their pharmacological activity. Software, used for computation of studied properties, has a significant role. A large number of descriptors allows a qualitative and quantitative assessment of the molecules of chemical compounds and prediction of their influence on cardiovascular system.
Curtice, Kigen J; Leavitt, Lee S; Chase, Kevin; Raghuraman, Shrinivasan; Horvath, Martin P; Olivera, Baldomero M; Teichert, Russell W
A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation-pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of α-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain.
Luijten, Maartje; Field, Matt; Franken, Ingmar H A
Attentional bias in substance-dependent patients is the tendency to automatically direct attention to substance-related cues in the environment. Preclinical models suggest that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The aim of the current review is to describe pharmacological mechanisms underlying attentional bias in humans and to critically review empirical studies that aimed to modulate attentional bias in substance-dependent patients by using pharmacological agents. The findings of the reviewed studies suggest that attentional bias and related brain activation may be modulated by dopamine. All of the reviewed studies investigated acute effects of pharmacological agents, while measurements of chronic pharmacological treatments on attentional bias and clinically relevant measures such as relapse are yet lacking. Therefore, the current findings should be interpreted as a proof of principle concerning the role of dopamine in attentional bias. At the moment, there is too little evidence for clinical applications. While the literature search was not limited to dopamine, there is a lack of studies investigating the role of non-dopaminergic neurotransmitter systems in substance-related attentional bias. A focus on neurotransmitter systems such as acetylcholine and noradrenaline could provide new insights regarding the pharmacology of substance-related attentional bias.
Devi, Vasudha; Bhat, Vishal; Shenoy, Ganesh K.
Pharmacology is an important aspect of rational therapeutics. There has been a long-standing need for a change in the undergraduate medical curriculum of pharmacology. A review of literature throws up different approaches to improve the curriculum and to provide more importance to conceptualization and relevance to clinical practice. This article describes the undergraduate pharmacology curriculum which is revised to meet the needs of our unique status as an international medical college in India. We highlight how our curriculum prepares the students for future clinical practice by inculcating higher cognitive skills and soft skills. This article also provides a model for program evaluation and also challenges faced by our department while executing the planned curriculum. PMID:28031601
PROBLEM: Discovering the causes of unusual phenotypes in human subjects is an important aspect of patient-oriented research. MATERIAL: The tools of clinical pharmacology are uniquely useful in addressing these problems. PATIENTS, SUBJECTS, OR CASE HISTORIES: We evaluated a 42-year-old patient with lifelong orthostatic hypotension and ptosis of the eyelids. He underwent a series of biochemical, physiological, and pharmacological tests outlined in this article. RESULTS: These studies indicated that sympathetic innervation was intact but that the sympathetic neurotransmitter was dopamine rather than norepinephrine. These results demonstrated that dopamine-beta-hydroxylase deficiency underlies the clinical abnormalities of this patient. CONCLUSION: In selected individuals with unusual phenotypes, the techniques of clinical chemistry and clinical pharmacology can define the nature of the defect at almost the resolution of the human genome.
Yadav, Rajnish Kumar; Nandy, Bankim Chandra; Maity, Siddhartha; Sarkar, Srimanta; Saha, Sudipta
Ficus racemosa is an important medicinal plant, found in India, Australia, and Southeast Asia. It is popularly known as ‘gular.’ It reduces blood glucose concentration due to the presence of β-sitosterol. Many active constituents that have been isolated from various parts of this plant possess useful pharmacological activities. The literature survey proposed that it has multiple pharmacological actions that include antidiabetic, antioxidant, antidiarrhoeal, anti-inflammatory, antipyretic, antifungal, antibacterial, hypolipidemic, antifilarial, and hepatoprotection. This review article elaborately describes the traditional uses, phytochemistry, pharmacology, and toxicology of this plant. We also provide useful structures of the secondary metabolites along with their nuclear magnetic resonance (NMR) data. Some clinical trial data have also been provided in this review. This review would assist researchers to gather scientific information in future. PMID:26009696
Dubey, Suchita; Maity, Siddhartha; Singh, Mahendra; Saraf, Shubhini A; Saha, Sudipta
Spilanthes acmella is an important medicinal plant, found in tropical and subtropical countries mainly India and South America. Popularly, it is known as toothache plant which reduces the pain associated with toothaches and can induce saliva secretion. Various extracts and active metabolites from various parts of this plant possess useful pharmacological activities. Literature survey proposed that it has multiple pharmacological actions, which include antifungal, antipyretic, local anaesthetic, bioinsecticide, anticonvulsant, antioxidant, aphrodisiac, analgesic, pancreatic lipase inhibitor, antimicrobial, antinociception, diuretic, vasorelaxant, anti-human immunodeficiency virus, toothache relieve and anti-inflammatory effects. This review is elaborately describing the traditional uses, phytochemistry, pharmacology, and toxicology of this plant. This review would assist researchers to search scientific information in the future.
