WorldWideScience

Sample records for model state drug

  1. State Drug Utilization Data 2003

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  2. State Drug Utilization Data 2011

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  3. State Drug Utilization Data 2009

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  4. State Drug Utilization Data 2016

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  5. State Drug Utilization Data 2017

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  6. State Drug Utilization Data 1996

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  7. State Drug Utilization Data 2008

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  8. State Drug Utilization Data 1992

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  9. State Drug Utilization Data 1995

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  10. State Drug Utilization Data 1998

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  11. State Drug Utilization Data 2014

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  12. State Drug Utilization Data 2005

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  13. State Drug Utilization Data 2002

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  14. State Drug Utilization Data 2004

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  15. State Drug Utilization Data 1993

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  16. State Drug Utilization Data 2006

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  17. State Drug Utilization Data 2012

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  18. State Drug Utilization Data 1999

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  19. State Drug Utilization Data 2015

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  20. State Drug Utilization Data 1997

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  1. State Drug Utilization Data 1991

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  2. State Drug Utilization Data 2001

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  3. State Drug Utilization Data 2007

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  4. State Drug Utilization Data 2013

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  5. State Drug Utilization Data 1994

    Data.gov (United States)

    U.S. Department of Health & Human Services — Drug utilization data are reported by states for covered outpatient drugs that are paid for by state Medicaid agencies since the start of the Medicaid Drug Rebate...

  6. Drug Poisoning Mortality by State: United States

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset describes drug poisoning deaths at the U.S. and state level by selected demographic characteristics, and includes age-adjusted death rates for drug...

  7. A state-of-the-art multi-criteria model for drug benefit-risk analysis

    NARCIS (Netherlands)

    Tervonen, T.; Hillege, H.L.; Buskens, E.; Postmus, D.

    2010-01-01

    Drug benefit-risk analysis is based on firm clinical evidence related to various safety and efficacy outcomes, such as tolerability, treatment response, and adverse events. In this paper, we propose a new approach for constructing a supporting multi-criteria model that fully takes into account this

  8. Non steady-state descriptions of drug permeation through stratum corneum. I. The biphasic brick-and-mortar model.

    Science.gov (United States)

    Heisig, M; Lieckfeldt, R; Wittum, G; Mazurkevich, G; Lee, G

    1996-03-01

    The diffusion equation should be solved for the non-steady-state problem of drug diffusion within a two-dimensional, biphasic stratum corneum membrane having homogeneous lipid and corneocyte phases. A numerical method was developed for a brick-and-mortar SC-geometry, enabling an explicit solution for time-dependent drug concentration within both phases. The lag time and permeability were calculated. It is shown how the barrier property of this model membrane depends on relative phase permeability, corneocyte alignment, and corneocyte-lipid partition coefficient. Additionally, the time-dependent drug concentration profiles within the membrane can be observed during the lag and steady-state phases. The model SC-membrane predicts, from purely morphological principles, lag times and permeabilities that are in good agreement with experimental values. The long lag times and very small permeabilities reported for human SC can only be predicted for a highly-staggered corneocyte geometry and corneocytes that are 1000 times less permeable than the lipid phase. Although the former conclusion is reasonable, the latter is questionable. The elongated, flattened corneocyte shape renders lag time and permeability insensitive to large changes in their alignment within the SC. Corneocyte/lipid partitioning is found to be fundamentally different to SC/donor partitioning, since increasing drug lipophilicity always reduces both lag time and permeability.

  9. Vaginal drug distribution modeling.

    Science.gov (United States)

    Katz, David F; Yuan, Andrew; Gao, Yajing

    2015-09-15

    This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Mathematical modeling of drug dissolution.

    Science.gov (United States)

    Siepmann, J; Siepmann, F

    2013-08-30

    The dissolution of a drug administered in the solid state is a pre-requisite for efficient subsequent transport within the human body. This is because only dissolved drug molecules/ions/atoms are able to diffuse, e.g. through living tissue. Thus, generally major barriers, including the mucosa of the gastro intestinal tract, can only be crossed after dissolution. Consequently, the process of dissolution is of fundamental importance for the bioavailability and, hence, therapeutic efficacy of various pharmaco-treatments. Poor aqueous solubility and/or very low dissolution rates potentially lead to insufficient availability at the site of action and, hence, failure of the treatment in vivo, despite a potentially ideal chemical structure of the drug to interact with its target site. Different physical phenomena are involved in the process of drug dissolution in an aqueous body fluid, namely the wetting of the particle's surface, breakdown of solid state bonds, solvation, diffusion through the liquid unstirred boundary layer surrounding the particle as well as convection in the surrounding bulk fluid. Appropriate mathematical equations can be used to quantify these mass transport steps, and more or less complex theories can be developed to describe the resulting drug dissolution kinetics. This article gives an overview on the current state of the art of modeling drug dissolution and points out the assumptions the different theories are based on. Various practical examples are given in order to illustrate the benefits of such models. This review is not restricted to mathematical theories considering drugs exhibiting poor aqueous solubility and/or low dissolution rates, but also addresses models quantifying drug release from controlled release dosage forms, in which the process of drug dissolution plays a major role. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Drug-model membrane interactions

    International Nuclear Information System (INIS)

    Deniz, Usha K.

    1994-01-01

    In the present day world, drugs play a very important role in medicine and it is necessary to understand their mode of action at the molecular level, in order to optimise their use. Studies of drug-biomembrane interactions are essential for gaining such as understanding. However, it would be prohibitively difficult to carry out such studies, since biomembranes are highly complex systems. Hence, model membranes (made up of these lipids which are important components of biomembranes) of varying degrees of complexity are used to investigate drug-membrane interactions. Bio- as well as model-membranes undergo a chain melting transition when heated, the chains being in a disordered state above the transition point, T CM . This transition is of physiological importance since biomembranes select their components such that T CM is less than the ambient temperature but not very much so, so that membrane flexibility is ensured and porosity, avoided. The influence of drugs on the transition gives valuable clues about various parameters such as the location of the drug in the membrane. Deep insights into drug-membrane interactions are obtained by observing the effect of drugs on membrane structure and the mobilities of the various groups in lipids, near T CM . Investigation of such changes have been carried out with several drugs, using techniques such as DSC, XRD and NMR. The results indicate that the drug-membrane interaction not only depends on the nature of drug and lipids but also on the form of the model membrane - stacked bilayer or vesicles. The light that these results shed on the nature of drug-membrane interactions is discussed. (author). 13 refs., 13 figs., 1 tab

  12. Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions.

    Science.gov (United States)

    Salmas, Ramin Ekhteiari; Yurtsever, Mine; Stein, Matthias; Durdagi, Serdar

    2015-05-01

    Homology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of β2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MODELLER and ROSETTA programs. Top-ranked models have been validated with ligand docking simulations and in silico Alanine-scanning mutagenesis studies. The derived extra-cellular loop region of the protein models is directed toward the binding site cavity which is often involved in ligand binding. The binding sites of protein models were refined using induced fit docking to enable the side-chain refinement during ligand docking simulations. The derived models were then tested using molecular modeling techniques on several marketed drugs for schizophrenia. Alanine-scanning mutagenesis and molecular docking studies gave similar results for marketed drugs tested. We believe that these new D2 receptor models will be very useful for a better understanding of the mechanisms of action of drugs to be targeted to the binding sites of D2Rs and they will contribute significantly to drug design studies involving G-protein-coupled receptors in the future.

  13. Drug Poisoning Mortality by County: United States

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset describes drug poisoning deaths at the U.S. and state level by selected demographic characteristics, and includes age-adjusted death rates for drug...

  14. NCHS - Drug Poisoning Mortality by State: United States

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset describes drug poisoning deaths at the U.S. and state level by selected demographic characteristics, and includes age-adjusted death rates for drug...

  15. Animal models of drug addiction.

    Science.gov (United States)

    García Pardo, María Pilar; Roger Sánchez, Concepción; De la Rubia Ortí, José Enrique; Aguilar Calpe, María Asunción

    2017-09-29

    The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

  16. The Food and Drug Administration and Drug Legalization: A Brief Model of Regulation

    OpenAIRE

    Kalam, Murad

    2002-01-01

    This paper offers a brief model of FDA regulation of currently illegal narcotics in the United States. Given that nearly three out of four Americans believe that the drug war has failed, recent calls from prominent liberal and conservative thinkers to legalize drugs, and state “compassionate use†ballot initiatives, future drug legalization is at least conceivable in the United States. Yet, how would the FDA regulate NLD’s under its current st...

  17. Moisture and drug solid-state monitoring during a continuous drying process using empirical and mass balance models

    DEFF Research Database (Denmark)

    Fonteyne, Margot; Gildemyn, Delphine; Peeters, Elisabeth

    2014-01-01

    of Process Analytical Technology (PAT) tools (Raman and NIR spectroscopy) and a mass balance approach. The six-segmented fluid bed drying system being part of a fully continuous from-powder-to-tablet production line (ConsiGma™-25) was used for this study. A theophylline:lactose:PVP (30:67.5:2.5) blend......, the different size fractions of the dried granules obtained during different experiments (fines, yield and oversized granules) were compared separately, revealing differences in both solid state of theophylline and moisture content between the different granule size fractions. © 2014 Elsevier B.V. All rights...... reserved...

  18. Multiscale modeling of transdermal drug delivery

    Science.gov (United States)

    Rim, Jee Eun

    2006-04-01

    This study addresses the modeling of transdermal diffusion of drugs, to better understand the permeation of molecules through the skin, and especially the stratum corneum, which forms the main permeation barrier of the skin. In transdermal delivery of systemic drugs, the drugs diffuse from a patch placed on the skin through the epidermis to the underlying blood vessels. The epidermis is the outermost layer of the skin and can be further divided into the stratum corneum (SC) and the viable epidermis layers. The SC consists of keratinous cells (corneocytes) embedded in the lipid multi-bilayers of the intercellular space. It is widely accepted that the barrier properties of the skin mostly arises from the ordered structure of the lipid bilayers. The diffusion path, at least for lipophilic molecules, seems to be mainly through the lipid bilayers. Despite the advantages of transdermal drug delivery compared to other drug delivery routes such as oral dosing and injections, the low percutaneous permeability of most compounds is a major difficulty in the wide application of transdermal drug delivery. In fact, many transdermal drug formulations include one or more permeation enhancers that increase the permeation of the drug significantly. During the last two decades, many researchers have studied percutaneous absorption of drugs both experimentally and theoretically. However, many are based on pharmacokinetic compartmental models, in which steady or pseudo-steady state conditions are assumed, with constant diffusivity and partitioning for single component systems. This study presents a framework for studying the multi-component diffusion of drugs coupled with enhancers through the skin by considering the microstructure of the stratum corneum (SC). A multiscale framework of modeling the transdermal diffusion of molecules is presented, by first calculating the microscopic diffusion coefficient in the lipid bilayers of the SC using molecular dynamics (MD). Then a

  19. Multiscale Modeling in the Clinic: Drug Design and Development

    Energy Technology Data Exchange (ETDEWEB)

    Clancy, Colleen E.; An, Gary; Cannon, William R.; Liu, Yaling; May, Elebeoba E.; Ortoleva, Peter; Popel, Aleksander S.; Sluka, James P.; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M.

    2016-02-17

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

  20. QSAR Modeling and Prediction of Drug-Drug Interactions.

    Science.gov (United States)

    Zakharov, Alexey V; Varlamova, Ekaterina V; Lagunin, Alexey A; Dmitriev, Alexander V; Muratov, Eugene N; Fourches, Denis; Kuz'min, Victor E; Poroikov, Vladimir V; Tropsha, Alexander; Nicklaus, Marc C

    2016-02-01

    Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100,000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27,966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database.

  1. Estimation of the cost-effectiveness of HIV prevention portfolios for people who inject drugs in the United States: A model-based analysis.

    Directory of Open Access Journals (Sweden)

    Cora L Bernard

    2017-05-01

    Full Text Available The risks of HIV transmission associated with the opioid epidemic make cost-effective programs for people who inject drugs (PWID a public health priority. Some of these programs have benefits beyond prevention of HIV-a critical consideration given that injection drug use is increasing across most United States demographic groups. To identify high-value HIV prevention program portfolios for US PWID, we consider combinations of four interventions with demonstrated efficacy: opioid agonist therapy (OAT, needle and syringe programs (NSPs, HIV testing and treatment (Test & Treat, and oral HIV pre-exposure prophylaxis (PrEP.We adapted an empirically calibrated dynamic compartmental model and used it to assess the discounted costs (in 2015 US dollars, health outcomes (HIV infections averted, change in HIV prevalence, and discounted quality-adjusted life years [QALYs], and incremental cost-effectiveness ratios (ICERs of the four prevention programs, considered singly and in combination over a 20-y time horizon. We obtained epidemiologic, economic, and health utility parameter estimates from the literature, previously published models, and expert opinion. We estimate that expansions of OAT, NSPs, and Test & Treat implemented singly up to 50% coverage levels can be cost-effective relative to the next highest coverage level (low, medium, and high at 40%, 45%, and 50%, respectively and that OAT, which we assume to have immediate and direct health benefits for the individual, has the potential to be the highest value investment, even under scenarios where it prevents fewer infections than other programs. Although a model-based analysis can provide only estimates of health outcomes, we project that, over 20 y, 50% coverage with OAT could avert up to 22,000 (95% CI: 5,200, 46,000 infections and cost US$18,000 (95% CI: US$14,000, US$24,000 per QALY gained, 50% NSP coverage could avert up to 35,000 (95% CI: 8,900, 43,000 infections and cost US$25,000 (95% CI: US

  2. Drug policy in United States of America

    OpenAIRE

    Stahl, Edmundo G.; Médico internista, President and Chief Executive Officer, LatAmScience. Florida, USA.

    2009-01-01

    The USA federal prescription drug policies are inconsistent. The federal government regulates the development, production, marketing and safety of prescription drugs in the country through various legal mechanisms as well as private and governmental institutions. Patent laws also play an important role in this process protecting the pharmaceutical industry. The government has no direct mechanism to control prices of prescription drugs nor does it have a policy to cover the whole US popula...

  3. Drug Policy: the "Dutch Model"

    NARCIS (Netherlands)

    van Ooijen-Houben, M.M.J.; Kleemans, E.R.

    2015-01-01

    Dutch drug policy, once considered pragmatic and lenient and rooted in a generally tolerant attitude toward drug use, has slowly but surely shifted from a primarily public health focus to an increasing focus on law enforcement. The "coffee shop" policy and the policy toward MDMA/ecstasy are

  4. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

    Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

    2015-01-01

    BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery....

  5. Market power and state costs of HIV/AIDS drugs.

    Science.gov (United States)

    Leibowitz, Arleen A; Sood, Neeraj

    2007-03-01

    We examine whether U.S. states can use their market power to reduce the costs of supplying prescription drugs to uninsured and underinsured persons with HIV through a public program, the AIDS Drug Assistance Program (ADAP). Among states that purchase drugs from manufacturers and distribute them directly to clients, those that purchase a greater volume pay lower average costs per prescription. Among states depending on retail pharmacies to distribute drugs and then claiming rebates from manufacturers, those that contract with smaller numbers of pharmacy networks have lower average costs. Average costs per prescription do not differ between the two purchase methods.

  6. Models of multiquark states

    International Nuclear Information System (INIS)

    Lipkin, H.J.

    1986-01-01

    The success of simple constituent quark models in single-hardon physics and their failure in multiquark physics is discussed, emphasizing the relation between meson and baryon spectra, hidden color and the color matrix, breakup decay modes, coupled channels, and hadron-hadron interactions via flipping and tunneling of flux tubes. Model-independent predictions for possible multiquark bound states are considered and the most promising candidates suggested. A quark approach to baryon-baryon interactions is discussed

  7. A two-dimensional mathematical model of percutaneous drug absorption

    Directory of Open Access Journals (Sweden)

    Kubota K

    2004-06-01

    Full Text Available Abstract Background When a drug is applied on the skin surface, the concentration of the drug accumulated in the skin and the amount of the drug eliminated into the blood vessel depend on the value of a parameter, r. The values of r depend on the amount of diffusion and the normalized skin-capillary clearence. It is defined as the ratio of the steady-state drug concentration at the skin-capillary boundary to that at the skin-surface in one-dimensional models. The present paper studies the effect of the parameter values, when the region of contact of the skin with the drug, is a line segment on the skin surface. Methods Though a simple one-dimensional model is often useful to describe percutaneous drug absorption, it may be better represented by multi-dimensional models. A two-dimensional mathematical model is developed for percutaneous absorption of a drug, which may be used when the diffusion of the drug in the direction parallel to the skin surface must be examined, as well as in the direction into the skin, examined in one-dimensional models. This model consists of a linear second-order parabolic equation with appropriate initial conditions and boundary conditions. These boundary conditions are of Dirichlet type, Neumann type or Robin type. A finite-difference method which maintains second-order accuracy in space along the boundary, is developed to solve the parabolic equation. Extrapolation in time is applied to improve the accuracy in time. Solution of the parabolic equation gives the concentration of the drug in the skin at a given time. Results Simulation of the numerical methods described is carried out with various values of the parameter r. The illustrations are given in the form of figures. Conclusion Based on the values of r, conclusions are drawn about (1 the flow rate of the drug, (2 the flux and the cumulative amount of drug eliminated into the receptor cell, (3 the steady-state value of the flux, (4 the time to reach the steady-state

  8. Drug Release from ß-Cyclodextrin Complexes and Drug Transfer into Model Membranes Studied by Affinity Capillary Electrophoresis.

    Science.gov (United States)

    Darwish, Kinda A; Mrestani, Yahya; Rüttinger, Hans-Hermann; Neubert, Reinhard H H

    2016-05-01

    Is to characterize the drug release from the ß-cyclodextrin (ß-CD) cavity and the drug transfer into model membranes by affinity capillary electrophoresis. Phospholipid liposomes with and without cholesterol were used to mimic the natural biological membrane. The interaction of cationic and anionic drugs with ß-CD and the interaction of the drugs with liposomes were detected separately by measuring the drug mobility in ß-CD containing buffer and liposome containing buffer; respectively. Moreover, the kinetics of drug release from ß-CD and its transfer into liposomes with or without cholesterol was studied by investigation of changes in the migration behaviours of the drugs in samples, contained drug, ß-CD and liposome, at 1:1:1 molar ratio at different time intervals; zero time, 30 min, 1, 2, 4, 6, 8, 10 and 24 h. Lipophilic drugs such as propranolol and ibuprofen were chosen for this study, because they form complexes with ß-CD. The mobility of the both drug liposome mixtures changed with time to a final state. For samples of liposomal membranes with cholesterol the final state was faster reached than without cholesterol. The study confirmed that the drug release from the CD cavity and its transfer into the model membrane was more enhanced by the competitive displacement of the drug from the ß-CD cavity by cholesterol, the membrane component. The ACE method here developed can be used to optimize the drug release from CD complexes and the drug transfer into model membranes.