Kim, J K; Forger, D B; Marconi, M; Wood, D; Doran, A; Wager, T; Chang, C; Walton, K M
Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1δ/ε inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from the molecular to the behavioral level. By developing a systems pharmacology model, we predict and experimentally validate that chronic CK1δ/ε inhibition during the earlier hours of a LD cycle can produce a constant stable delay of rhythm. However, chronic dosing later during the day, or in the presence of longer light intervals, is not predicted to yield an entrained rhythm. We also propose a simple method based on phase response curves (PRCs) that predicts the effects of a LD cycle and chronic dosing of a circadian drug. This work indicates that dosing timing and environmental signals must be carefully considered for accurate pharmacological manipulation of circadian phase. PMID:23863866
Escolar, D M; Scacheri, C G
The outstanding advances in the molecular characterization of muscle diseases, including muscular dystrophies, inflammatory myopathies, and ion channel disorders, have resulted in the identification of potential targets for pharmacologic and genetic therapy in the best characterized of these diseases. The most common myopathy in children, Duchenne muscular dystrophy (DMD), is the focus of active pharmacologic clinical trials. Genetic transfer therapy research for this and other dystrophies is rapidly moving forward. However, as new approaches for treatment are being actively investigated, the current modality of treatment for all myopathies is still in the realm of physical medicine and rehabilitation. The focus of this review is on the advances in pharmacologic and genetic therapy research in DMD and limb girdle muscular dystrophies.
Singh, Mahendra; Saraf, Shubhini A.
Spilanthes acmella is an important medicinal plant, found in tropical and subtropical countries mainly India and South America. Popularly, it is known as toothache plant which reduces the pain associated with toothaches and can induce saliva secretion. Various extracts and active metabolites from various parts of this plant possess useful pharmacological activities. Literature survey proposed that it has multiple pharmacological actions, which include antifungal, antipyretic, local anaesthetic, bioinsecticide, anticonvulsant, antioxidant, aphrodisiac, analgesic, pancreatic lipase inhibitor, antimicrobial, antinociception, diuretic, vasorelaxant, anti-human immunodeficiency virus, toothache relieve and anti-inflammatory effects. This review is elaborately describing the traditional uses, phytochemistry, pharmacology, and toxicology of this plant. This review would assist researchers to search scientific information in the future. PMID:24371437
Huang, Linzhang; Zhao, Hongfang; Huang, Baokang; Zheng, Chengjian; Peng, Wei; Qin, Luping
Acanthopanax senticosus (Rupr. et Maxim) Harms (Araliaceae), also called Siberian Ginseng, Eleutherococcus senticosus, and Ciwujia in Chinese, is a widely used traditional Chinese herb that could invigorate qi, strengthen the spleen, and nourish kidney in the theory of Traditional Chinese Medicine. With high medicinal value, Acanthopanax senticosus (AS, thereafter) is popularly used as an "adaptogen" like Panax ginseng. In recent decades, a great number of chemical, pharmacological, and clinical studies on AS have been carried out worldwide. Several kinds of chemical compounds have been reported, including triterpenoid saponins, lignans, coumarins, and flavones, among which, phenolic compounds such as syringin and eleutheroside E, were considered to be the most active components. Considerable pharmacological experiments both in vitro and in vivo have persuasively demonstrated that AS possessed anti-stress, antiulcer, anti-irradiation, anticancer, anti-inflammatory and hepatoprotective activities, etc. The present review is an up-to-date and comprehensive analysis of the botany, chemistry, pharmacology, toxicity and clinical trials of AS.