  9. MODELING OF TARGETED DRUG DELIVERY PART II. MULTIPLE DRUG ADMINISTRATION

    Directory of Open Access Journals (Sweden)

    A. V. Zaborovskiy

    2017-01-01

    Full Text Available In oncology practice, despite significant advances in early cancer detection, surgery, radiotherapy, laser therapy, targeted therapy, etc., chemotherapy is unlikely to lose its relevance in the near future. In this context, the development of new antitumor agents is one of the most important problems of cancer research. In spite of the importance of searching for new compounds with antitumor activity, the possibilities of the “old” agents have not been fully exhausted. Targeted delivery of antitumor agents can give them a “second life”. When developing new targeted drugs and their further introduction into clinical practice, the change in their pharmacodynamics and pharmacokinetics plays a special role. The paper describes a pharmacokinetic model of the targeted drug delivery. The conditions under which it is meaningful to search for a delivery vehicle for the active substance were described. Primary screening of antitumor agents was undertaken to modify them for the targeted delivery based on underlying assumptions of the model.

  10. A Profile of Substance Abuse, Gender, Crime, and Drug Policy in the United States and Canada

    Science.gov (United States)

    Grant, Judith

    2009-01-01

    The climate of domestic drug policy in the United States as it pertains to both women and men at the beginning of the 21st century is the criminalization mode of regulation--a mode that is based on the model of addiction as a crime and one that is used to prohibit the use of illegal drugs. In Canada, drug policy is based mainly on the harm…

  11. A State-by-State Analysis of Laws Dealing With Driving Under the Influence of Drugs

    Science.gov (United States)

    2009-12-01

    This study reviewed each State statute regarding drug-impaired driving as of December 2008. There : is a high degree of variability across the States in the ways they approach drug-impaired driving. : Current laws in many States contain provisions ma...

  12. [A model list of high risk drugs].

    Science.gov (United States)

    Cotrina Luque, J; Guerrero Aznar, M D; Alvarez del Vayo Benito, C; Jimenez Mesa, E; Guzman Laura, K P; Fernández Fernández, L

    2013-12-01

    «High-risk drugs» are those that have a very high «risk» of causing death or serious injury if an error occurs during its use. The Institute for Safe Medication Practices (ISMP) has prepared a high-risk drugs list applicable to the general population (with no differences between the pediatric and adult population). Thus, there is a lack of information for the pediatric population. The main objective of this work is to develop a high-risk drug list adapted to the neonatal or pediatric population as a reference model for the pediatric hospital health workforce. We made a literature search in May 2012 to identify any published lists or references in relation to pediatric and/or neonatal high-risk drugs. A total of 15 studies were found, from which 9 were selected. A model list was developed mainly based on the ISMP one, adding strongly perceived pediatric risk drugs and removing those where the pediatric use was anecdotal. There is no published list that suits pediatric risk management. The list of pediatric and neonatal high-risk drugs presented here could be a «reference list of high-risk drugs » for pediatric hospitals. Using this list and training will help to prevent medication errors in each drug supply chain (prescribing, transcribing, dispensing and administration). Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  13. Mathematical modeling and computational prediction of cancer drug resistance.

    Science.gov (United States)

    Sun, Xiaoqiang; Hu, Bin

    2017-06-23

    Diverse forms of resistance to anticancer drugs can lead to the failure of chemotherapy. Drug resistance is one of the most intractable issues for successfully treating cancer in current clinical practice. Effective clinical approaches that could counter drug resistance by restoring the sensitivity of tumors to the targeted agents are urgently needed. As numerous experimental results on resistance mechanisms have been obtained and a mass of high-throughput data has been accumulated, mathematical modeling and computational predictions using systematic and quantitative approaches have become increasingly important, as they can potentially provide deeper insights into resistance mechanisms, generate novel hypotheses or suggest promising treatment strategies for future testing. In this review, we first briefly summarize the current progress of experimentally revealed resistance mechanisms of targeted therapy, including genetic mechanisms, epigenetic mechanisms, posttranslational mechanisms, cellular mechanisms, microenvironmental mechanisms and pharmacokinetic mechanisms. Subsequently, we list several currently available databases and Web-based tools related to drug sensitivity and resistance. Then, we focus primarily on introducing some state-of-the-art computational methods used in drug resistance studies, including mechanism-based mathematical modeling approaches (e.g. molecular dynamics simulation, kinetic model of molecular networks, ordinary differential equation model of cellular dynamics, stochastic model, partial differential equation model, agent-based model, pharmacokinetic-pharmacodynamic model, etc.) and data-driven prediction methods (e.g. omics data-based conventional screening approach for node biomarkers, static network approach for edge biomarkers and module biomarkers, dynamic network approach for dynamic network biomarkers and dynamic module network biomarkers, etc.). Finally, we discuss several further questions and future directions for the use of

  14. Context Sensitive Modeling of Cancer Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  15. Modelling drug flux through microporated skin.

    Science.gov (United States)

    Rzhevskiy, Alexey S; Guy, Richard H; Anissimov, Yuri G

    2016-11-10

    A simple mathematical equation has been developed to predict drug flux through microporated skin. The theoretical model is based on an approach applied previously to water evaporation through leaf stomata. Pore density, pore radius and drug molecular weight are key model parameters. The predictions of the model were compared with results derived from a simple, intuitive method using porated area alone to estimate the flux enhancement. It is shown that the new approach predicts significantly higher fluxes than the intuitive analysis, with transport being proportional to the total pore perimeter rather than area as intuitively anticipated. Predicted fluxes were in good general agreement with experimental data on drug delivery from the literature, and were quantitatively closer to the measured values than those derived from the intuitive, area-based approach. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Orphan diseases: state of the drug discovery art.

    Science.gov (United States)

    Volmar, Claude-Henry; Wahlestedt, Claes; Brothers, Shaun P

    2017-06-01

    Since 1983 more than 300 drugs have been developed and approved for orphan diseases. However, considering the development of novel diagnosis tools, the number of rare diseases vastly outpaces therapeutic discovery. Academic centers and nonprofit institutes are now at the forefront of rare disease R&D, partnering with pharmaceutical companies when academic researchers discover novel drugs or targets for specific diseases, thus reducing the failure risk and cost for pharmaceutical companies. Considerable progress has occurred in the art of orphan drug discovery, and a symbiotic relationship now exists between pharmaceutical industry, academia, and philanthropists that provides a useful framework for orphan disease therapeutic discovery. Here, the current state-of-the-art of drug discovery for orphan diseases is reviewed. Current technological approaches and challenges for drug discovery are considered, some of which can present somewhat unique challenges and opportunities in orphan diseases, including the potential for personalized medicine, gene therapy, and phenotypic screening.

  17. From Product Models to Product State Models

    DEFF Research Database (Denmark)

    Larsen, Michael Holm

    1999-01-01

    A well-known technology designed to handle product data is Product Models. Product Models are in their current form not able to handle all types of product state information. Hence, the concept of a Product State Model (PSM) is proposed. The PSM and in particular how to model a PSM is the Research...

  18. Target-mediated drug disposition model and its approximations for antibody-drug conjugates.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2014-02-01

    Antibody-drug conjugate (ADC) is a complex structure composed of an antibody linked to several molecules of a biologically active cytotoxic drug. The number of ADC compounds in clinical development now exceeds 30, with two of them already on the market. However, there is no rigorous mechanistic model that describes pharmacokinetic (PK) properties of these compounds. PK modeling of ADCs is even more complicated than that of other biologics as the model should describe distribution, binding, and elimination of antibodies with different toxin load, and also the deconjugation process and PK of the released toxin. This work extends the target-mediated drug disposition (TMDD) model to describe ADCs, derives the rapid binding (quasi-equilibrium), quasi-steady-state, and Michaelis-Menten approximations of the TMDD model as applied to ADCs, derives the TMDD model and its approximations for ADCs with load-independent properties, and discusses further simplifications of the system under various assumptions. The developed models are shown to describe data simulated from the available clinical population PK models of trastuzumab emtansine (T-DM1), one of the two currently approved ADCs. Identifiability of model parameters is also discussed and illustrated on the simulated T-DM1 examples.

  19. Mathematical modeling of drug release from lipid dosage forms.

    Science.gov (United States)

    Siepmann, J; Siepmann, F

    2011-10-10

    Lipid dosage forms provide an interesting potential for controlled drug delivery. In contrast to frequently used poly(ester) based devices for parenteral administration, they do not lead to acidification upon degradation and potential drug inactivation, especially in the case of protein drugs and other acid-labile active agents. The aim of this article is to give an overview on the current state of the art of mathematical modeling of drug release from this type of advanced drug delivery systems. Empirical and semi-empirical models are described as well as mechanistic theories, considering diffusional mass transport, potentially limited drug solubility and the leaching of other, water-soluble excipients into the surrounding bulk fluid. Various practical examples are given, including lipid microparticles, beads and implants, which can successfully be used to control the release of an incorporated drug during periods ranging from a few hours up to several years. The great benefit of mechanistic mathematical theories is the possibility to quantitatively predict the effects of different formulation parameters and device dimensions on the resulting drug release kinetics. Thus, in silico simulations can significantly speed up product optimization. This is particularly useful if long release periods (e.g., several months) are targeted, since experimental trial-and-error studies are highly time-consuming in these cases. In the future it would be highly desirable to combine mechanistic theories with the quantitative description of the drug fate in vivo, ideally including the pharmacodynamic efficacy of the treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Animal Migraine Models for Drug Development

    DEFF Research Database (Denmark)

    Jansen-Olesen, Inger; Tfelt-Hansen, Peer; Olesen, Jes

    2013-01-01

    Migraine is number seven in WHO's list of all diseases causing disability and the third most costly neurological disorder in Europe. Acute attacks are treatable by highly selective drugs such as the triptans but there is still a huge unmet therapeutic need. Unfortunately, drug development...... for headache has almost come to a standstill partly because of a lack of valid animal models. Here we review previous models with emphasis on optimal characteristics of a future model. In addition to selection of animal species, the method of induction of migraine-like changes and the method of recording...... responses elicited by such measures are crucial. The most naturalistic way of inducing attacks is by infusion of endogenous signaling molecules that are known to cause migraine in patients. The most valid response is recording of neural activity in the trigeminal system. The most useful headache related...

  1. Beyond the drug-terror nexus: drug trafficking and state-crime relations in Central Asia.

    Science.gov (United States)

    De Danieli, Filippo

    2014-11-01

    In the wake of collapse of the Soviet Union, Central Asia has transformed into a key hub along the Afghan opiates trafficking routes. Around 30 percent of the heroin manufactured in Afghanistan is estimated to be smuggled through Central Asian republics in its way to booming drug markets in Russia and Eastern Europe. Building upon available evidence and extensive fieldwork research, the article seeks to confute mainstream analyses which emphasize connections between criminal and terrorist networks. The focus is on conducive factors for the establishment of drug routes in Central Asia, the characteristics of drug related networks, and the nature of political-criminal relations across the region. It is argued that in all five Central Asia republics strategic partnerships have formed between drug traffickers and state actors around the exploitation of drug rents and that mafias' influence on politics is stronger in Tajikistan and Kyrgyzstan, the region's poorest countries. By moving the focus from narco-terror to the state-crime connections, the article provides a critical insight into political economy issues surrounding a complex and multifaceted phenomenon such as the drug trade. Copyright © 2014. Published by Elsevier B.V.

  2. A Novel Chronic Opioid Monitoring Tool to Assess Prescription Drug Steady State Levels in Oral Fluid.

    Science.gov (United States)

    Shaparin, Naum; Mehta, Neel; Kunkel, Frank; Stripp, Richard; Borg, Damon; Kolb, Elizabeth

    2017-11-01

    Interpretation limitations of urine drug testing and the invasiveness of blood toxicology have motivated the desire for the development of simpler methods to assess biologically active drug levels on an individualized patient basis. Oral fluid is a matrix well-suited for the challenge because collections are based on simple noninvasive procedures and drug concentrations better correlate to blood drug levels as oral fluid is a filtrate of the blood. Well-established pharmacokinetic models were utilized to generate oral fluid steady state concentration ranges to assess the interpretive value of the alternative matrix to monitor steady state plasma oxycodone levels. Paired oral fluid and plasma samples were collected from patients chronically prescribed oxycodone and quantitatively analyzed by liquid chromatography tandem mass spectrometry. Steady state plasma concentration ranges were calculated for each donor and converted to an equivalent range in oral fluid. Measured plasma and oral fluid oxycodone concentrations were compared with respective matrix-matched steady state ranges, using each plasma steady state classification as the control. A high degree of correlation was observed between matrices when classifying donors according to expected steady state oxycodone concentration. Agreement between plasma and oral fluid steady state classifications was observed in 75.6% of paired samples. This study supports novel application of basic pharmacokinetic knowledge to the pain management industry, simplifying and improving individualized drug monitoring and risk assessment through the use of oral fluid drug testing. Many benefits of established therapeutic drug monitoring in plasma can be realized in oral fluid for patients chronically prescribed oxycodone at steady state. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  3. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  4. Illicit Drug Use, Illicit Drug Use Disorders, and Drug Overdose Deaths in Metropolitan and Nonmetropolitan Areas - United States.

    Science.gov (United States)

    Mack, Karin A; Jones, Christopher M; Ballesteros, Michael F

    2017-10-20

    Drug overdoses are a leading cause of injury death in the United States, resulting in approximately 52,000 deaths in 2015. Understanding differences in illicit drug use, illicit drug use disorders, and overall drug overdose deaths in metropolitan and nonmetropolitan areas is important for informing public health programs, interventions, and policies. Illicit drug use and drug use disorders during 2003-2014, and drug overdose deaths during 1999-2015. The National Survey of Drug Use and Health (NSDUH) collects information through face-to-face household interviews about the use of illicit drugs, alcohol, and tobacco among the U.S. noninstitutionalized civilian population aged ≥12 years. Respondents include residents of households and noninstitutional group quarters (e.g., shelters, rooming houses, dormitories, migratory workers' camps, and halfway houses) and civilians living on military bases. NSDUH variables include sex, age, race/ethnicity, residence (metropolitan/nonmetropolitan), annual household income, self-reported drug use, and drug use disorders. National Vital Statistics System Mortality (NVSS-M) data for U.S. residents include information from death certificates filed in the 50 states and the District of Columbia. Cases were selected with an underlying cause of death based on the ICD-10 codes for drug overdoses (X40-X44, X60-X64, X85, and Y10-Y14). NVSS-M variables include decedent characteristics (sex, age, and race/ethnicity) and information on intent (unintentional, suicide, homicide, or undetermined), location of death (medical facility, in a home, or other [including nursing homes, hospices, unknown, and other locations]) and county of residence (metropolitan/nonmetropolitan). Metropolitan/nonmetropolitan status is assigned independently in each data system. NSDUH uses a three-category system: Core Based Statistical Area (CBSA) of ≥1 million persons; CBSA of illicit drugs, the prevalence was highest for the large metropolitan areas compared with

  5. Modeling chemical reactions for drug design.

    Science.gov (United States)

    Gasteiger, Johann

    2007-01-01

    Chemical reactions are involved at many stages of the drug design process. This starts with the analysis of biochemical pathways that are controlled by enzymes that might be downregulated in certain diseases. In the lead discovery and lead optimization process compounds have to be synthesized in order to test them for their biological activity. And finally, the metabolism of a drug has to be established. A better understanding of chemical reactions could strongly help in making the drug design process more efficient. We have developed methods for quantifying the concepts an organic chemist is using in rationalizing reaction mechanisms. These methods allow a comprehensive modeling of chemical reactivity and thus are applicable to a wide variety of chemical reactions, from gas phase reactions to biochemical pathways. They are empirical in nature and therefore allow the rapid processing of large sets of structures and reactions. We will show here how methods have been developed for the prediction of acidity values and of the regioselectivity in organic reactions, for designing the synthesis of organic molecules and of combinatorial libraries, and for furthering our understanding of enzyme-catalyzed reactions and of the metabolism of drugs.

  6. State Space Modeling Using SAS

    Directory of Open Access Journals (Sweden)

    Rajesh Selukar

    2011-05-01

    Full Text Available This article provides a brief introduction to the state space modeling capabilities in SAS, a well-known statistical software system. SAS provides state space modeling in a few different settings. SAS/ETS, the econometric and time series analysis module of the SAS system, contains many procedures that use state space models to analyze univariate and multivariate time series data. In addition, SAS/IML, an interactive matrix language in the SAS system, provides Kalman filtering and smoothing routines for stationary and nonstationary state space models. SAS/IML also provides support for linear algebra and nonlinear function optimization, which makes it a convenient environment for general-purpose state space modeling.

  7. Econometric modelling of multiple self-reports of health states: The switch from EQ-5D-3L to EQ-5D-5L in evaluating drug therapies for rheumatoid arthritis.

    Science.gov (United States)

    Hernández-Alava, Mónica; Pudney, Stephen

    2017-09-01

    EQ-5D is used in cost-effectiveness studies underlying many important health policy decisions. It comprises a survey instrument describing health states across five domains, and a system of utility values for each state. The original 3-level version of EQ-5D is being replaced with a more sensitive 5-level version but the consequences of this change are uncertain. We develop a multi-equation ordinal response model incorporating a copula specification with normal mixture marginals to analyse joint responses to EQ-5D-3L and EQ-5D-5L in a survey of people with rheumatic disease, and use it to generate mappings between the alternative descriptive systems. We revisit a major cost-effectiveness study of drug therapies for rheumatoid arthritis, mapping the original EQ-5D-3L measure onto a 5L valuation basis. Working within a comprehensive, flexible econometric framework, we find that use of simpler restricted specifications can make very large changes to cost-effectiveness estimates with serious implications for decision-making. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Undocumented Immigration, Drug Problems, and Driving Under the Influence in the United States, 1990-2014.

    Science.gov (United States)

    Light, Michael T; Miller, Ty; Kelly, Brian C

    2017-09-01

    To examine the influence of undocumented immigration in the United States on 4 different metrics of drug and alcohol problems: drug arrests, drug overdose fatalities, driving under the influence (DUI) arrests, and DUI deaths. We combined newly developed state-level estimates of the undocumented population between 1990 and 2014 from the Center for Migration Studies with arrest data from the Federal Bureau of Investigation Uniform Crime Reports and fatality information from the Fatality Analysis Reporting System and the Centers for Disease Control and Prevention Underlying Cause of Death database. We used fixed-effects regression models to examine the longitudinal association between increased undocumented immigration and drug problems and drunk driving. Increased undocumented immigration was significantly associated with reductions in drug arrests, drug overdose deaths, and DUI arrests, net of other factors. There was no significant relationship between increased undocumented immigration and DUI deaths. This study provides evidence that undocumented immigration has not increased the prevalence of drug or alcohol problems, but may be associated with reductions in these public health concerns.

  9. Challenges in modelling nanoparticles for drug delivery

    International Nuclear Information System (INIS)

    Barnard, Amanda S

    2016-01-01

    Although there have been significant advances in the fields of theoretical condensed matter and computational physics, when confronted with the complexity and diversity of nanoparticles available in conventional laboratories a number of modeling challenges remain. These challenges are generally shared among application domains, but the impacts of the limitations and approximations we make to overcome them (or circumvent them) can be more significant one area than another. In the case of nanoparticles for drug delivery applications some immediate challenges include the incompatibility of length-scales, our ability to model weak interactions and solvation, the complexity of the thermochemical environment surrounding the nanoparticles, and the role of polydispersivity in determining properties and performance. Some of these challenges can be met with existing technologies, others with emerging technologies including the data-driven sciences; some others require new methods to be developed. In this article we will briefly review some simple methods and techniques that can be applied to these (and other) challenges, and demonstrate some results using nanodiamond-based drug delivery platforms as an exemplar. (topical review)

  10. Investigating drug repositioning opportunities in FDA drug labels through topic modeling.

    Science.gov (United States)

    Bisgin, Halil; Liu, Zhichao; Kelly, Reagan; Fang, Hong; Xu, Xiaowei; Tong, Weida

    2012-01-01

    Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach. A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels. Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In

  11. Drug-Excipient Interactions in the Solid State: The Role of Different Stress Factors.

    Science.gov (United States)

    Gressl, Corinna; Brunsteiner, Michael; Davis, Adrian; Landis, Margaret; Pencheva, Klimentina; Scrivens, Garry; Sluggett, Gregory W; Wood, Geoffrey P F; Gruber-Woelfler, Heidrun; Khinast, Johannes G; Paudel, Amrit

    2017-12-04

    Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

  12. Modeling volatility using state space models.

    Science.gov (United States)

    Timmer, J; Weigend, A S

    1997-08-01

    In time series problems, noise can be divided into two categories: dynamic noise which drives the process, and observational noise which is added in the measurement process, but does not influence future values of the system. In this framework, we show that empirical volatilities (the squared relative returns of prices) exhibit a significant amount of observational noise. To model and predict their time evolution adequately, we estimate state space models that explicitly include observational noise. We obtain relaxation times for shocks in the logarithm of volatility ranging from three weeks (for foreign exchange) to three to five months (for stock indices). In most cases, a two-dimensional hidden state is required to yield residuals that are consistent with white noise. We compare these results with ordinary autoregressive models (without a hidden state) and find that autoregressive models underestimate the relaxation times by about two orders of magnitude since they do not distinguish between observational and dynamic noise. This new interpretation of the dynamics of volatility in terms of relaxators in a state space model carries over to stochastic volatility models and to GARCH models, and is useful for several problems in finance, including risk management and the pricing of derivative securities. Data sets used: Olsen & Associates high frequency DEM/USD foreign exchange rates (8 years). Nikkei 225 index (40 years). Dow Jones Industrial Average (25 years).

  13. Preclinical experimental models of drug metabolism and disposition in drug discovery and development

    Directory of Open Access Journals (Sweden)

    Donglu Zhang

    2012-12-01

    Full Text Available Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.

  14. A Model for Random Student Drug Testing

    Science.gov (United States)

    Nelson, Judith A.; Rose, Nancy L.; Lutz, Danielle

    2011-01-01

    The purpose of this case study was to examine random student drug testing in one school district relevant to: (a) the perceptions of students participating in competitive extracurricular activities regarding drug use and abuse; (b) the attitudes and perceptions of parents, school staff, and community members regarding student drug involvement; (c)…

  15. An attention-based effective neural model for drug-drug interactions extraction.

    Science.gov (United States)

    Zheng, Wei; Lin, Hongfei; Luo, Ling; Zhao, Zhehuan; Li, Zhengguang; Zhang, Yijia; Yang, Zhihao; Wang, Jian

    2017-10-10

    Drug-drug interactions (DDIs) often bring unexpected side effects. The clinical recognition of DDIs is a crucial issue for both patient safety and healthcare cost control. However, although text-mining-based systems explore various methods to classify DDIs, the classification performance with regard to DDIs in long and complex sentences is still unsatisfactory. In this study, we propose an effective model that classifies DDIs from the literature by combining an attention mechanism and a recurrent neural network with long short-term memory (LSTM) units. In our approach, first, a candidate-drug-oriented input attention acting on word-embedding vectors automatically learns which words are more influential for a given drug pair. Next, the inputs merging the position- and POS-embedding vectors are passed to a bidirectional LSTM layer whose outputs at the last time step represent the high-level semantic information of the whole sentence. Finally, a softmax layer performs DDI classification. Experimental results from the DDIExtraction 2013 corpus show that our system performs the best with respect to detection and classification (84.0% and 77.3%, respectively) compared with other state-of-the-art methods. In particular, for the Medline-2013 dataset with long and complex sentences, our F-score far exceeds those of top-ranking systems by 12.6%. Our approach effectively improves the performance of DDI classification tasks. Experimental analysis demonstrates that our model performs better with respect to recognizing not only close-range but also long-range patterns among words, especially for long, complex and compound sentences.

  16. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    )-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers......The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R...... indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site...

  17. Application of Model Animals in the Study of Drug Toxicology

    Science.gov (United States)

    Song, Yagang; Miao, Mingsan

    2018-01-01

    Drug safety is a key factor in drug research and development, Drug toxicology test is the main method to evaluate the safety of drugs, The body condition of an animal has important implications for the results of the study, Previous toxicological studies of drugs were carried out in normal animals in the past, There is a great deviation from the clinical practice.The purpose of this study is to investigate the necessity of model animals as a substitute for normal animals for toxicological studies, It is expected to provide exact guidance for future drug safety evaluation.

  18. THE JUST DRUG DISTRIBUTION IN THE PERSPECTIVE OF WELFARE STATE

    Directory of Open Access Journals (Sweden)

    Aktieva Tri Tjitrawati

    2014-03-01

    Full Text Available States have obligations to improve equitability of welfare and prosperity of the community. Pharmaceutical is one of the important and strategic industries because of its vital role to support the development of health sector. Lack of regulation on pricing-products, and diversion of social aspects in the drugs trade, either by government or industry, are associated with the paradigm that underlies regulation of the distributions. Prospective policy analysis and functional approach of law are used to find a level of balance of various interest related to the subject, and to find concepts as a basis to construct new paradigm on drugs distribution. Negara berkewajiban untuk meningkatkan kesejahteraan dan kemakmuran masyarakat secara berkeadilan. Industri farmasi merupakan salah satu industri penting dan strategis karena perannya yang vital menunjang pembangunan bidang kesehatan.Terdapat kecenderungan kurangnya peran Pemerintah dalam pricing policy obat, serta diabaikannya aspek sosial dalam perdagangan produk farmasi, baik oleh Pemerintah maupun industri farmasi. Carut marut ini berkaitan dengan ketidakjelasan paradigma yang berujung pada ketidakjelasan kebijakan yang melandasi tatanan distribusi obat. Makalah ini menggunakan analisis kebijakan prospektif dan pendekatan fungsional hukum untuk mengkaji kebijakan distribusi obat yang bersifat multi disiplin dan menemukan konsep baru untuk menemukan titik keseimbangan dari berbagai kepentingan terkait.

  19. U.S. Food and Drug Administration drug approval: slow advances in obstetric care in the United States.

    Science.gov (United States)

    Wing, Deborah A; Powers, Barbara; Hickok, Durlin

    2010-04-01

    The process for drug approval in the United States is complex and time-consuming. There are comparatively few drugs with U.S. Food and Drug Administration (FDA)-approved indications for obstetric use in this country at this time; however, several are under development. We review the process for drug approval and recount the approval histories of obstetric drugs reviewed in the recent past. We also outline the current status of two progestational agents that are under development. For a variety of reasons, including a small market compared with others such as cardiology or oncology, and the potential of being drawn into medical-legal litigation, sponsors are disinclined to pursue drug development for obstetric purposes in this country. We compare the procedures for review and approval of drugs in the United States with those in Europe, and note that recent changes within the FDA may result in not only more drugs being approved but also changes in labeling of already approved drugs. Special programs to facilitate drug development and reforms to modernize the process and improve safety are discussed. These may result in changes in labeling of already approved drugs. Obstacles such as funding and liability are also discussed.

  20. [Organization of the drug supply chain in state health services: potential consequences of the public-private mix].

    Science.gov (United States)

    López-Moreno, Sergio; Martínez-Ojeda, Rosa Haydeé; López-Arellano, Oliva; Jarillo-Soto, Edgar; Castro-Albarrán, Juan Manuel

    2011-01-01

    To assess the consequences of private outsourcing on the overall supply and filling of prescriptions in state health services. The research was conducted using quantitative and qualitative techniques in 13 states. The information was collected through interviews and direct observation. The interviews were carried on staff of state health services related to the drug supply chain and users of health services. The quantitative approach examined the percentage of stocked full recipes in a sample of users. States that have opted for the fully outsourced model, and properly monitored this choice, have increased the supply of drugs to their users and guaranteed the supply in the care units in charge. Other states with the outsourced model have multiple problems: direct purchase of drugs not included in the basic drugs catalogue, failure of suppliers and shortage of supplies in the laboratories that provide the company. The main disadvantages identified in all models were: the subordination of the medical criteria to administrative criteria, insufficient planning based on local care needs, heterogeneous procedures, insufficient knowledge of regulations and lack of normativity. The results indicate that the incorporation of private providers in the drug supply chain may not be the solution to bring down the shortage faced by health services, especially at the hospital level. The shift to outsourcing models has developed without incorporating evaluation mechanisms and the consequences that this transition can have on state health systems must be investigated more deeply.

  1. Modeling the modified drug release from curved shape drug delivery systems - Dome Matrix®.

    Science.gov (United States)

    Caccavo, D; Barba, A A; d'Amore, M; De Piano, R; Lamberti, G; Rossi, A; Colombo, P

    2017-12-01

    The controlled drug release from hydrogel-based drug delivery systems is a topic of large interest for research in pharmacology. The mathematical modeling of the behavior of these systems is a tool of emerging relevance, since the simulations can be of use in the design of novel systems, in particular for complex shaped tablets. In this work a model, previously developed, was applied to complex-shaped oral drug delivery systems based on hydrogels (Dome Matrix®). Furthermore, the model was successfully adopted in the description of drug release from partially accessible Dome Matrix® systems (systems with some surfaces coated). In these simulations, the erosion rate was used asa fitting parameter, and its dependence upon the surface area/volume ratio and upon the local fluid dynamics was discussed. The model parameters were determined by comparison with the drug release profile from a cylindrical tablet, then the model was successfully used for the prediction of the drug release from a Dome Matrix® system, for simple module configuration and for module assembled (void and piled) configurations. It was also demonstrated that, given the same initial S/V ratio, the drug release is independent upon the shape of the tablets but it is only influenced by the S/V evolution. The model reveals itself able to describe the observed phenomena, and thus it can be of use for the design of oral drug delivery systems, even if complex shaped. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Rhodamine/Nanodiamond as a System Model for Drug Carrier.

    Science.gov (United States)

    Reina, G; Orlanducci, S; Cairone, C; Tamburri, E; Lenti, S; Cianchetta, I; Rossi, M; Terranova, M L

    2015-02-01

    In this paper we present some strategies that are being developed in our labs towards enabling nanodiamond-based applications for drug delivery. Rhodamine B (RhB) has been choosen as model molecule to study the loading of nanodiamonds with active moieties and the conditions for their controlled release. In order to test the chemical/physical interactions between functionalized detonation nanodiamond (DND) and complex molecules, we prepared and tested different RhB@DND systems, with RhB adsorbed or linked by ionic bonding to the DND surface. The chemical state of the DND surfaces before conjugation with the RhB molecules, and the chemical features of the DND-RhB interactions have been deeply analysed by coupling DND with Au nanoparticles and taking advantage of surface enhanced Raman spectroscopy SERS. The effects due to temperature and pH variations on the process of RhB release from the DND carrier have been also investigated. The amounts of released molecules are consistent with those required for effective drug action in conventional therapeutic applications, and this makes the DND promising nanostructured cargos for drug delivery applications.

  3. Cell physiology based pharmacodynamic modeling of antimicrobial drug combinations

    OpenAIRE

    Hethey, Christoph Philipp

    2017-01-01

    Mathematical models of bacterial growth have been successfully applied to study the relationship between antibiotic drug exposure and the antibacterial effect. Since these models typically lack a representation of cellular processes and cell physiology, the mechanistic integration of drug action is not possible on the cellular level. The cellular mechanisms of drug action, however, are particularly relevant for the prediction, analysis and understanding of interactions between antibiotics. In...

  4. A Structural Model of the Retail Market for Illicit Drugs.

    Science.gov (United States)

    Galenianos, Manolis; Gavazza, Alessandro

    2017-03-01

    We estimate a model of illicit drugs markets using data on purchases of crack cocaine. Buyers are searching for high-quality drugs, but they determine drugs' quality (i.e., their purity) only after consuming them. Hence, sellers can rip off first-time buyers or can offer higher-quality drugs to induce buyers to purchase from them again. In equilibrium, a distribution of qualities persists. The estimated model implies that if drugs were legalized, in which case purity could be regulated and hence observable, the average purity of drugs would increase by approximately 20 percent and the dispersion would decrease by approximately 80 percent. Moreover, increasing penalties may raise the purity and affordability of the drugs traded by increasing sellers’ relative profitability of targeting loyal buyers versus first-time buyers.

  5. NCHS - Drug Poisoning Mortality by County: United States

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset describes drug poisoning deaths at the county level by selected demographic characteristics and includes age-adjusted death rates for drug poisoning...

  6. Intestinal Oxidative State Can Alter Nutrient and Drug Bioavailability

    Directory of Open Access Journals (Sweden)

    Faria Ana

    2009-01-01

    Full Text Available Organic cations (OCs are substances of endogenous (e.g., dopamine, choline or exogenous (e.g., drugs like cimetidine origin that are positively charged at physiological ph. since many of these compounds can not pass the cell membrane freely, their transport in or out of cells must be mediated by specific transport systems. Transport by organic cation transporters (OCTs can be regulated rapidly by altering their trafficking and/or affinities in response to stimuli. However, for example, a specific disease could lead to modifications in the expression of OCTs. Chronic exposure to oxidative stress has been suggested to alter regulation and functional activity of proteins through several pathways. According to results from a previous work, oxidation-reduction pathways were thought to be involved in intestinal organic cation uptake modulation. The present work was performed in order to evaluate the influence of oxidative stressors, especially glutathione, on the intestinal organic cation absorption. For this purpose, the effect of compounds with different redox potential (glutathione, an endogenous antioxidant, and procyanidins, diet antioxidants was assessed on MPP+ (1-methyl-4-phenylpyridinium iodide uptake in an enterocyte cell line (Caco-2. Caco-2 cells were subcultured with two different media conditions (physiological: 5 mM glucose, referred as control cells; and high-glucose: 25 mM glucose, referred as HG cells. In HG cells, the uptake was significantly lower than in control cells. Redox changing interventions affected Mpp+ uptake, both in control and in high-glucose Caco-2 cells. Cellular glutathione levels could have an important impact on membrane transporter activity. The results indicate that modifications in the cellular oxidative state modulate MPP+ uptake by Caco-2 cells. Such modifications may reflect in changes of nutrient and drug bioavailability.

  7. Modelling Formation of a Drug Reservoir in the Stratum Corneum and Its Impact on Drug Monitoring Using Reverse Iontophoresis

    Directory of Open Access Journals (Sweden)

    Yvonne Paulley

    2010-01-01

    Full Text Available Reverse iontophoresis is a relatively new technique for non-invasive drug monitoring in the body. It involves a small electrical current being passed through the skin to facilitate the movement of small charged ions and polar molecules on the skin's surface where the amount of drug can then be measured and hence an accurate estimate of the blood concentration can be made. In vivo studies for several molecules show that initially large amounts of drug are extracted from the body, which are unrelated to the magnitude of the blood concentration; over time the fluxes of extraction decrease to a level proportional to the steady state blood concentration. This suggests that, at first, the drug is being extracted from some source other than the blood; one such candidate for this source is the dead cells which form the stratum corneum. In this paper, we construct two related mathematical models; the first describes the formation of the drug reservoir in the stratum corneum as a consequence of repeated drug intake and natural death of skin cells in the body. The output from this model provides initial conditions for the model of reverse iontophoresis in which charged ions from both the blood and the stratum corneum reservoir compete for the electric current. Model parameters are estimated from data collected for lithium monitoring. Our models will improve interpretation of reverse iontophoretic data by discriminating the subdermal from the skin contribution to the fluxes of extraction. They also suggest that analysis of the skin reservoir might be a valuable tool to investigate patients' exposure to chemicals including therapeutic drugs.

  8. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  9. Modeling Drug-Carrier Interaction in the Drug Release from Nanocarriers

    Directory of Open Access Journals (Sweden)

    Like Zeng

    2011-01-01

    Full Text Available Numerous nanocarriers of various compositions and geometries have been developed for the delivery and release of therapeutic and imaging agents. Due to the high specific surface areas of nanocarriers, different mechanisms such as ion pairing and hydrophobic interaction need to be explored for achieving sustained release. Recently, we developed a three-parameter model that considers reversible drug-carrier interaction and first-order drug release from liposomes. A closed-form analytical solution was obtained. Here, we further explore the ability of the model to capture the release of bioactive molecules such as drugs and growth factors from various nanocarriers. A parameter study demonstrates that the model is capable of resembling major categories of drug release kinetics. We further fit the model to 60 sets of experimental data from various drug release systems, including nanoparticles, hollow particles, fibers, and hollow fibers. Additionally, bootstrapping is used to evaluate the accuracy of parameter determination and validate the model in selected cases. The simplicity and universality of the model and the clear physical meanings of each model parameter render the model useful for the design and development of new drug delivery systems.

  10. Functional State Modelling of Cultivation Processes: Dissolved Oxygen Limitation State

    Directory of Open Access Journals (Sweden)

    Olympia Roeva

    2015-04-01

    Full Text Available A new functional state, namely dissolved oxygen limitation state for both bacteria Escherichia coli and yeast Saccharomyces cerevisiae fed-batch cultivation processes is presented in this study. Functional state modelling approach is applied to cultivation processes in order to overcome the main disadvantages of using global process model, namely complex model structure and a big number of model parameters. Alongwith the newly introduced dissolved oxygen limitation state, second acetate production state and first acetate production state are recognized during the fed-batch cultivation of E. coli, while mixed oxidative state and first ethanol production state are recognized during the fed-batch cultivation of S. cerevisiae. For all mentioned above functional states both structural and parameter identification is here performed based on experimental data of E. coli and S. cerevisiae fed-batch cultivations.

  11. United States National Library of Medicine Drug Information Portal.

    Science.gov (United States)

    Hochstein, Colette; Goshorn, Jeanne; Chang, Florence

    2009-01-01

    The Drug Information Portal is a free Web resource from the National Library of Medicine (NLM) that provides a user-friendly gateway to current information for more than 15,000 drugs. The site guides users to related resources of NLM, the National Institutes of Health (NIH), and other government agencies. Current drug-related information regarding consumer health, clinical trials, AIDS, MeSH pharmacological actions, MEDLINE/PubMed biomedical literature, and physical properties and structure is easily retrieved by searching on a drug name. A varied selection of focused topics in medicine and drugs is also available from displayed subject headings. This column provides background information about the Drug Information Portal, as well as search basics.