Zhang, Ru-Xue; Li, Mao-Xing; Jia, Zheng-Ping
Rehmannia glutinosa, a widely used traditional Chinese herb, belongs to the family of Scrophulariaceae, and is taken to nourish Yin and invigorate the kidney in traditional Chinese medicine (TCM) and has a very high medicinal value. In recent decades, a great number of chemical and pharmacological studies have been done on Rehmannia glutinosa. More than 70 compounds including iridoids, saccharides, amino acid, inorganic ions, as well as other trace elements have been found in the herb. Studies show that Rehmannia glutinosa and its active principles possess wide pharmacological actions on the blood system, immune system, endocrine system, cardiovascular system and the nervous system. Currently, the effective monomeric compounds or active parts have been screened for the pharmacological activity of Rehmannia glutinosa and the highest quality scientific data is delivered to support the further application and exploitation for new drug development.
Guo, Qiang; Bai, Ruifeng; Zhao, Baosheng; Feng, Xiao; Zhao, Yunfang; Tu, Pengfei; Chai, Xingyun
The Meconopsis plants (Chinese: ), belonging to the family Papaveraceae, have been used as traditional Tibetan medicine (TTM) for thousands of years. Meconopsis has the effects of clearing heat, reducing swelling, and easing pain, and is mainly prescribed for heat syndromes, hepatitis, pneumonia, and pain in joints. Phytochemical studies have revealed the presence of major isoquinoline alkaloids and flavonoids. Modern pharmacological research has demonstrated its antitumor, hepatoprotective, analgestic, antimicrobial, anti-oxidant, antitussive, and anti-inflammatory activities. However, resource availability, in-depth in vivo pharmacological study and qualitative and quantitative analysis are still insufficient and deserve further efforts. This paper provides a comprehensive advance on the ethnopharmacological, phytochemical, and pharmacological studies of the genus, in hopes of promoting a better understanding of their medicinal values.
Perazella, M A
Treatment of symptomatic intradialytic hypotension (IDH) is a difficult task for the practicing nephrologist. Minimizing patient factors that precipitate IDH as well as dialysis procedure-related components that lower blood pressure are the initial approaches to this problem. However, despite these maneuvers, hypotension often persists in a group of high-risk patients. Pharmacologic interventions are often used to reduce IDH. Unfortunately, many of the available therapies are marginally effective and/or poorly tolerated. A few therapies appear to be efficacious and well tolerated-carnitine, sertraline, and midodrine. This article reviews the various pharmacologic therapies used for IDH and makes recommendations for treatment of this difficult problem.
Siniscalchi, Antonio; Gallelli, Luca; Labate, Angelo; Malferrari, Giovanni; Palleria, Caterina; Sarro, Giovambattista De
Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in post-stroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach. PMID:23449883
Li, Jing; Yu, Fei; Chen, Yi; Oupický, David
Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809
Trame, Mirjam N; Biliouris, Konstantinos; Lesko, Lawrence J; Mettetal, Jerome T
Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach. This commentary offers an overview of the current trends and challenges of using systems pharmacology to reduce the risks of unintended adverse events.
Castel, Josep-Maria; Figueras, Albert; Vigo, Joan-Miquel
The invention of the internet and the world-wide web was a landmark that has affected many aspects of everyday life, but is so recent and dynamic that many of its potential uses are still being explored. Aside from its purely commercial use as a virtual pharmacy (e-commerce), the internet is useful in at least three aspects related to clinical pharmacology: communication, training and research. In this paper we briefly review several internet applications related to clinical pharmacology and describe, as an example, the logistics of a multicentre research collaboration related to the promotion of rational drug use in the prevention of postpartum haemorrhage. PMID:16722847
Schreuder, Willem H; Coumou, Annet W; Kessler, Peter A H W; de Lange, Jan
In the search for new pharmacologic therapies for central giant cell granuloma (CGCG), proteins that are essential to osteoclastogenesis are intriguing potential targets. In the present case report, we describe a 25-year-old patient with an aggressive CGCG of the maxilla, who was successfully treated with the antiresorptive agent denosumab, after other pharmacologic treatment had failed to achieve regression or stabilization of the tumor. Denosumab could be a promising alternative to potentially mutilating surgery for CGCG. However, more research is needed before definite conclusions can be drawn about the potential role of this agent in the treatment of CGCG.