  12. Floating solid cellulose nanofibre nanofoams for sustained release of the poorly soluble model drug furosemide

    DEFF Research Database (Denmark)

    Svagan, Anna Justina; Müllertz, Anette; Löbmann, Korbinian

    2017-01-01

    OBJECTIVES: This study aimed to prepare a furosemide-loaded sustained release cellulose nanofibre (CNF)-based nanofoams with buoyancy. METHODS: Dry foams consisting of CNF and the model drug furosemide at concentrations of 21% and 50% (w/w) have been prepared by simply foaming a CNF-drug suspension...... followed by drying. The resulting foams were characterized towards their morphology, solid state properties and dissolution kinetics. KEY FINDINGS: Solid state analysis of the resulting drug-loaded foams revealed that the drug was present as an amorphous sodium furosemide salt and in form of furosemide...... form I crystals embedded in the CNF foam cell walls. The foams could easily be shaped and were flexible, and during the drug release study, the foam pieces remained intact and were floating on the surface due to their positive buoyancy. Both foams showed a sustained furosemide release compared...

  13. Mathematical modeling for novel cancer drug discovery and development.

    Science.gov (United States)

    Zhang, Ping; Brusic, Vladimir

    2014-10-01

    Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments. This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment. Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.

  14. Understanding public drug procurement in India: a comparative qualitative study of five Indian states.

    Science.gov (United States)

    Singh, Prabal Vikram; Tatambhotla, Anand; Kalvakuntla, Rohini; Chokshi, Maulik

    2013-01-01

    To perform an initial qualitative comparison of the different procurement models in India to frame questions for future research in this area; to capture the finer differences between the state models through 53 process and price parameters to determine their functional efficiencies. Qualitative analysis is performed for the study. Five states: Tamil Nadu, Kerala, Odisha, Punjab and Maharashtra were chosen to ensure heterogeneity in a number of factors such as procurement type (centralised, decentralised or mixed); autonomy of the procurement organisation; state of public health infrastructure; geography and availability of data through Right to Information Act (RTI). Data on procurement processes were collected through key informant analysis by way of semistructured interviews with leadership teams of procuring organisations. These process data were validated through interviews with field staff (stakeholders of district hospitals, taluk hospitals, community health centres and primary health centres) in each state. A total of 30 actors were interviewed in all five states. The data collected are analysed against 52 process and price parameters to determine the functional efficiency of the model. The analysis indicated that autonomous procurement organisations were more efficient in relation to payments to suppliers, had relatively lower drug procurement prices and managed their inventory more scientifically. The authors highlight critical success factors that significantly influence the outcome of any procurement model. In a way, this study raises more questions and seeks the need for further research in this arena to aid policy makers.

  15. In silico modeling to predict drug-induced phospholipidosis

    International Nuclear Information System (INIS)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G.; Sadrieh, Nakissa

    2013-01-01

    Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL

  16. Drug Per Se Laws: A Review of their Use in States

    Science.gov (United States)

    2010-07-01

    This report summarizes a study of the implementation of drug per se laws in 15 States. These laws generally make it an : impaired-driving offense to drive with a measurable amount of certain drugs in ones system. The specific prohibited : drugs va...

  17. The Impact of an Indiana (United States Drug Court on Criminal Recidivism

    Directory of Open Access Journals (Sweden)

    John R. Gallagher

    2014-07-01

    Full Text Available This study evaluated a drug court located in a metropolitan area of Indiana (United States, focusing specifically on identifying variables that predicted recidivism among drug court participants and comparing criminal recidivism patterns among drug court and probation participants. Drug court participants were most likely to recidivate if they were younger, had a violation within the first 30 days of the program, had a previous criminal record, and were terminated unsuccessfully from the program. Furthermore, drug court participants were less likely to recidivate than probationers who had similar offense and demographic characteristics. Implications for drug court practice, policy advocacy, and future research are discussed.

  18. Prediction of adverse drug reactions using decision tree modeling.

    Science.gov (United States)

    Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

    2010-07-01

    Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

  19. Dosage and dose schedule screening of drug combinations in agent-based models reveals hidden synergies

    Directory of Open Access Journals (Sweden)

    Lisa Corina Barros de Andrade e Sousa1

    2016-01-01

    Full Text Available The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  20. Constructing Markov State Models to elucidate the functional conformational changes of complex biomolecules

    KAUST Repository

    Wang, Wei; Cao, Siqin; Zhu, Lizhe; Huang, Xuhui

    2017-01-01

    bioengineering applications and rational drug design. Constructing Markov State Models (MSMs) based on large-scale molecular dynamics simulations has emerged as a powerful approach to model functional conformational changes of the biomolecular system

  1. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity

    Science.gov (United States)

    Ellinwood, Nicholas; Dobrev, Dobromir; Morotti, Stefano; Grandi, Eleonora

    2017-09-01

    The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti

  3. Characteristics of Suicides Caused by Drug Overdose in the State of Maryland

    Directory of Open Access Journals (Sweden)

    Ling Li

    2015-01-01

    Full Text Available Suicidal drug overdose is a major public health issue. In the United States, every year more than 33,000 people commit suicides. Our study focused on the characteristics of suicide victims in the state of Maryland. Material and methods: This study was a retrospective review of autopsy cases of all suicide deaths caused by drug (s or drug (s with alcohol intoxication investigated by the OCME in Maryland over a 7-year period from January 2004 to December 2011. All deaths investigated by the OCME that require autopsy examination are subject to comprehensive toxicology testing for drugs and alcohol. The screen tests were performed using gas chromatography (GC and radioimmunoassay techniques. All detected drugs and/or metabolites were confirmed using GC-mass spectrometry (GC-MS. Results: From 2004 to 2011, 434 deaths were certified as suicide. Of the 434 suicidal overdose deaths, 84% were white, 11% were African-American, and about 5% were either Hispanic or Asian. The male and female ratio was almost equal. Their ages ranged 15-82 years. Of the 434 suicidal drug overdose deaths, 277 victims (63.8% consumed a single drug type and 157 (36.2% consumed more than one type of drug. Of the 277 single-drug overdose cases, 71.1% suicides were due to prescription drugs, 23.5% due to over-the-counter drugs, and 5.4% due to street/recreational drugs. Among single-type prescription drugs, analgesic (N = 76, antidepressant (N = 45, and neuroleptic (N = 35 classes were the three leading type of drugs used in suicidal deaths. Oxycodone, morphine, quetiapine, and amitriptyline were the most common prescription drugs in suicidal overdose. Diphenhydramine was the leading over-the-counter drug. Of the 157 victims who consumed more than one drug, combined prescription drugs were present in 54.1%, mixed prescription and over-the-counter drugs in 29.3%, and prescription drugs/over-the-counter drugs and street drugs in 16.6% of cases. Of the multiple-drug overdose suicides

  4. Thermosensitive liposomal drug delivery systems: state of the art review

    Directory of Open Access Journals (Sweden)

    Kneidl B

    2014-09-01

    Full Text Available Barbara Kneidl,1,2 Michael Peller,3 Gerhard Winter,2 Lars H Lindner,1 Martin Hossann11Department of Internal Medicine III, University Hospital Munich, 2Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, 3Institute for Clinical Radiology, University Hospital Munich, Ludwig-Maximilians University, Munich, GermanyAbstract: Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine.Keywords: thermosensitive liposomes, phosphatidyloligoglycerol, hyperthermia, high intensity focused ultrasound, drug delivery, drug targeting

  5. A graph theoretical perspective of a drug abuse epidemic model

    Science.gov (United States)

    Nyabadza, F.; Mukwembi, S.; Rodrigues, B. G.

    2011-05-01

    A drug use epidemic can be represented by a finite number of states and transition rules that govern the dynamics of drug use in each discrete time step. This paper investigates the spread of drug use in a community where some users are in treatment and others are not in treatment, citing South Africa as an example. In our analysis, we consider the neighbourhood prevalence of each individual, i.e., the proportion of the individual’s drug user contacts who are not in treatment amongst all of his or her contacts. We introduce parameters α∗, β∗ and γ∗, depending on the neighbourhood prevalence, which govern the spread of drug use. We examine how changes in α∗, β∗ and γ∗ affect the system dynamics. Simulations presented support the theoretical results.

  6. Mathematical models for drug diffusion through the compartments of ...

    African Journals Online (AJOL)

    M.A. Khanday

    2016-07-26

    Jul 26, 2016 ... partments have both favourable and adverse effects on human body. The researchers ... absorption, distribution and elimination process of the drug within the body ... models can be used to understand the transport processes.

  7. State and Community Responses to Drug-related Violence in Mexico

    International Development Research Centre (IDRC) Digital Library (Canada)

    Extrants. Études. State and community responses to drug-related violence in Mexico. Rapports. Respuestas estatales y comunitarias a la violencia asociada al narcotráfico en México : informe técnico. Rapports. State and community responses to drug-related violence in Mexico ...

  8. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    Science.gov (United States)

    di Clemente, Riccardo; Pietronero, Luciano

    2012-07-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  9. My Life with State Space Models

    DEFF Research Database (Denmark)

    Lundbye-Christensen, Søren

    2007-01-01

    . The conceptual idea behind the state space model is that the evolution over time in the object we are observing and the measurement process itself are modelled separately. My very first serious analysis of a data set was done using a state space model, and since then I seem to have been "haunted" by state space...

  10. The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment.

    Science.gov (United States)

    Pringle, Abbie; Harmer, Catherine J

    2015-12-01

    Human models of emotional processing suggest that the direct effect of successful antidepressant drug treatment may be to modify biases in the processing of emotional information. Negative biases in emotional processing are documented in depression, and single or short-term dosing with conventional antidepressant drugs reverses these biases in depressed patients prior to any subjective change in mood. Antidepressant drug treatments also modulate emotional processing in healthy volunteers, which allows the consideration of the psychological effects of these drugs without the confound of changes in mood. As such, human models of emotional processing may prove to be useful for testing the efficacy of novel treatments and for matching treatments to individual patients or subgroups of patients.

  11. Association between unemployment rates and prescription drug utilization in the United States, 2007–2010

    Science.gov (United States)

    2012-01-01

    Background While extensive evidence suggests that the economic recession has had far reaching effects on many economic sectors, little is known regarding its impact on prescription drug utilization. The purpose of this study is to describe the association between state-level unemployment rates and retail sales of seven therapeutic classes (statins, antidepressants, antipsychotics, angiotensin-converting enzyme [ACE] inhibitors, opiates, phosphodiesterase [PDE] inhibitors and oral contraceptives) in the United States. Methods Using a retrospective mixed ecological design, we examined retail prescription sales using IMS Health Xponent™ from September 2007 through July 2010, and we used the Bureau of Labor Statistics to derive population-based rates and mixed-effects modeling with state-level controls to examine the association between unemployment and utilization. Our main outcome measure was state-level utilization per 100,000 people for each class. Results Monthly unemployment levels and rates of use of each class varied substantially across the states. There were no statistically significant associations between use of ACE inhibitors or SSRIs/SNRIs and average unemployment in analyses across states, while for opioids and PDE inhibitors there were small statistically significant direct associations, and for the remaining classes inverse associations. Analyses using each state as its own control collectively exhibited statistically significant positive associations between increases in unemployment and prescription drug utilization for five of seven areas examined. This relationship was greatest for statins (on average, a 4% increase in utilization per 1% increased unemployment) and PDE inhibitors (3% increase in utilization per 1% increased unemployment), and lower for oral contraceptives and atypical antipsychotics. Conclusion We found no evidence of an association between increasing unemployment and decreasing prescription utilization, suggesting that any

  12. SEIIrR: Drug abuse model with rehabilitation

    Science.gov (United States)

    Sutanto, Azizah, Afina; Widyaningsih, Purnami; Saputro, Dewi Retno Sari

    2017-05-01

    Drug abuse in the world quite astonish and tend to increase. The increase and decrease on the number of drug abusers showed a pattern of spread that had the same characteristics with patterns of spread of infectious disease. The susceptible infected removed (SIR) and susceptible exposed infected removed (SEIR) epidemic models for infectious disease was developed to study social epidemic. In this paper, SEIR model for disease epidemic was developed to study drug abuse epidemic with rehabilitation treatment. The aims of this paper were to analogize susceptible exposed infected isolated recovered (SEIIrR) model on the drug abusers, to determine solutions of the model, to determine equilibrium point, and to do simulation on β. The solutions of SEIIrR model was determined by using fourth order of Runge-Kutta algorithm, equilibrium point obtained was free-drug equilibrium point. Solutions of SEIIrR showed that the model was able to suppress the spread of drug abuse. The increasing value of contact rate was not affect the number of infected individuals due to rehabilitation treatment.

  13. The FDA Unapproved Drugs Initiative: An Observational Study of the Consequences for Drug Prices and Shortages in the United States.

    Science.gov (United States)

    Gupta, Ravi; Dhruva, Sanket S; Fox, Erin R; Ross, Joseph S

    2017-10-01

    Hundreds of drug products are currently marketed in the United States without approval from the FDA. The 2006 Unapproved Drugs Initiative (UDI) requires manufacturers to remove these drug products from the market or obtain FDA approval by demonstrating evidence of safety and efficacy. Once the FDA acts against an unapproved drug, fewer manufacturers remain in the market, potentially enabling drug price increases and greater susceptibility to drug shortages. There is a need for systematic study of the UDI's effect on prices and shortages of all targeted drugs. To examine the clinical evidence for approval and association with prices and shortages of previously unapproved prescription drugs after being addressed by the UDI. Previously unapproved prescription drugs that faced UDI regulatory action or with at least 1 product that received FDA approval through manufacturers' voluntary compliance with the UDI between 2006 and 2015 were identified. The clinical evidence was categorized as either newly conducted clinical trials or use of previously published literature and/or bioequivalence studies to demonstrate safety and efficacy. We determined the change in average wholesale price, presence of shortage, and duration of shortage for each drug during the 2 years before and after UDI regulatory action or approval through voluntary compliance. Between 2006 and 2015, 34 previously unapproved prescription drugs were addressed by the UDI. Nearly 90% of those with a drug product that received FDA approval were supported by literature reviews or bioequivalence studies, not new clinical trial evidence. Among the 26 drugs with available pricing data, average wholesale price during the 2 years before and after voluntary approval or UDI action increased by a median of 37% (interquartile range [IQR] = 23%-204%; P Innovation; from the Blue Cross Blue Shield Association to better understand medical technology evidence generation; from the Centers for Medicare & Medicaid Services to

  14. Zebrafish models in neuropsychopharmacology and CNS drug discovery.

    Science.gov (United States)

    Khan, Kanza M; Collier, Adam D; Meshalkina, Darya A; Kysil, Elana V; Khatsko, Sergey L; Kolesnikova, Tatyana; Morzherin, Yury Yu; Warnick, Jason E; Kalueff, Allan V; Echevarria, David J

    2017-07-01

    Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets. © 2017 The British Pharmacological Society.

  15. Drug-loaded electrospun mats of poly(vinyl alcohol) fibres and their release characteristics of four model drugs

    Science.gov (United States)

    Taepaiboon, Pattama; Rungsardthong, Uracha; Supaphol, Pitt

    2006-05-01

    Mats of PVA nanofibres were successfully prepared by the electrospinning process and were developed as carriers of drugs for a transdermal drug delivery system. Four types of non-steroidal anti-inflammatory drug with varying water solubility property, i.e. sodium salicylate (freely soluble in water), diclofenac sodium (sparingly soluble in water), naproxen (NAP), and indomethacin (IND) (both insoluble in water), were selected as model drugs. The morphological appearance of the drug-loaded electrospun PVA mats depended on the nature of the model drugs. The 1H-nuclear magnetic resonance results confirmed that the electrospinning process did not affect the chemical integrity of the drugs. Thermal properties of the drug-loaded electrospun PVA mats were analysed by differential scanning calorimetry and thermogravimetric analysis. The molecular weight of the model drugs played a major role on both the rate and the total amount of drugs released from the as-prepared drug-loaded electrospun PVA mats, with the rate and the total amount of the drugs released decreasing with increasing molecular weight of the drugs. Lastly, the drug-loaded electrospun PVA mats exhibited much better release characteristics of the model drugs than drug-loaded as-cast films.

  16. A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States.

    Science.gov (United States)

    Calderon, Silvia N; Klein, Michael

    2014-12-01

    In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'. Published by Elsevier Ltd.

  17. Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs.

    Science.gov (United States)

    Kianfar, Farnoosh; Chowdhry, Babur Z; Antonijevic, Milan D; Boateng, Joshua S

    2012-10-01

    Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w κ-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a T(g) at 22.25 and 30.77°C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40 min of contact with dissolution medium simulating saliva.

  18. Regulation of chromatin states by drugs of abuse.

    Science.gov (United States)

    Walker, Deena M; Cates, Hannah M; Heller, Elizabeth A; Nestler, Eric J

    2015-02-01

    Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors. There is a complex interplay between these enzymes, resulting in a histone signature of the addicted phenotype. Insights gained from these studies are key to identifying novel targets for diagnosis and therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Functional State Modelling of Saccharomyces cerevisiae Cultivations

    Directory of Open Access Journals (Sweden)

    Iasen Hristozov

    2004-10-01

    Full Text Available The implementation of functional state approach for modelling of yeast cultivation is considered in this paper. This concept helps in monitoring and control of complex processes such as bioprocesses. Using of functional state modelling approach for fermentation processes aims to overcome the main disadvantage of using global process model, namely complex model structure and big number of model parameters. The main advantage of functional state modelling is that the parameters of each local model can be separately estimated from other local models parameters. The results achieved from batch, as well as from fed-batch, cultivations are presented.

  20. State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery

    Science.gov (United States)

    Sirsi, Shashank; Borden, Mark

    2014-01-01

    Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents. PMID:24389162

  1. Comparing Generic Drug Markets in Europe and the United States: Prices, Volumes, and Spending.

    Science.gov (United States)

    Wouters, Olivier J; Kanavos, Panos G; McKEE, Martin

    2017-09-01

    Policy Points: Our study indicates that there are opportunities for cost savings in generic drug markets in Europe and the United States. Regulators should make it easier for generic drugs to reach the market. Regulators and payers should apply measures to stimulate price competition among generic drugmakers and to increase generic drug use. To meaningfully evaluate policy options, it is important to analyze historical context and understand why similar initiatives failed previously. Rising drug prices are putting pressure on health care budgets. Policymakers are assessing how they can save money through generic drugs. We compared generic drug prices and market shares in 13 European countries, using data from 2013, to assess the amount of variation that exists between countries. To place these results in context, we reviewed evidence from recent studies on the prices and use of generics in Europe and the United States. We also surveyed peer-reviewed studies, gray literature, and books published since 2000 to (1) outline existing generic drug policies in European countries and the United States; (2) identify ways to increase generic drug use and to promote price competition among generic drug companies; and (3) explore barriers to implementing reform of generic drug policies, using a historical example from the United States as a case study. The prices and market shares of generics vary widely across Europe. For example, prices charged by manufacturers in Switzerland are, on average, more than 2.5 times those in Germany and more than 6 times those in the United Kingdom, based on the results of a commonly used price index. The proportion of prescriptions filled with generics ranges from 17% in Switzerland to 83% in the United Kingdom. By comparison, the United States has historically had low generic drug prices and high rates of generic drug use (84% in 2013), but has in recent years experienced sharp price increases for some off-patent products. There are policy

  2. Novel Nanostructured Solid Materials for Modulating Oral Drug Delivery from Solid-State Lipid-Based Drug Delivery Systems.