Liu, Yi; Wang, Jihui; Wang, Wei; Zhang, Hanyue; Zhang, Xuelan; Han, Chunchao
Cordyceps sinensis, also called DongChongXiaCao (winter worm, summer grass) in Chinese, is becoming increasingly popular and important in the public and scientific communities. This study summarizes the chemical constituents and their corresponding pharmacological actions of Cordyceps sinensis. Many bioactive components of Cordyceps sinensis have been extracted including nucleoside, polysaccharide, sterol, protein, amino acid, and polypeptide. In addition, these constituents' corresponding pharmacological actions were also shown in the study such as anti-inflammatory, antioxidant, antitumour, antiapoptosis, and immunomodulatory actions. Therefore can use different effects of C. sinensis against different diseases and provide reference for the study of Cordyceps sinensis in the future. PMID:25960753
Mao, Xin; Wu, Ling-Fang; Guo, Hong-Ling; Chen, Wen-Jing; Cui, Ya-Ping; Qi, Qi; Li, Shi; Liang, Wen-Yi; Yang, Guang-Hui; Shao, Yan-Yan; Zhu, Dan; She, Gai-Mei; You, Yun; Zhang, Lan-Zhen
The plants of the genus Phyllanthus (Euphorbiaceae) have been used as traditional medicinal materials for a long time in China, India, Brazil, and the Southeast Asian countries. They can be used for the treatment of digestive disease, jaundice, and renal calculus. This review discusses the ethnopharmacological, phytochemical, and pharmacological studies of Phyllanthus over the past few decades. More than 510 compounds have been isolated, the majority of which are lignins, triterpenoids, flavonoids, and tannins. The researches of their remarkable antiviral, antioxidant, antidiabetic, and anticancer activities have become hot topics. More pharmacological screenings and phytochemical investigations are required to support the traditional uses and develop leading compounds. PMID:27200104
Karpa, Kelly Dowhower; Vrana, Kent E
Integrating pharmacology education into a problem-based learning (PBL) curriculum has proven challenging for many medical schools, including the Pennsylvania State University College of Medicine (Penn State COM). In response to pharmacology content gaps in its PBL-intensive curriculum, Penn State COM in 2003 hired a director of medical pharmacology instruction to oversee efforts to improve the structure of pharmacology education in the absence of a stand-alone course. In this article, the authors describe the ongoing development of the virtual pharmacology curriculum, which weaves pharmacology instruction through the entire medical school curriculum with particular emphasis on the organ-based second year. Pharmacology is taught in a spiraling manner designed to add to and build upon students' knowledge and competency. Key aspects of the virtual curriculum (as of 2011) include clearly stated and behaviorally oriented pharmacology learning objectives, pharmacology study guides that correspond to each PBL case, pharmacology review sessions that feature discussions of United States Medical Licensing Examination (USMLE)-type questions, and pharmacology questions for each PBL case on course examinations to increase student accountability. The authors report a trend toward improved USMLE Step 1 scores since these initiatives were introduced. Furthermore, graduates' ratings of their pharmacology education have improved on the Medical School Graduation Questionnaire. The authors suggest that the initiatives they describe for enhancing pharmacology medical education are relevant to other medical schools that are also seeking ways to better integrate pharmacology into PBL-based curricula.