    Science.gov (United States)

    Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

    2016-01-01

    Lipid-based drug delivery systems (LBDDS) have gained significant attention in recent times, owing to their ability to overcome the challenges limiting the oral delivery of poorly water-soluble drugs. Despite the successful commercialization of several LBDDS products over the years, a large discrepancy exists between the number of poorly water-soluble drugs displaying suboptimal in vivo performances and the application of LBDDS to mitigate their various delivery challenges. Conventional LBDDS, including lipid solutions and suspensions, emulsions, and self-emulsifying formulations, suffer from various drawbacks limiting their widespread use and commercialization. Accordingly, solid-state LBDDS, fabricated by adsorbing LBDDS onto a chemically inert solid carrier material, have attracted substantial interest as a viable means of stabilizing LBDDS whilst eliminating some of the various limitations. This review describes the impact of solid carrier choice on LBDDS performance and highlights the importance of appropriate solid carrier material selection when designing hybrid solid-state LBDDS. Specifically, emphasis is placed on discussing the ability of the specific solid carrier to modulate drug release, control lipase action and lipid digestion, and enhance biopharmaceutical performance above the original liquid-state LBDDS. To encourage the interested reader to consider their solid carrier choice on a higher level, various novel materials with the potential for future use as solid carriers for LBDDS are described. This review is highly significant in guiding future research directions in the solid-state LBDDS field and fostering the translation of these delivery systems to the pharmaceutical marketplace.

  3. Denatured protein-coated docetaxel nanoparticles: Alterable drug state and cytosolic delivery.

    Science.gov (United States)

    Zhang, Li; Xiao, Qingqing; Wang, Yiran; Zhang, Chenshuang; He, Wei; Yin, Lifang

    2017-05-15

    Many lead compounds have a low solubility in water, which substantially hinders their clinical application. Nanosuspensions have been considered a promising strategy for the delivery of water-insoluble drugs. Here, denatured soy protein isolate (SPI)-coated docetaxel nanosuspensions (DTX-NS) were developed using an anti-solvent precipitation-ultrasonication method to improve the water-solubility of DTX, thus improving its intracellular delivery. DTX-NS, with a diameter of 150-250nm and drug-loading up to 18.18%, were successfully prepared by coating drug particles with SPI. Interestingly, the drug state of DTX-NS was alterable. Amorphous drug nanoparticles were obtained at low drug-loading, whereas at a high drug-loading, the DTX-NS drug was mainly present in the crystalline state. Moreover, DTX-NS could be internalized at high levels by cancer cells and enter the cytosol by lysosomal escape, enhancing cell cytotoxicity and apoptosis compared with free DTX. Taken together, denatured SPI has a strong stabilization effect on nanosuspensions, and the drug state in SPI-coated nanosuspensions is alterable by changing the drug-loading. Moreover, DTX-NS could achieve cytosolic delivery, generating enhanced cell cytotoxicity against cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Model Checking Multivariate State Rewards

    DEFF Research Database (Denmark)

    Nielsen, Bo Friis; Nielson, Flemming; Nielson, Hanne Riis

    2010-01-01

    We consider continuous stochastic logics with state rewards that are interpreted over continuous time Markov chains. We show how results from multivariate phase type distributions can be used to obtain higher-order moments for multivariate state rewards (including covariance). We also generalise...

  5. Modelling of drug release from ensembles of aspirin microcapsules ...

    African Journals Online (AJOL)

    Purpose: In order to determine the drug release profile of an ensemble of aspirin crystals or microcapsules from its particle distribution a mathematical model that considered the individual release characteristics of the component single particles was developed. The model assumed that under sink conditions the release ...

  6. Computational modeling of drug transport across the in vitro cornea.

    Science.gov (United States)

    Pak, Joseph; Chen, Z J; Sun, Kay; Przekwas, Andrzej; Walenga, Ross; Fan, Jianghong

    2018-01-01

    A novel quasi-3D (Q3D) modeling approach was developed to model networks of one dimensional structures like tubes and vessels common in human anatomy such as vascular and lymphatic systems, neural networks, and respiratory airways. Instead of a branching network of the same tissue type, this approach was extended to model an interconnected stack of different corneal tissue layers with membrane junction conditions assigned between the tissues. The multi-laminate structure of the cornea presents a unique barrier design and opportunity for investigation using Q3D modeling. A Q3D model of an in vitro rabbit cornea was created to simulate the drug transport across the cornea, accounting for transcellular and paracellular pathways of passive and convective drug transport as well as physicochemistry of lipophilic partitioning and protein binding. Lipophilic Rhodamine B and hydrophilic fluorescein were used as drug analogs. The model predictions for both hydrophilic and lipophilic tracers were able to match the experimental measurements along with the sharp discontinuities at the epithelium-stroma and stroma-endothelium interfaces. This new modeling approach was successfully applied towards pharmacokinetic modeling for use in topical ophthalmic drug design. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Animal models of pain and migraine in drug discovery

    DEFF Research Database (Denmark)

    Munro, Gordon; Jansen-Olesen, Inger; Olesen, Jes

    2017-01-01

    of the most commonly used models and methods employed within 'pain and migraine' drug development will be presented. Recent advances within these disciplines suggest that, with the addition of a few extra carefully chosen ancillary models and/or endpoints, the relative value in terms of resources used...

  8. Modeling Per Capita State Health Expenditure Variat...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Modeling Per Capita State Health Expenditure Variation State-Level Characteristics Matter, published in Volume 3, Issue 4, of the Medicare and Medicaid Research...

  9. Toward a normalized clinical drug knowledge base in China-applying the RxNorm model to Chinese clinical drugs.

    Science.gov (United States)

    Wang, Li; Zhang, Yaoyun; Jiang, Min; Wang, Jingqi; Dong, Jiancheng; Liu, Yun; Tao, Cui; Jiang, Guoqian; Zhou, Yi; Xu, Hua

    2018-04-04

    In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Chinese drugs were collected from 4 major resources-China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia-for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems

  10. Depoliticising the political: Market solutions and the retreat of Swedish institutional drug treatment from state management.

    Science.gov (United States)

    Edman, Johan

    2016-06-01

    This article examines developments in the Swedish drug treatment services in 1982-2000 and explores the ways in which political initiatives and the state administration's management have contributed to the major privatisations of institutional drug treatment during this period. The empirical basis for the textual analysis lies in official reports, parliamentary material and archived records from the Stockholm County Administrative Board's management of treatment facilities. The major privatisations of drug treatment services in the 1980s were both unintentional and unwanted and mainly arose from a lack of bureaucratic control and ideological anchorage. The privatisations were, however, reinforced by ideologically driven NPM-oriented political initiatives in the 1990s. The market-oriented treatment services have failed to fulfil the needs for diversity and availability within a publicly financed sector, which deals with unevenly informed and often socio-economically weak citizens. New management models in this field must ensure that ideological considerations are taken into account to meet politically decided goals and means. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Drug use and AIDS: estimating injection prevalence in a rural state.

    Science.gov (United States)

    Leukefeld, Carl G; Logan, T K; Farabee, David; Clayton, Richard

    2002-01-01

    This paper presents approaches used in one rural U.S. state to describe the level of injecting drug use and to estimate the number of injectors not receiving drug-user treatment. The focus is on two broad areas of estimation that were used to present the prevalence of injecting drug use in Kentucky. The first estimation approach uses available data from secondary data sources. The second approach involves three small community studies.

  12. Rural Adolescent Alcohol, Tobacco, and Illicit Drug Use: A Comparison of Students in Victoria, Australia, and Washington State, United States

    Science.gov (United States)

    Coomber, Kerri; Toumbourou, John W.; Miller, Peter; Staiger, Petra K.; Hemphill, Sheryl A.; Catalano, Richard F.

    2011-01-01

    Purpose: There are inconsistent research findings regarding the impact of rurality on adolescent alcohol, tobacco, and illicit substance use. Therefore, the current study reports on the effect of rurality on alcohol, tobacco, and illicit drug use among adolescents in 2 state representative samples in 2 countries, Washington State (WA) in the…

  13. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    Science.gov (United States)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  14. Computational and experimental model of transdermal iontophorethic drug delivery system.

    Science.gov (United States)

    Filipovic, Nenad; Saveljic, Igor; Rac, Vladislav; Graells, Beatriz Olalde; Bijelic, Goran

    2017-11-30

    The concept of iontophoresis is often applied to increase the transdermal transport of drugs and other bioactive agents into the skin or other tissues. It is a non-invasive drug delivery method which involves electromigration and electroosmosis in addition to diffusion and is shown to be a viable alternative to conventional administration routs such as oral, hypodermic and intravenous injection. In this study we investigated, experimentally and numerically, in vitro drug delivery of dexamethasone sodium phosphate to porcine skin. Different current densities, delivery durations and drug loads were investigated experimentally and introduced as boundary conditions for numerical simulations. Nernst-Planck equation was used for calculation of active substance flux through equivalent model of homogeneous hydrogel and skin layers. The obtained numerical results were in good agreement with experimental observations. A comprehensive in-silico platform, which includes appropriate numerical tools for fitting, could contribute to iontophoretic drug-delivery devices design and correct dosage and drug clearance profiles as well as to perform much faster in-silico experiments to better determine parameters and performance criteria of iontophoretic drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Racism in United States: Drug Legislation and the Trade-Off Behind It

    Science.gov (United States)

    Heiligman, Avron C.

    1978-01-01

    This paper attempts to show that drug legislation in the United States has been the result of racial discrimination as rationalized by labeling specific target populations deviant. The author suggests that organized medicine can also be linked to the controlling measures of drug legislation. (Author)

  16. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  17. Structural Model of Drug Use among Students: The Role of Spirituality, Social Modeling and Attitude to Drugs

    Directory of Open Access Journals (Sweden)

    samira yavari

    2015-06-01

    Full Text Available Objective: This study was an attempt to explore the structural relationship between religious activity, religious struggle, attitude to drugs, social modeling, spiritual well-being, and cigarette and tobacco smoking among students. Method: For this purpose, 504 male and female students from Kharazmi University, Agricultural Paradise, and Azad University of Karaj were selected by cluster sampling and they were asked to complete spiritual well-being scale, religious activity scale, religious struggle scale, social modeling scale, negative beliefs about drugs, and the tobacco section of the high-risk behavior questionnaire. Results: The results showed that the effect of religious activity on cigarette and tobacco smoking was mediated by negative beliefs about drugs, social modeling, spiritual well-being, and incentives for drug use. Similarly, the effect of religious struggle on cigarette and tobacco smoking was mediated by spiritual well-being. Conclusion: It seems that religion prevents people joining the unhealthy peer groups by the establishment of moral discipline, internal and external rules, and healthy coping styles therefore, people get less attracted to cigarette and tobacco smoking. Accordingly, these factors should be paid more attention in prevention programs for drug use, particularly cigarette and tobacco that are considered as the gateway to other drugs.

  18. Bioresorbable polymer coated drug eluting stent: a model study.

    Science.gov (United States)

    Rossi, Filippo; Casalini, Tommaso; Raffa, Edoardo; Masi, Maurizio; Perale, Giuseppe

    2012-07-02

    In drug eluting stent technologies, an increased demand for better control, higher reliability, and enhanced performances of drug delivery systems emerged in the last years and thus offered the opportunity to introduce model-based approaches aimed to overcome the remarkable limits of trial-and-error methods. In this context a mathematical model was studied, based on detailed conservation equations and taking into account the main physical-chemical mechanisms involved in polymeric coating degradation, drug release, and restenosis inhibition. It allowed highlighting the interdependence between factors affecting each of these phenomena and, in particular, the influence of stent design parameters on drug antirestenotic efficacy. Therefore, the here-proposed model is aimed to simulate the diffusional release, for both in vitro and the in vivo conditions: results were verified against various literature data, confirming the reliability of the parameter estimation procedure. The hierarchical structure of this model also allows easily modifying the set of equations describing restenosis evolution to enhance model reliability and taking advantage of the deep understanding of physiological mechanisms governing the different stages of smooth muscle cell growth and proliferation. In addition, thanks to its simplicity and to the very low system requirements and central processing unit (CPU) time, our model allows obtaining immediate views of system behavior.

  19. Marijuana, other drugs, and alcohol use by drivers in Washington State.

    Science.gov (United States)

    2016-07-01

    In Washington State legal sales of marijuana began July 8, 2014. A voluntary, anonymous roadside study was conducted to assess the prevalence of drivers testing positive for alcohol and other drugs, including marijuana, on Washingtons roads. Data ...

  20. Marijuana, other drugs, and alcohol use by drivers in Washington state : appendices.

    Science.gov (United States)

    2016-07-01

    In Washington State legal sales of marijuana began July 8, 2014. A voluntary, anonymous roadside study was conducted to assess the prevalence of drivers testing positive for alcohol and other drugs, including marijuana, on Washingtons roads. Data ...

  1. Modeling of transdermal drug delivery with a microneedle array

    Science.gov (United States)

    Lv, Y.-G.; Liu, J.; Gao, Y.-H.; Xu, B.

    2006-11-01

    Transdermal drug delivery is generally limited by the extraordinary barrier properties of the stratum corneum, the outer 10-15 µm layer of skin. A conventional needle inserted across this barrier and into deeper tissues could effectively deliver drugs. However, it would lead to infection and cause pain, thereby reducing patient compliance. In order to administer a frequent injection of insulin and other therapeutic agents more efficiently, integrated arrays with very short microneedles were recently proposed as very good candidates for painless injection or extraction. A variety of microneedle designs have thus been made available by employing the fabrication tools of the microelectronics industry and using materials such as silicon, metals, polymers and glass with feature sizes ranging from sub-micron to nanometers. At the same time, experiments were also made to test the capability of the microneedles to inject drugs into tissues. However, due to the difficulty encountered in measurement, a detailed understanding of the spatial and transient drug delivery process still remains unclear up to now. To better grasp the mechanisms involved, quantitative theoretical models were developed in this paper to simultaneously characterize the flow and drug transport, and numerical solutions were performed to predict the kinetics of dispersed drugs injected into the skin from a microneedle array. Calculations indicated that increasing the initial injection velocity and accelerating the blood circulation in skin tissue with high porosity are helpful to enhance the transdermal drug delivery. This study provides the first quantitative simulation of fluid injection through a microneedle array and drug species transport inside the skin. The modeling strategy can also possibly be extended to deal with a wider range of clinical issues such as targeted nanoparticle delivery for therapeutics or molecular imaging.

  2. Comparing the Medicaid Retrospective Drug Utilization Review Program Cost-Savings Methods Used by State Agencies.

    Science.gov (United States)

    Prada, Sergio I

    2017-12-01

    The Medicaid Drug Utilization Review (DUR) program is a 2-phase process conducted by Medicaid state agencies. The first phase is a prospective DUR and involves electronically monitoring prescription drug claims to identify prescription-related problems, such as therapeutic duplication, contraindications, incorrect dosage, or duration of treatment. The second phase is a retrospective DUR and involves ongoing and periodic examinations of claims data to identify patterns of fraud, abuse, underutilization, drug-drug interaction, or medically unnecessary care, implementing corrective actions when needed. The Centers for Medicare & Medicaid Services requires each state to measure prescription drug cost-savings generated from its DUR programs on an annual basis, but it provides no guidance or unified methodology for doing so. To describe and synthesize the methodologies used by states to measure cost-savings using their Medicaid retrospective DUR program in federal fiscal years 2014 and 2015. For each state, the cost-savings methodologies included in the Medicaid DUR 2014 and 2015 reports were downloaded from Medicaid's website. The reports were then reviewed and synthesized. Methods described by the states were classified according to research designs often described in evaluation textbooks. In 2014, the most often used prescription drugs cost-savings estimation methodology for the Medicaid retrospective DUR program was a simple pre-post intervention method, without a comparison group (ie, 12 states). In 2015, the most common methodology used was a pre-post intervention method, with a comparison group (ie, 14 states). Comparisons of savings attributed to the program among states are still unreliable, because of a lack of a common methodology available for measuring cost-savings. There is great variation among states in the methods used to measure prescription drug utilization cost-savings. This analysis suggests that there is still room for improvement in terms of

  3. Animal models of pancreatic cancer for drug research.

    Science.gov (United States)

    Kapischke, Matthias; Pries, Alexandra

    2008-10-01

    The operative and conservative results of therapy in pancreatic ductal adenocarcinoma remain appallingly poor. This underlines the demand for further research for effective anticancer drugs. The various animal models remain the essential method for the determination of efficacy of substances during preclinical phase. Unfortunately, most of these tested substances showed a good efficacy in pancreatic carcinoma in the animal model but were not confirmed during the clinical phase. The available literature in PubMed, Medline, Ovid and secondary literature was searched regarding the available animal models for drug testing against pancreatic cancer. The models were analyzed regarding their pros and cons in anticancer drug testing. The different modifications of the orthotopic model (especially in mice) seem at present to be the best model for anticancer testing in pancreatic carcinoma. The value of genetically engineered animal model (GEM) and syngeneic models is on debate. A good selection of the model concerning the questions supposed to be clarified may improve the comparability of the results of animal experiments compared to clinical trials.

  4. Steady-State Process Modelling

    DEFF Research Database (Denmark)

    Cameron, Ian; Gani, Rafiqul

    2011-01-01

    illustrate the “equation oriented” approach as well as the “sequential modular” approach to solving complex flowsheets for steady state applications. The applications include the Williams-Otto plant, the hydrodealkylation (HDA) of toluene, conversion of ethylene to ethanol and a bio-ethanol process....

  5. Major Source of Error in QSPR Prediction of Intrinsic Thermodynamic Solubility of Drugs: Solid vs Nonsolid State Contributions?

    Science.gov (United States)

    Abramov, Yuriy A

    2015-06-01

    The main purpose of this study is to define the major limiting factor in the accuracy of the quantitative structure-property relationship (QSPR) models of the thermodynamic intrinsic aqueous solubility of the drug-like compounds. For doing this, the thermodynamic intrinsic aqueous solubility property was suggested to be indirectly "measured" from the contributions of solid state, ΔGfus, and nonsolid state, ΔGmix, properties, which are estimated by the corresponding QSPR models. The QSPR models of ΔGfus and ΔGmix properties were built based on a set of drug-like compounds with available accurate measurements of fusion and thermodynamic solubility properties. For consistency ΔGfus and ΔGmix models were developed using similar algorithms and descriptor sets, and validated against the similar test compounds. Analysis of the relative performances of these two QSPR models clearly demonstrates that it is the solid state contribution which is the limiting factor in the accuracy and predictive power of the QSPR models of the thermodynamic intrinsic solubility. The performed analysis outlines a necessity of development of new descriptor sets for an accurate description of the long-range order (periodicity) phenomenon in the crystalline state. The proposed approach to the analysis of limitations and suggestions for improvement of QSPR-type models may be generalized to other applications in the pharmaceutical industry.

  6. New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.

    Science.gov (United States)

    Peletier, Lambertus A; Gabrielsson, Johan

    2018-05-14

    In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

  7. An analysis of respondent-driven sampling with injecting drug users in a high HIV prevalent state of India.

    Science.gov (United States)

    Phukan, Sanjib Kumar; Medhi, Gajendra Kumar; Mahanta, Jagadish; Adhikary, Rajatashuvra; Thongamba, Gay; Paranjape, Ramesh S; Akoijam, Brogen S

    2017-07-03

    Personal networks are significant social spaces to spread of HIV or other blood-borne infections among hard-to-reach population, viz., injecting drug users, female sex workers, etc. Sharing of infected needles or syringes among drug users is one of the major routes of HIV transmission in Manipur, a high HIV prevalence state in India. This study was carried out to describe the network characteristics and recruitment patterns of injecting drug users and to assess the association of personal network with injecting risky behaviors in Manipur. A total of 821 injecting drug users were recruited into the study using respondent-driven sampling (RDS) from Bishnupur and Churachandpur districts of Manipur; data on demographic characteristics, HIV risk behaviors, and network size were collected from them. Transition probability matrices and homophily indices were used to describe the network characteristics, and recruitment patterns of injecting drug users. Univariate and multivariate binary logistic regression models were performed to analyze the association between the personal networks and sharing of needles or syringes. The average network size was similar in both the districts. Recruitment analysis indicates injecting drug users were mostly engaged in mixed age group setting for injecting practice. Ever married and new injectors showed lack of in-group ties. Younger injecting drug users had mainly recruited older injecting drug users from their personal network. In logistic regression analysis, higher personal network was found to be significantly associated with increased likelihood of injecting risky behaviors. Because of mixed personal network of new injectors and higher network density associated with HIV exposure, older injecting drug users may act as a link for HIV transmission or other blood-borne infections to new injectors and also to their sexual partners. The information from this study may be useful to understanding the network pattern of injecting drug users

  8. [Alternatives to the drug research and development model].

    Science.gov (United States)

    Velásquez, Germán

    2015-03-01

    One-third of the global population lacks access to medications; the situation is worse in poor countries, where up to 50% of the population lacks access. The failure of current incentive systems based in intellectual property to offer the necessary pharmaceutical products, especially in the global south, is a call to action. Problems related to drug access cannot be solved solely through improvements or modifications in the existing incentive models. The intellectual property system model does not offer sufficient innovation for developing countries; new mechanisms that effectively promote innovation and drug access simultaneously are needed. A binding international agreement on research and development, negotiated under the auspices of the World Health Organization, could provide an adequate framework for guaranteeing priority-setting, coordination, and sustainable financing of drugs at reasonable prices for developing countries.

  9. Multimodality imaging and mathematical modelling of drug delivery to glioblastomas.

    Science.gov (United States)

    Boujelben, Ahmed; Watson, Michael; McDougall, Steven; Yen, Yi-Fen; Gerstner, Elizabeth R; Catana, Ciprian; Deisboeck, Thomas; Batchelor, Tracy T; Boas, David; Rosen, Bruce; Kalpathy-Cramer, Jayashree; Chaplain, Mark A J

    2016-10-06

    Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization, and they typically exhibit a disrupted blood-brain barrier (BBB). Although it has been hypothesized that the 'normalization' of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of BBB integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper, we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated-flow rate, vessel permeability and tissue diffusion coefficient-interact nonlinearly to produce the observed average drug concentration in the microenvironment.

  10. Fed-state gastric media and drug analysis techniques: Current status and points to consider.

    Science.gov (United States)

    Baxevanis, Fotios; Kuiper, Jesse; Fotaki, Nikoletta

    2016-10-01

    Gastric fed state conditions can have a significant effect on drug dissolution and absorption. In vitro dissolution tests with simple aqueous media cannot usually predict drugs' in vivo response, as several factors such as the meal content, the gastric emptying and possible interactions between food and drug formulations can affect drug's pharmacokinetics. Good understanding of the effect of the in vivo fed gastric conditions on the drug is essential for the development of biorelevant dissolution media simulating the gastric environment after the administration of the standard high fat meal proposed by the FDA and the EMA in bioavailability/bioequivalence (BA/BE) studies. The analysis of drugs in fed state media can be quite challenging as most analytical protocols currently employed are time consuming and labour intensive. In this review, an overview of the in vivo gastric conditions and the biorelevant media used for their in vitro simulation are described. Furthermore an analysis of the physicochemical properties of the drugs and the formulations related to food effect is given. In terms of drug analysis, the protocols currently used for the fed state media sample treatment and analysis and the analytical challenges and needs emerging for more efficient and time saving techniques for a broad spectrum of compounds are being discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Model Checking Infinite-State Markov Chains

    NARCIS (Netherlands)

    Remke, Anne Katharina Ingrid; Haverkort, Boudewijn R.H.M.; Cloth, L.

    2004-01-01

    In this paper algorithms for model checking CSL (continuous stochastic logic) against infinite-state continuous-time Markov chains of so-called quasi birth-death type are developed. In doing so we extend the applicability of CSL model checking beyond the recently proposed case for finite-state

  12. Cell and small animal models for phenotypic drug discovery

    Directory of Open Access Journals (Sweden)

    Szabo M

    2017-06-01

    Full Text Available Mihaly Szabo,1 Sara Svensson Akusjärvi,1 Ankur Saxena,1 Jianping Liu,2 Gayathri Chandrasekar,1 Satish S Kitambi1 1Department of Microbiology Tumor, and Cell Biology, 2Department of Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden Abstract: The phenotype-based drug discovery (PDD approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery. Keywords: phenotype, screening, PDD, discovery, zebrafish, drug

  13. Steady state HNG combustion modeling

    Energy Technology Data Exchange (ETDEWEB)

    Louwers, J.; Gadiot, G.M.H.J.L. [TNO Prins Maurits Lab., Rijswijk (Netherlands); Brewster, M.Q. [Univ. of Illinois, Urbana, IL (United States); Son, S.F. [Los Alamos National Lab., NM (United States); Parr, T.; Hanson-Parr, D. [Naval Air Warfare Center, China Lake, CA (United States)

    1998-04-01

    Two simplified modeling approaches are used to model the combustion of Hydrazinium Nitroformate (HNF, N{sub 2}H{sub 5}-C(NO{sub 2}){sub 3}). The condensed phase is treated by high activation energy asymptotics. The gas phase is treated by two limit cases: the classical high activation energy, and the recently introduced low activation energy approach. This results in simplification of the gas phase energy equation, making an (approximate) analytical solution possible. The results of both models are compared with experimental results of HNF combustion. It is shown that the low activation energy approach yields better agreement with experimental observations (e.g. regression rate and temperature sensitivity), than the high activation energy approach.

  14. Racialized risk environments in a large sample of people who inject drugs in the United States.

    Science.gov (United States)

    Cooper, Hannah L F; Linton, Sabriya; Kelley, Mary E; Ross, Zev; Wolfe, Mary E; Chen, Yen-Tyng; Zlotorzynska, Maria; Hunter-Jones, Josalin; Friedman, Samuel R; Des Jarlais, Don; Semaan, Salaam; Tempalski, Barbara; DiNenno, Elizabeth; Broz, Dita; Wejnert, Cyprian; Paz-Bailey, Gabriela

    2016-01-01

    Substantial racial/ethnic disparities exist in HIV infection among people who inject drugs (PWID) in many countries. To strengthen efforts to understand the causes of disparities in HIV-related outcomes and eliminate them, we expand the "Risk Environment Model" to encompass the construct "racialized risk environments," and investigate whether PWID risk environments in the United States are racialized. Specifically, we investigate whether black and Latino PWID are more likely than white PWID to live in places that create vulnerability to adverse HIV-related outcomes. As part of the Centers for Disease Control and Prevention's National HIV Behavioral Surveillance, 9170 PWID were sampled from 19 metropolitan statistical areas (MSAs) in 2009. Self-reported data were used to ascertain PWID race/ethnicity. Using Census data and other administrative sources, we characterized features of PWID risk environments at four geographic scales (i.e., ZIP codes, counties, MSAs, and states). Means for each feature of the risk environment were computed for each racial/ethnic group of PWID, and were compared across racial/ethnic groups. Almost universally across measures, black PWID were more likely than white PWID to live in environments associated with vulnerability to adverse HIV-related outcomes. Compared to white PWID, black PWID lived in ZIP codes with higher poverty rates and worse spatial access to substance abuse treatment and in counties with higher violent crime rates. Black PWID were less likely to live in states with laws facilitating sterile syringe access (e.g., laws permitting over-the-counter syringe sales). Latino/white differences in risk environments emerged at the MSA level (e.g., Latino PWID lived in MSAs with higher drug-related arrest rates). PWID risk environments in the US are racialized. Future research should explore the implications of this racialization for racial/ethnic disparities in HIV-related outcomes, using appropriate methods. Copyright © 2015

  15. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  16. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.

    2008-01-01

    log K ow. These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

  17. Addressing drug adherence using an operations management model.

    Science.gov (United States)

    Nunlee, Martin; Bones, Michelle

    2014-01-01

    OBJECTIVE To provide a model that enables health systems and pharmacy benefit managers to provide medications reliably and test for reliability and validity in the analysis of adherence to drug therapy of chronic disease. SUMMARY The quantifiable model described here can be used in conjunction with behavioral designs of drug adherence assessments. The model identifies variables that can be reproduced and expanded across the management of chronic diseases with drug therapy. By creating a reorder point system for reordering medications, the model uses a methodology commonly seen in operations research. The design includes a safety stock of medication and current supply of medication, which increases the likelihood that patients will have a continuous supply of medications, thereby positively affecting adherence by removing barriers. CONCLUSION This method identifies an adherence model that quantifies variables related to recommendations from health care providers; it can assist health care and service delivery systems in making decisions that influence adherence based on the expected order cycle days and the expected daily quantity of medication administered. This model addresses the possession of medication as a barrier to adherence.

  18. Optimal Control of Drug Therapy in a Hepatitis B Model

    Directory of Open Access Journals (Sweden)

    Jonathan E. Forde

    2016-08-01

    Full Text Available Combination antiviral drug therapy improves the survival rates of patients chronically infected with hepatitis B virus by controlling viral replication and enhancing immune responses. Some of these drugs have side effects that make them unsuitable for long-term administration. To address the trade-off between the positive and negative effects of the combination therapy, we investigated an optimal control problem for a delay differential equation model of immune responses to hepatitis virus B infection. Our optimal control problem investigates the interplay between virological and immunomodulatory effects of therapy, the control of viremia and the administration of the minimal dosage over a short period of time. Our numerical results show that the high drug levels that induce immune modulation rather than suppression of virological factors are essential for the clearance of hepatitis B virus.

  19. Updating of states in operational hydrological models

    Science.gov (United States)

    Bruland, O.; Kolberg, S.; Engeland, K.; Gragne, A. S.; Liston, G.; Sand, K.; Tøfte, L.; Alfredsen, K.

    2012-04-01

    Operationally the main purpose of hydrological models is to provide runoff forecasts. The quality of the model state and the accuracy of the weather forecast together with the model quality define the runoff forecast quality. Input and model errors accumulate over time and may leave the model in a poor state. Usually model states can be related to observable conditions in the catchment. Updating of these states, knowing their relation to observable catchment conditions, influence directly the forecast quality. Norway is internationally in the forefront in hydropower scheduling both on short and long terms. The inflow forecasts are fundamental to this scheduling. Their quality directly influence the producers profit as they optimize hydropower production to market demand and at the same time minimize spill of water and maximize available hydraulic head. The quality of the inflow forecasts strongly depends on the quality of the models applied and the quality of the information they use. In this project the focus has been to improve the quality of the model states which the forecast is based upon. Runoff and snow storage are two observable quantities that reflect the model state and are used in this project for updating. Generally the methods used can be divided in three groups: The first re-estimates the forcing data in the updating period; the second alters the weights in the forecast ensemble; and the third directly changes the model states. The uncertainty related to the forcing data through the updating period is due to both uncertainty in the actual observation and to how well the gauging stations represent the catchment both in respect to temperatures and precipitation. The project looks at methodologies that automatically re-estimates the forcing data and tests the result against observed response. Model uncertainty is reflected in a joint distribution of model parameters estimated using the Dream algorithm.

  20. Drug repurposing for aging research using model organisms.

    Science.gov (United States)

    Ziehm, Matthias; Kaur, Satwant; Ivanov, Dobril K; Ballester, Pedro J; Marcus, David; Partridge, Linda; Thornton, Janet M

    2017-10-01

    Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies

    Directory of Open Access Journals (Sweden)

    Gregory H. Underhill

    2018-01-01

    Full Text Available In vitro models of the human liver are important for the following: (1 mitigating the risk of drug-induced liver injury to human beings, (2 modeling human liver diseases, (3 elucidating the role of single and combinatorial microenvironmental cues on liver cell function, and (4 enabling cell-based therapies in the clinic. Methods to isolate and culture primary human hepatocytes (PHHs, the gold standard for building human liver models, were developed several decades ago; however, PHHs show a precipitous decline in phenotypic functions in 2-dimensional extracellular matrix–coated conventional culture formats, which does not allow chronic treatment with drugs and other stimuli. The development of several engineering tools, such as cellular microarrays, protein micropatterning, microfluidics, biomaterial scaffolds, and bioprinting, now allow precise control over the cellular microenvironment for enhancing the function of both PHHs and induced pluripotent stem cell–derived human hepatocyte-like cells; long-term (4+ weeks stabilization of hepatocellular function typically requires co-cultivation with liver-derived or non–liver-derived nonparenchymal cell types. In addition, the recent development of liver organoid culture systems can provide a strategy for the enhanced expansion of therapeutically relevant cell types. Here, we discuss advances in engineering approaches for constructing in vitro human liver models that have utility in drug screening and for determining microenvironmental determinants of liver cell differentiation/function. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues that need to be addressed. Overall, bioengineered liver models have significantly advanced our understanding of liver function and injury, which will prove useful for drug development and ultimately cell-based therapies.

  2. Biomembrane models and drug-biomembrane interaction studies: Involvement in drug design and development

    Directory of Open Access Journals (Sweden)

    R Pignatello

    2011-01-01

    Full Text Available Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy.

  3. Animal models for testing anti-prion drugs.

    Science.gov (United States)

    Fernández-Borges, Natalia; Elezgarai, Saioa R; Eraña, Hasier; Castilla, Joaquín

    2013-01-01

    Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models.

  4. Modeling HIV-1 drug resistance as episodic directional selection.

    Science.gov (United States)

    Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L; Scheffler, Konrad

    2012-01-01

    The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  5. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  6. Secondary Prevention Services for Clients Who Are Low Risk in Drug Court: A Conceptual Model

    Science.gov (United States)

    DeMatteo, David S.; Marlowe, Douglas B.; Festinger, David S.

    2006-01-01

    The drug court model assumes that most drug offenders are addicts, and that drug use fuels other criminal activity. As a result, drug court clients must satisfy an intensive regimen of treatment and supervisory obligations. However, research suggests that roughly one third of drug court clients do not have a clinically significant substance use…

  7. Sovereignty Under Siege: Drug Trafficking and State Capacity in the Caribbean and Central America

    Science.gov (United States)

    2016-06-01

    million people consume illicit drugs (of the cannabis , opioid, cocaine, or amphetamine classifications), which corresponds to 3.5–7 percent of the world...prevalent.28 Last, failed states have flawed institutions, lack infrastructural capacity (potholes), have poor, privatized education and medical ...drug assaults.149 Colombian DTOs moved into the Caribbean like a cancerous growth, taking root, and then malignantly spreading to destabilize or

  8. Cyclodextrins as drug carriers in Pharmaceutical Technology: The state of the art.

    Science.gov (United States)

    Conceição, Jaime; Adeoye, Oluwatomide; Cabral-Marques, Helena Maria; Lobo, Jose Manuel Sousa

    2017-12-18

    Cyclodextrins (CDs) are versatile excipients with an essential role in drug delivery, as they can form non-covalently bonded inclusion complexes (host-guest complexes) with several drugs either in solution or in the solid state. The main purpose of this publication was to carry out a state of the art of CDs as complexing agents in drug carrier systems. In this way, the history, properties and pharmaceutical applications of the CDs were highlighted with typical examples. The methods to enhance the complexation efficiency (CE) and the CDs applications in solid dosage forms were emphasized in more detail. The main advantages of using these cyclic oligosaccharides are as follows: (1) to enhance solubility/dissolution/ bioavailability of poorly soluble drugs; (2) to enhance drug stability; (3) to modify the drug release site and/or time profile; and (4) to reduce drug side effects (for example, gastric or ocular irritation). These compounds present favorable toxicological profile for human use and therefore there are various medicines containing CDs approved by regulatory authorities worldwide. On the other hand, the major drawback of CDs is the increase in formulation bulk, once the CE is, in general, very low. This aspect is particularly relevant in solid dosage forms and limits the use of CDs to potent drugs. CDs have great potential as drug carriers in Pharmaceutical Technology and can be used by the formulator in order to improve the drug properties such as solubility, bioavailability and stability. Additionally, recent studies have shown that these compounds can be applied as active pharmaceutical ingredients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Successful importation of cytarabine into the United States during a critical national drug shortage.

    Science.gov (United States)

    Hunnisett-Dritz, Dee

    2012-08-15

    The importation of cytarabine into the United States during a critical national drug shortage is described. In March 2011, the hospital pharmacy team at an acute care hospital was struggling to supply cytarabine for four specific patients, all of whom needed critical maintenance therapy after induction. Cytarabine was not available from any source in the United States, and the team had no realistic projected release dates for back orders. Idis UK, a pharmaceutical distributor, was asked to identify available drug and eventually found an unrestricted source of cytarabine in Switzerland. Once available drug was identified, a price quote for the supply amount was written for our consideration. This was inspected carefully to ensure that the drug, strength, dosage form, and any other ingredients listed were indeed what were expected. The pharmacy department worked with the hospital's department of finance and accounting to submit the necessary financial paperwork. Payment was electronically sent to the distributor before the drug was shipped. Before the order for cytarabine was placed, the associated risks and benefits were assessed. The patients provided consent to treatment with the unapproved product. Acceptance of the price quote and instructions to order the drug were e-mailed to the distributor. The necessary documentation was completed and included with the shipment. The importation process, from initial inquiries to delivery, took 21 days. The importation of cytarabine amid a drug shortage required a complex process that involved the efforts of an overseas distributor, the cooperation of multiple health professionals, and meticulous attention to detail.