When the Arabic-Islamic medicine evolved partly as a consequence of the wave of translations from mainly Greek medical books to Arabic in the 9th century the pharmacological works, which were available, were also translated. The books of Dioscurides and Galen on pharmacological matters became the decisive books of pharmacological translated literature and they formed the basis of the pharmacological understanding in the subsequent extensive literature on pharmacognosy and pharmacology written in Arabic. Nevertheless the Arabs united these two disciplines in a regular pharmacy and they evolved it as an independent discipline, which although attached to medicine was regarded as having its own praxis. The physicians and scientists rationalized and systematized their knowledge of medicinal plants and drugs and extended their knowledge by using original observations and research. Many books on medicaments were written, both as materia medica, i.e. records on simple drugs, and dispensatories, i.e. books on compounded drugs. These two kinds of books were always written separately as they were seen by the Arabs themselves as pertaining to two different subdisciplines, which meant that they were separated too in independent chapters or books in general Arabic works on medicine. When the extensive translations of Arabic medical literature to Latin took place in Italy and Spain in the 11th and 12th centuries, the Arabic pharmacological literature was of course also translated, and its decisive influence on later medieval European medical writings is easy to demonstrate. In the 18th century Peter Forsskaal was one of the first Europeans in the modern scientific tradition to collect and make notes on drugs used in Cairo and in Yemen.
Alexander, Stephen PH; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Spedding, Michael; Peters, John A; Harmar, Anthony J
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Enzymes are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates. PMID:24528243
Chan, Eric Wei-Chiang; Lye, Phui-Yan; Wong, Siu-Kuin
The present review is aimed at providing a comprehensive summary on the botany, utility, phytochemistry, pharmacology, and clinical trials of Morus alba (mulberry or sang shu). The mulberry foliage has remained the primary food for silkworms for centuries. Its leaves have also been used as animal feed for livestock and its fruits have been made into a variety of food products. With flavonoids as major constituents, mulberry leaves possess various biological activities, including antioxidant, antimicrobial, skin-whitening, cytotoxic, anti-diabetic, glucosidase inhibition, anti-hyperlipidemic, anti-atherosclerotic, anti-obesity, cardioprotective, and cognitive enhancement activities. Rich in anthocyanins and alkaloids, mulberry fruits have pharmacological properties, such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-obesity, and hepatoprotective activities. The root bark of mulberry, containing flavonoids, alkaloids and stilbenoids, has antimicrobial, skin-whitening, cytotoxic, anti-inflammatory, and anti-hyperlipidemic properties. Other pharmacological properties of M. alba include anti-platelet, anxiolytic, anti-asthmatic, anthelmintic, antidepressant, cardioprotective, and immunomodulatory activities. Clinical trials on the efficiency of M. alba extracts in reducing blood glucose and cholesterol levels and enhancing cognitive ability have been conducted. The phytochemistry and pharmacology of the different parts of the mulberry tree confer its traditional and current uses as fodder, food, cosmetics, and medicine. Overall, M. alba is a multi-functional plant with promising medicinal properties.
Yang, Ming; Chen, Jia-Lei; Xu, Li-Wen; Ji, Guang
The concept of "network target" has ushered in a new era in the field of traditional Chinese medicine (TCM). As a new research approach, network pharmacology is based on the analysis of network models and systems biology. Taking advantage of advancements in systems biology, a high degree of integration data analysis strategy and interpretable visualization provides deeper insights into the underlying mechanisms of TCM theories, including the principles of herb combination, biological foundations of herb or herbal formulae action, and molecular basis of TCM syndromes. In this study, we review several recent developments in TCM network pharmacology research and discuss their potential for bridging the gap between traditional and modern medicine. We briefly summarize the two main functional applications of TCM network models: understanding/uncovering and predicting/discovering. In particular, we focus on how TCM network pharmacology research is conducted and highlight different computational tools, such as network-based and machine learning algorithms, and sources that have been proposed and applied to the different steps involved in the research process. To make network pharmacology research commonplace, some basic network definitions and analysis methods are presented.
Lung carcinomas are now the most common form of cancer. Clinical data suggest that tumors are found preferentially in upper airways, perhaps specifically at carina within bifurcations. The disease can be treated by aerosolized pharmacologic drugs. To enhance their...
Ryan, Joseph B.; Reid, Robert; Epstein, Michael H.; Ellis, Cynthia; Evans, Joseph H.
This study reviews the status and trends of pharmacological intervention research focused on the academic functioning of children and adolescents with attention deficit hyperactivity disorder (ADHD). Forty-two studies involving 1,668 participants were included in the review. Results indicated: (1) information on participants is limited; (2)…