  10. Mesoporous silica for drug delivery: Interactions with model fluorescent lipid vesicles and live cells.

    Science.gov (United States)

    Bardhan, Munmun; Majumdar, Anupa; Jana, Sayantan; Ghosh, Tapas; Pal, Uttam; Swarnakar, Snehasikta; Senapati, Dulal

    2018-01-01

    Formulated mesoporous silica nanoparticle (MSN) systems offer the best possible drug delivery system through the release of drug molecules from the accessible pores. In the present investigation, steady state and time resolved fluorescence techniques along with the fluorescence imaging were applied to investigate the interactions of dye loaded MSN with fluorescent unilamellar vesicles and live cells. Here 1,2-dimyristoyl-sn-glycero-3-phospocholine (DMPC) was used to prepare Small Unilamellar Vesicles (SUVs) as the model membrane with fluorescent 1,6-diphenyl-1,3,5-hexatriene (DPH) molecule incorporated inside the lipid bilayer. The interaction of DPH incorporated DMPC membrane with Fluorescein loaded MSN lead to the release of Fluorescein (Fl) dye from the interior pores of MSN systems. The extent of release of Fl and spatial distribution of the DPH molecule has been explored by monitoring steady-state fluorescence intensity and fluorescence lifetime at physiological condition. To investigate the fate of drug molecule released from MSN, fluorescence anisotropy has been used. The drug delivery efficiency of the MSN as a carrier for doxorubicin (DOX), a fluorescent chemotherapeutic drug, has also been investigated at physiological conditions. The study gives a definite confirmation for high uptake and steady release of DOX in primary oral mucosal non-keratinized squamous cells in comparison to naked DOX treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug-Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2016-01-20

    Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

  12. Five-Factor Model personality profiles of drug users

    Directory of Open Access Journals (Sweden)

    Crum Rosa M

    2008-04-01

    Full Text Available Abstract Background Personality traits are considered risk factors for drug use, and, in turn, the psychoactive substances impact individuals' traits. Furthermore, there is increasing interest in developing treatment approaches that match an individual's personality profile. To advance our knowledge of the role of individual differences in drug use, the present study compares the personality profile of tobacco, marijuana, cocaine, and heroin users and non-users using the wide spectrum Five-Factor Model (FFM of personality in a diverse community sample. Method Participants (N = 1,102; mean age = 57 were part of the Epidemiologic Catchment Area (ECA program in Baltimore, MD, USA. The sample was drawn from a community with a wide range of socio-economic conditions. Personality traits were assessed with the Revised NEO Personality Inventory (NEO-PI-R, and psychoactive substance use was assessed with systematic interview. Results Compared to never smokers, current cigarette smokers score lower on Conscientiousness and higher on Neuroticism. Similar, but more extreme, is the profile of cocaine/heroin users, which score very high on Neuroticism, especially Vulnerability, and very low on Conscientiousness, particularly Competence, Achievement-Striving, and Deliberation. By contrast, marijuana users score high on Openness to Experience, average on Neuroticism, but low on Agreeableness and Conscientiousness. Conclusion In addition to confirming high levels of negative affect and impulsive traits, this study highlights the links between drug use and low Conscientiousness. These links provide insight into the etiology of drug use and have implications for public health interventions.

  13. Rhodotorula Endogenous Endophthalmitis: A Novel Harbinger of the Injection Drug Epidemic in the United States

    Directory of Open Access Journals (Sweden)

    Preston M. Luong

    2017-01-01

    Full Text Available Endogenous endophthalmitis is a rare but feared infectious ocular complication of injection drug use (IDU. The recent opioid epidemic in the United States threatens to increase the incidence of this disease. We report the first case of endogenous endophthalmitis in the United States caused by the emerging fungal pathogen Rhodotorula in an injection drug user which led to no light perception vision (NLP. Worldwide experience with Rhodotorula endogenous endophthalmitis is limited, but existing cases suggest infection by this particular fungal genus has a grim prognosis.

  14. Modeling in the Common Core State Standards

    Science.gov (United States)

    Tam, Kai Chung

    2011-01-01

    The inclusion of modeling and applications into the mathematics curriculum has proven to be a challenging task over the last fifty years. The Common Core State Standards (CCSS) has made mathematical modeling both one of its Standards for Mathematical Practice and one of its Conceptual Categories. This article discusses the need for mathematical…

  15. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

    Science.gov (United States)

    Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

    2011-12-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

  16. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

    Science.gov (United States)

    Ahuja, Naveen; Katare, Om Prakash; Singh, Bhupinder

    2007-01-01

    Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.

  17. Towards a pragmatic human migraine model for drug testing

    DEFF Research Database (Denmark)

    Hansen, Emma Katrine; Olesen, Jes

    2017-01-01

    Background A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity.......003). Difference in area under the headache score curve (AUC) 0-4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future...

  18. Modeling of corneal and retinal pharmacokinetics after periocular drug administration.

    Science.gov (United States)

    Amrite, Aniruddha C; Edelhauser, Henry F; Kompella, Uday B

    2008-01-01

    the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal t(max). Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.

  19. IN VITRO MODELS TO EVALUATE DRUG-INDUCED HYPERSENSITIVITY: POTENTIAL TEST BASED ON ACTIVATION OF DENDRITIC CELLS

    Directory of Open Access Journals (Sweden)

    Valentina Galbiati

    2016-07-01

    Full Text Available Hypersensitivity drug reactions (HDRs are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated ('allergic' and non immune-mediated ('pseudo allergic' reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon.We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells.

  20. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    Directory of Open Access Journals (Sweden)

    Ijaz Ahmad

    2016-01-01

    Full Text Available Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

  1. Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

    KAUST Repository

    Hossain, Shaolie S.

    2011-08-20

    The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A threedimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate. © Springer-Verlag 2011.

  2. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    Science.gov (United States)

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

  3. Pharmacists' advancing roles in drug and disease management: a review of states' legislation.

    Science.gov (United States)

    McKnight, Alicia G; Thomason, Angela R

    2009-01-01

    To determine which states in the United States have provisions in place for pharmacist participation in drug and disease management programs and/or collaborative practice agreements and to provide comparison and discussion regarding such provisions. A secondary endpoint was the requirements of certification, credentialing, and registration with the specific state's rules and regulations. Information was gathered from states' statutes, rules, and regulations. Acquisition of each state's laws was achieved through various forms of electronic media. Data were accessed from January to March 2008. 19 states (38%) had specific provisions for disease management, 33 (66%) had provisions for drug therapy management, and 37 (74%) had provisions for collaborative practice. A total of 11 states (22%) specified that pharmacists receive specialized training to participate in such endeavors. Board approval or notification for collaborative practice agreements was required in 16 states (32%). With varying degrees of autonomy and restriction, pharmacists in certain states have the ability to develop disease management and/or collaborative practice programs. For pharmacists to take advantage of these new direct patient care opportunities, knowing the rules and requirements of their state's legislation is essential.

  4. Mechanistic systems modeling to guide drug discovery and development.

    Science.gov (United States)

    Schmidt, Brian J; Papin, Jason A; Musante, Cynthia J

    2013-02-01

    A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

    OpenAIRE

    Canet, Mark J.; Hardwick, Rhiannon N.; Lake, April D.; Dzierlenga, Anika L.; Clarke, John D.; Cherrington, Nathan J.

    2014-01-01

    Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine whic...

  6. Polar drug residues in sewage and natural waters in the state of Rio de Janeiro, Brazil.

    Science.gov (United States)

    Stumpf, M; Ternes, T A; Wilken, R D; Rodrigues, S V; Baumann, W

    1999-01-12

    The drug residues of lipid regulators, anti-inflammatories and some drug metabolites have been detected in raw sewage, treated waste water and river water in the state of Rio de Janeiro, Brazil. These residues are mainly derived from humans via excretion. The median concentrations in the effluents of sewage treatment plants (STPs) of most drugs investigated in this study ranged from 0.1 to 1 microgram/l. The removal rates of individual drugs during passage through a Brazilian STP varied from 12 to 90%. As a consequence of the incomplete removal of these residues during passage through a STP, rivers were also found to be contaminated. Median concentrations ranged from between 0.02 and 0.04 microgram/l in river water, whereas the maximum values were observed to be up to 0.5 microgram/l.

  7. Modern state of the assortment drugs for the treatment of vaginal candidosis

    Directory of Open Access Journals (Sweden)

    Юлия Валентиновна Левачкова

    2015-12-01

    Full Text Available Today the problem of treatment of vaginal candidosis and creation of effective drugs for the treatment of this disease is actual for modern gynecology and pharmacy.Aim: to explore the structure of the assortment of drugs for the treatment of vaginal candidosis, presented in the Ukrainian pharmaceutical market.Methods: Statistical and marketing methods of investigation of electronic and paper sources of information. Implemented analysis assortment based on the materials of the State Register drugs in Ukraine and Compendium.Results: in the treatment of vaginal candidosis greatest efficiency belongs fluconazole. According to the ATC classification drugs with fluconazole includes to 2 anatomical groups, among which the main proportion of drugs for systemic use. In the pharmaceutical market of Ukraine registered 103 drugs with a fluconazole, which are mainly represented by import manufacturers. The largest share of preparations (84.8% constitute solid forms (capsules and tablets.Conclusions: vaginal medications with fluconazole are not present. Considering that the suppositories have several advantages over other pharmaceutical forms, creation of the new drugs with fluconazole is a perspective direction for modern medicine and pharmacy

  8. A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

    Science.gov (United States)

    Poulin, Patrick

    2015-07-01

    A basic assumption in pharmacokinetics-pharmacodynamics research is that the free drug concentration is similar in plasma and tissue, and, hence, in vitro plasma data can be used to estimate the in vivo condition in tissue. However, in a companion manuscript, it has been demonstrated that this assumption is violated for the ionized drugs. Nonetheless, these observations focus on in vitro static environments and do not challenge data with an in vivo dynamic system. Therefore, an extension from an in vitro to an in vivo system becomes the necessary next step. The objective of this study was to perform theoretical simulations of the free drug concentration in tissue and plasma by using a physiologically based pharmacokinetics (PBPK) model reproducing the in vivo conditions in human. Therefore, the effects of drug ionization, lipophilicity, and clearance have been taken into account in a dynamic system. This modeling exercise was performed as a proof of concept to demonstrate that free drug concentration in tissue and plasma may also differ in a dynamic system for passively permeable drugs that are ionized at the physiological pH. The PBPK model simulations indicated that free drug concentrations in tissue cells and plasma significantly differ for the ionized drugs because of the pH gradient effect between cells and interstitial space. Hence, a rule of thumb for potentially performing more accurate PBPK/PD modeling is suggested, which states that the free drug concentration in tissue and plasma will differ for the ionizable drugs in contrast to the neutral drugs. In addition to the pH gradient effect for the ionizable drugs, lipophilicity and clearance effects will increase or decrease the free drug concentration in tissue and plasma for each class of drugs; thus, higher will be the drug lipophilicity and clearance, lower would be the free drug concentration in plasma, and, hence, in tissue, in a dynamic in vivo system. Therefore, only considering the value of free

  9. [Modeling asthma evolution by a multi-state model].

    Science.gov (United States)

    Boudemaghe, T; Daurès, J P

    2000-06-01

    There are many scores for the evaluation of asthma. However, most do not take into account the evolutionary aspects of this illness. We propose a model for the clinical course of asthma by a homogeneous Markov model process based on data provided by the A.R.I.A. (Association de Recherche en Intelligence Artificielle dans le cadre de l'asthme et des maladies respiratoires). The criterion used is the activity of the illness during the month before consultation. The activity is divided into three levels: light (state 1), mild (state 2) and severe (state 3). The model allows the evaluation of the strength of transition between states. We found that strong intensities were implicated towards state 2 (lambda(12) and lambda(32)), less towards state 1 (lambda(21) and lambda(31)), and minimum towards state 3 (lambda(23)). This results in an equilibrium distribution essentially divided between state 1 and 2 (44.6% and 51.0% respectively) with a small proportion in state 3 (4.4%). In the future, the increasing amount of available data should permit the introduction of covariables, the distinction of subgroups and the implementation of clinical studies. The interest of this model falls within the domain of the quantification of the illness as well as the representation allowed thereof, while offering a formal framework for the clinical notion of time and evolution.

  10. State-Space Modelling in Marine Science

    DEFF Research Database (Denmark)

    Albertsen, Christoffer Moesgaard

    State-space models provide a natural framework for analysing time series that cannot be observed without error. This is the case for fisheries stock assessments and movement data from marine animals. In fisheries stock assessments, the aim is to estimate the stock size; however, the only data...... available is the number of fish removed from the population and samples on a small fraction of the population. In marine animal movement, accurate position systems such as GPS cannot be used. Instead, inaccurate alternative must be used yielding observations with large errors. Both assessment and individual...... animal movement models are important for management and conservation of marine animals. Consequently, models should be developed to be operational in a management context while adequately evaluating uncertainties in the models. This thesis develops state-space models using the Laplace approximation...

  11. Sovereignty under siege: drug trafficking and state capacity in the Caribbean and Central America

    OpenAIRE

    King, Ryan Thomas

    2016-01-01

    Approved for public release; distribution is unlimited Drug trafficking organizations have increased their prominence throughout the Caribbean and Central America. These organizations undermine the rule of law, increase levels of violence and corruption, and hamper development, all of which can weaken a state. Weak or failing states become domestic and regional burdens that spill over into neighboring countries and cause secondary and tertiary problems. This thesis examines causes for diff...

  12. Latest animal models for anti-HIV drug discovery.

    Science.gov (United States)

    Sliva, Katja

    2015-02-01

    HIV research is limited by the fact that lentiviruses are highly species specific. The need for appropriate models to promote research has led to the development of many elaborate surrogate animal models. This review looks at the history of animal models for HIV research. Although natural animal lentivirus infections and chimeric viruses such as chimera between HIV and simian immunodeficiency virus and simian-tropic HIV are briefly discussed, the main focus is on small animal models, including the complex design of the 'humanized' mouse. The review also traces the historic evolution and milestones as well as depicting current models and future prospects for HIV research. HIV research is a complex and challenging task that is highly manpower-, money- and time-consuming. Besides factors such as hypervariability and latency, the lack of appropriate animal models that exhibit and recapitulate the entire infectious process of HIV, is one of the reasons behind the failure to eliminate the lentivirus from the human population. This obstacle has led to the exploitation and further development of many sophisticated surrogate animal models for HIV research. While there is no animal model that perfectly mirrors and mimics HIV infections in humans, there are a variety of host species and viruses that complement each other. Combining the insights from each model, and critically comparing the results obtained with data from human clinical trials should help expand our understanding of HIV pathogenesis and drive future drug development.

  13. Tracking Ecstasy Trends in the United States with Data from Three National Drug Surveillance Systems

    Science.gov (United States)

    Yacoubian, George S., Jr.

    2003-01-01

    Anecdotal reports have suggested that the use of 3,4-methylenedioxymeth-amphetamine (MDMA or "ecstasy") is a prodigious problem across the United States. Unfortunately, no longitudinal evidence exists to support this contention. In the current study, data from the Drug Abuse Warning Network (DAWN), Monitoring the Future (MTF), and…

  14. College Student Drug Usage in a State System as a Function of Type of Institution

    Science.gov (United States)

    Schoenfeldt, Lyle F.; Strimbu, Jerry L.

    1975-01-01

    Over 4,500 students from 28 universities, colleges, and junior colleges constituting a state system of higher education were compared on extent of drug use. The largest differences were between universities and junior colleges on alcohol and marihuana. Differences in terms of actual numbers of users were small. Implications are discussed.…

  15. Experimental psychiatric illness and drug abuse models: from human to animal, an overview.

    Science.gov (United States)

    Edwards, Scott; Koob, George F

    2012-01-01

    Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

  16. Prescription Opioid Usage and Abuse Relationships: An Evaluation of State Prescription Drug Monitoring Program Efficacy

    Directory of Open Access Journals (Sweden)

    Richard M. Reisman

    2009-01-01

    Full Text Available Context The dramatic rise in the use of prescription opioids to treat non-cancer pain has been paralleled by increasing prescription opioid abuse. However, detailed analyses of these trends and programs to address them are lacking. Objective To study the association between state shipments of prescription opioids for medical use and prescription opioid abuse admissions and to assess the effects of state prescription drug monitoring programs (PDMPs on prescription opioid abuse admissions. Design and Setting A retrospective ecological cohort study comparing state prescription opioid shipments (source: Automation of Reports and Consolidated Orders Systems database and inpatient admissions for prescription opioid abuse (source: Treatment Episode Data Set in 14 states with PDMPs (intervention group and 36 states without PDMPs (control group for the period 1997–2003. Results From 1997 to 2003, oxycodone, morphine, and hydrocodone shipments increased by 479%, 100%, and 148% respectively. Increasing prescription oxycodone shipments were significantly associated with increasing prescription opioid admission rates (p < 0.001. PDMP states had significantly lower oxycodone shipments than the control group. PDMP states had less increase in prescription opioid admissions per year (p = 0.063. A patient admitted to an inpatient drug abuse rehabilitation program in a PDMP state was less likely to be admitted for prescription opioid drug abuse (Odds ratio = 0.775, 95% Confidence Interval 0.764–0.785. Conclusions PDMPs appear to decrease the quantity of oxycodone shipments and the prescription opioid admission rate for states with these programs. Overall, opioid shipments rose significantly in PDMP states during the study period indicating a negligible “chilling effect” on physician prescribing.

  17. COGNITIVE MODELING OF EPISTEMIC MENTAL STATES

    Directory of Open Access Journals (Sweden)

    Yurovitskaya, L.N.

    2017-03-01

    Full Text Available Epistemic states of mind, connected with the cognitive activity of a man, are aimed not only at apprehending the world around us, but also at the process of this apprehension. A very important step on this way is an attempt to model these states and processes in terms of formal logics and semantics, irrespective of the language of cognition. The article presents the idea of how formal logical and linguistic modeling of the process of thinking shows the correlation and the interdependence of semantic units connected with mental activities of human brain. The basic notions of the conceptual field of cognition are presented in the article

  18. Scaling predictive modeling in drug development with cloud computing.

    Science.gov (United States)

    Moghadam, Behrooz Torabi; Alvarsson, Jonathan; Holm, Marcus; Eklund, Martin; Carlsson, Lars; Spjuth, Ola

    2015-01-26

    Growing data sets with increased time for analysis is hampering predictive modeling in drug discovery. Model building can be carried out on high-performance computer clusters, but these can be expensive to purchase and maintain. We have evaluated ligand-based modeling on cloud computing resources where computations are parallelized and run on the Amazon Elastic Cloud. We trained models on open data sets of varying sizes for the end points logP and Ames mutagenicity and compare with model building parallelized on a traditional high-performance computing cluster. We show that while high-performance computing results in faster model building, the use of cloud computing resources is feasible for large data sets and scales well within cloud instances. An additional advantage of cloud computing is that the costs of predictive models can be easily quantified, and a choice can be made between speed and economy. The easy access to computational resources with no up-front investments makes cloud computing an attractive alternative for scientists, especially for those without access to a supercomputer, and our study shows that it enables cost-efficient modeling of large data sets on demand within reasonable time.

  19. A Model of Mental State Transition Network

    Science.gov (United States)

    Xiang, Hua; Jiang, Peilin; Xiao, Shuang; Ren, Fuji; Kuroiwa, Shingo

    Emotion is one of the most essential and basic attributes of human intelligence. Current AI (Artificial Intelligence) research is concentrating on physical components of emotion, rarely is it carried out from the view of psychology directly(1). Study on the model of artificial psychology is the first step in the development of human-computer interaction. As affective computing remains unpredictable, creating a reasonable mental model becomes the primary task for building a hybrid system. A pragmatic mental model is also the fundament of some key topics such as recognition and synthesis of emotions. In this paper a Mental State Transition Network Model(2) is proposed to detect human emotions. By a series of psychological experiments, we present a new way to predict coming human's emotions depending on the various current emotional states under various stimuli. Besides, people in different genders and characters are taken into consideration in our investigation. According to the psychological experiments data derived from 200 questionnaires, a Mental State Transition Network Model for describing the transitions in distribution among the emotions and relationships between internal mental situations and external are concluded. Further more the coefficients of the mental transition network model were achieved. Comparing seven relative evaluating experiments, an average precision rate of 0.843 is achieved using a set of samples for the proposed model.

  20. Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach

    Science.gov (United States)

    Buyukozturk, Fulden; Di Maio, Selena; Budil, David E.; Carrier, Rebecca L.

    2014-01-01

    Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs. PMID:24234918

  1. A Model of Solid State Gas Sensors

    Science.gov (United States)

    Woestman, J. T.; Brailsford, A. D.; Shane, M.; Logothetis, E. M.

    1997-03-01

    Solid state gas sensors are widely used to measure the concentrations of gases such as CO, CH_4, C_3H_6, H_2, C_3H8 and O2 The applications of these sensors range from air-to-fuel ratio control in combustion processes including those in automotive engines and industrial furnaces to leakage detection of inflammable and toxic gases in domestic and industrial environments. As the need increases to accurately measure smaller and smaller concentrations, problems such as poor selectivity, stability and response time limit the use of these sensors. In an effort to overcome some of these limitations, a theoretical model of the transient behavior of solid state gas sensors has been developed. In this presentation, a model for the transient response of an electrochemical gas sensor to gas mixtures containing O2 and one reducing species, such as CO, is discussed. This model accounts for the transport of the reactive species to the sampling electrode, the catalyzed oxidation/reduction reaction of these species and the generation of the resulting electrical signal. The model will be shown to reproduce the results of published steady state models and to agree with experimental steady state and transient data.

  2. Non-Clinical Models for Neurodegenerative Diseases: Therapeutic Approach and Drug Validation in Animal Models

    Directory of Open Access Journals (Sweden)

    Caridad Ivette Fernandez

    2017-12-01

    Full Text Available In 2016, 19.8% of the Cuban population was aged 60 or over. As a result, age-associated degenerative diseases and other diseases have become priority targets from a prophylactic, diagnostic and therapeutic perspective. As a result, the Cuban biomedical scientific community has addressed its basic, preclinical and epidemiological research in order to rise up to the challenge. A firm step in this direction has been the international congress “State of the art in non-clinical models for neurodegenerative diseases” which has brought together preclinical and clinical researchers, technicians and regulatory staff members from different countries to review the state of the art in neurodegenerations, find unifying ideas, objectives and collaborations or partnership. The objective is to expose the perspectives of new biotechnological products from Cuba and other countries from the diagnostic, therapeutic and neuroprotective point of view. It is crucial, therefore, that the irreplaceable role of laboratory animals in achieving these objectives is understood but they must be used in rational, adequate and ethical manner. We expose the current development trends in this field, being of common interest to the work directed to the search for potential drugs, diagnostic tools and the promotion of changes in lifestyle as a preventive projection.

  3. The impact of pharmacophore modeling in drug design.

    Science.gov (United States)

    Guner, Osman F

    2005-07-01

    With the reliable use of computer simulations in scientific research, it is possible to achieve significant increases in productivity as well as a reduction in research costs compared with experimental approaches. For example, computer-simulation can substantially enchance productivity by focusing the scientist to better, more informed choices, while also driving the 'fail-early' concept to result in a significant reduction in cost. Pharmacophore modeling is a reliable computer-aided design tool used in the discovery of new classes of compounds for a given therapeutic category. This commentary will briefly review the benefits and applications of this technology in drug discovery and design, and will also highlight its historical evolution. The two most commonly used approaches for pharmacophore model development will be discussed, and several examples of how this technology was successfully applied to identify new potent leads will be provided. The article concludes with a brief outline of the controversial issue of patentability of pharmacophore models.

  4. Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs.

    Science.gov (United States)

    Kollamaram, Gayathri; Croker, Denise M; Walker, Gavin M; Goyanes, Alvaro; Basit, Abdul W; Gaisford, Simon

    2018-07-10

    Fused deposition modelling (FDM) is the most commonly investigated 3D printing technology for the manufacture of personalized medicines, however, the high temperatures used in the process limit its wider application. The objective of this study was to print low-melting and thermolabile drugs by reducing the FDM printing temperature. Two immediate release polymers, Kollidon VA64 and Kollidon 12PF were investigated as potential candidates for low-temperature FDM printing. Ramipril was used as the model low melting temperature drug (109 °C); to the authors' knowledge this is the lowest melting point drug investigated to date by FDM printing. Filaments loaded with 3% drug were obtained by hot melt extrusion at 70 °C and ramipril printlets with a dose equivalent of 8.8 mg were printed at 90 °C. HPLC analysis confirmed that the drug was stable with no signs of degradation and dissolution studies revealed that drug release from the printlets reached 100% within 20-30 min. Variable temperature Raman and solid state nuclear magnetic resonance (SSNMR) spectroscopy techniques were used to evaluate drug stability over the processing temperature range. These data indicated that ramipril did not undergo degradation below its melting point (which is above the processing temperature range: 70-90 °C) but it was transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point. The use of the excipients Kollidon VA64 and Kollidon 12PF in FDM was further validated by printing with the drug 4-aminosalicylic acid (4-ASA), which in previous work was reported to undergo degradation in FDM printing, but here it was found to be stable. This work demonstrates that the selection and use of new excipients can overcome one of the major disadvantages in FDM printing, drug degradation due to thermal heating, making this technology suitable for drugs with lower melting temperatures. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Reuleaux models at St. Petersburg State University

    Science.gov (United States)

    Kuteeva, G. A.; Sinilshchikova, G. A.; Trifonenko, B. V.

    2018-05-01

    Franz Reuleaux (1829 - 1905) is a famous mechanical engineer, a Professor of the Berlin Royal Technical Academy. He became widely known as an engineer-scientist, a Professor and industrial consultant, education reformer and leader of the technical elite of Germany. He directed the design and manufacture of over 300 models of simple mechanisms. They were sold to many famous universities for pedagogical and scientific purposes. Today, the most complete set is at Cornell University, College of Engineering. In this article we discuss the history, the modern state and our using the Reuleaux models that survived at St. Petersburg State University for educational purposes. We present description of certain models and our electronic resource with these models. We provide the information of similar electronic resources from other universities.

  6. Multi-state modeling of biomolecules.

    Directory of Open Access Journals (Sweden)

    Melanie I Stefan

    2014-09-01

    Full Text Available Multi-state modeling of biomolecules refers to a series of techniques used to represent and compute the behavior of biological molecules or complexes that can adopt a large number of possible functional states. Biological signaling systems often rely on complexes of biological macromolecules that can undergo several functionally significant modifications that are mutually compatible. Thus, they can exist in a very large number of functionally different states. Modeling such multi-state systems poses two problems: the problem of how to describe and specify a multi-state system (the "specification problem" and the problem of how to use a computer to simulate the progress of the system over time (the "computation problem". To address the specification problem, modelers have in recent years moved away from explicit specification of all possible states and towards rule-based formalisms that allow for implicit model specification, including the κ-calculus, BioNetGen, the Allosteric Network Compiler, and others. To tackle the computation problem, they have turned to particle-based methods that have in many cases proved more computationally efficient than population-based methods based on ordinary differential equations, partial differential equations, or the Gillespie stochastic simulation algorithm. Given current computing technology, particle-based methods are sometimes the only possible option. Particle-based simulators fall into two further categories: nonspatial simulators, such as StochSim, DYNSTOC, RuleMonkey, and the Network-Free Stochastic Simulator (NFSim, and spatial simulators, including Meredys, SRSim, and MCell. Modelers can thus choose from a variety of tools, the best choice depending on the particular problem. Development of faster and more powerful methods is ongoing, promising the ability to simulate ever more complex signaling processes in the future.

  7. Sufficient conditions for optimality for a mathematical model of drug treatment with pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Maciej Leszczyński

    2017-01-01

    Full Text Available We consider an optimal control problem for a general mathematical model of drug treatment with a single agent. The control represents the concentration of the agent and its effect (pharmacodynamics is modelled by a Hill function (i.e., Michaelis-Menten type kinetics. The aim is to minimize a cost functional consisting of a weighted average related to the state of the system (both at the end and during a fixed therapy horizon and to the total amount of drugs given. The latter is an indirect measure for the side effects of treatment. It is shown that optimal controls are continuous functions of time that change between full or no dose segments with connecting pieces that take values in the interior of the control set. Sufficient conditions for the strong local optimality of an extremal controlled trajectory in terms of the existence of a solution to a piecewise defined Riccati differential equation are given.

  8. Teaching Note--No Peace without Justice: Addressing the United States' War on Drugs in Social Work Education

    Science.gov (United States)

    Bowen, Elizabeth A.; Redmond, Helen

    2016-01-01

    The United States' War on Drugs encompasses a body of legislation characterized by punitive approaches to drug control. These policies have resulted in escalating incarceration rates and have extracted a particularly harsh toll on low-income people of color. This article argues that education on the War on Drugs is essential for effective practice…

  9. Solvable model of quantum microcanonical states

    International Nuclear Information System (INIS)

    Bender, Carl M; Brody, Dorje C; Hook, Daniel W

    2005-01-01

    This letter examines the consequences of a recently proposed modification of the postulate of equal a priori probability in quantum statistical mechanics. This modification, called the quantum microcanonical postulate (QMP), asserts that for a system in microcanonical equilibrium all pure quantum states having the same energy expectation value are realized with equal probability. A simple model of a quantum system that obeys the QMP and that has a nondegenerate spectrum with equally spaced energy eigenvalues is studied. This model admits a closed-form expression for the density of states in terms of the energy eigenvalues. It is shown that in the limit as the number of energy levels approaches infinity, the expression for the density of states converges to a δ function centred at the intermediate value (E max + E min )/2 of the energy. Determining this limit requires an elaborate asymptotic study of an infinite sum whose terms alternate in sign. (letter to the editor)

  10. What Characterise the Nordic Welfare State Model

    DEFF Research Database (Denmark)

    Greve, Bent

    2007-01-01

    The main distinctive characteristics of the Nordic welfare states are presented. These include full employment, high degree of equality, a high level of taxes and public sector spending. The Nordic countries are compared to other European countries. The conclusion being that the Nordic Model...... is here to stay, although a movement in a European direction is underway....

  11. A Systems Dynamic Model for Drug Abuse and Drug-Related Crime in the Western Cape Province of South Africa

    Directory of Open Access Journals (Sweden)

    Farai Nyabadza

    2017-01-01

    Full Text Available The complex problem of drug abuse and drug-related crimes in communities in the Western Cape province cannot be studied in isolation but through the system they are embedded in. In this paper, a theoretical model to evaluate the syndemic of substance abuse and drug-related crimes within the Western Cape province of South Africa is constructed and explored. The dynamics of drug abuse and drug-related crimes within the Western Cape are simulated using STELLA software. The simulation results are consistent with the data from SACENDU and CrimeStats SA, highlighting the usefulness of such a model in designing and planning interventions to combat substance abuse and its related problems.

  12. Opportunities for AIDS prevention in a rural state in criminal justice and drug treatment settings.

    Science.gov (United States)

    Farabee, D; Leukefeld, C G

    1999-01-01

    This study examined the likelihood that drug users would receive HIV/ AIDS prevention information and supplies (e.g., condoms and bleach) in the rural state of Kentucky. Despite evidence of high HIV risk among criminal justice and substance-using populations, incarceration and substance-user treatment were only minimally associated with prior HIV prevention exposure or HIV testing. These data strongly support the use of criminal justice and treatment settings to provide AIDS prevention interventions for the high-risk drug-using populations they serve, and to target HIV prevention services in rural as well as urban areas.

  13. PBPK Modeling - A Predictive, Eco-Friendly, Bio-Waiver Tool for Drug Research.

    Science.gov (United States)

    De, Baishakhi; Bhandari, Koushik; Mukherjee, Ranjan; Katakam, Prakash; Adiki, Shanta K; Gundamaraju, Rohit; Mitra, Analava

    2017-01-01

    The world has witnessed growing complexities in disease scenario influenced by the drastic changes in host-pathogen- environment triadic relation. Pharmaceutical R&Ds are in constant search of novel therapeutic entities to hasten transition of drug molecules from lab bench to patient bedside. Extensive animal studies and human pharmacokinetics are still the "gold standard" in investigational new drug research and bio-equivalency studies. Apart from cost, time and ethical issues on animal experimentation, burning questions arise relating to ecological disturbances, environmental hazards and biodiversity issues. Grave concerns arises when the adverse outcomes of continued studies on one particular disease on environment gives rise to several other pathogenic agents finally complicating the total scenario. Thus Pharma R&Ds face a challenge to develop bio-waiver protocols. Lead optimization, drug candidate selection with favorable pharmacokinetics and pharmacodynamics, toxicity assessment are vital steps in drug development. Simulation tools like Gastro Plus™, PK Sim®, SimCyp find applications for the purpose. Advanced technologies like organ-on-a chip or human-on-a chip where a 3D representation of human organs and systems can mimic the related processes and activities, thereby linking them to major features of human biology can be successfully incorporated in the drug development tool box. PBPK provides the State of Art to serve as an optional of animal experimentation. PBPK models can successfully bypass bio-equivalency studies, predict bioavailability, drug interactions and on hyphenation with in vitro-in vivo correlation can be extrapolated to humans thus serving as bio-waiver. PBPK can serve as an eco-friendly bio-waiver predictive tool in drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. A theory of drug tolerance and dependence II: the mathematical model.

    Science.gov (United States)

    Peper, Abraham

    2004-08-21

    The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.

  15. DFT application for chlorin derivatives photosensitizer drugs modeling

    Science.gov (United States)

    Machado, Neila; Carvalho, B. G.; Téllez Soto, C. A.; Martin, A. A.; Favero, P. P.

    2018-04-01

    Photodynamic therapy is an alternative form of cancer treatment that meets the desire for a less aggressive approach to the body. It is based on the interaction between a photosensitizer, activating light, and molecular oxygen. This interaction results in a cascade of reactions that leads to localized cell death. Many studies have been conducted to discover an ideal photosensitizer, which aggregates all the desirable characteristics of a potent cell killer and generates minimal side effects. Using Density Functional Theory (DFT) implemented in the program Vienna Ab-initio Simulation Package, new chlorin derivatives with different functional groups were simulated to evaluate the different absorption wavelengths to permit resonant absorption with the incident laser. Gaussian 09 program was used to determine vibrational wave numbers and Natural Bond Orbitals. The chosen drug with the best characteristics for the photosensitizer was a modified model of the original chlorin, which was called as Thiol chlorin. According to our calculations it is stable and is 19.6% more efficient at optical absorption in 708 nm in comparison to the conventional chlorin e6. Vibrational modes, optical and electronic properties were predicted. In conclusion, this study is an attempt to improve the development of new photosensitizer drugs through computational methods that save time and contribute to decrease the numbers of animals for model application.

  16. Analyzing research trends on drug safety using topic modeling.

    Science.gov (United States)

    Zou, Chen

    2018-04-06

    Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts. Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years. Expert Opinion/Commentary: We found that 'benefit-risk assessment and communication', 'diabetes' and 'biologic therapy for autoimmune diseases' are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time.

  17. Multiple model predictive control for optimal drug administration of mixed immunotherapy and chemotherapy of tumours.

    Science.gov (United States)

    Sharifi, N; Ozgoli, S; Ramezani, A

    2017-06-01

    Mixed immunotherapy and chemotherapy of tumours is one of the most efficient ways to improve cancer treatment strategies. However, it is important to 'design' an effective treatment programme which can optimize the ways of combining immunotherapy and chemotherapy to diminish their imminent side effects. Control engineering techniques could be used for this. The method of multiple model predictive controller (MMPC) is applied to the modified Stepanova model to induce the best combination of drugs scheduling under a better health criteria profile. The proposed MMPC is a feedback scheme that can perform global optimization for both tumour volume and immune competent cell density by performing multiple constraints. Although current studies usually assume that immunotherapy has no side effect, this paper presents a new method of mixed drug administration by employing MMPC, which implements several constraints for chemotherapy and immunotherapy by considering both drug toxicity and autoimmune. With designed controller we need maximum 57% and 28% of full dosage of drugs for chemotherapy and immunotherapy in some instances, respectively. Therefore, through the proposed controller less dosage of drugs are needed, which contribute to suitable results with a perceptible reduction in medicine side effects. It is observed that in the presence of MMPC, the amount of required drugs is minimized, while the tumour volume is reduced. The efficiency of the presented method has been illustrated through simulations, as the system from an initial condition in the malignant region of the state space (macroscopic tumour volume) transfers into the benign region (microscopic tumour volume) in which the immune system can control tumour growth. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing...... of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although one Rheumatoid Arthritis in vivo model cannot mirror...

  19. Competing States in the t-J Model: Uniform d-Wave State versus Stripe State versus Stripe State

    NARCIS (Netherlands)

    Corboz, P.R.; Rice, T.M.; Troyer, M.

    2014-01-01

    Variational studies of the t-J model on the square lattice based on infinite projected-entangled pair states confirm an extremely close competition between a uniform d-wave superconducting state and different stripe states. The site-centered stripe with an in-phase d-wave order has an equal or only

  20. A developmental etiological model for drug abuse in men.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Edwards, Alexis C; Sundquist, Jan; Sundquist, Kristina

    2017-10-01

    We attempt to develop a relatively comprehensive structural model of risk factors for drug abuse (DA) in Swedish men that illustrates developmental and mediational processes. We examined 20 risk factors for DA in 48,369 men undergoing conscription examinations in 1969-70 followed until 2011 when 2.34% (n=1134) of them had DA ascertained in medical, criminal and pharmacy registries. Risk factors were organized into four developmental tiers reflecting i) birth, ii) childhood/early adolescence, iii) late adolescence, and iv) young adulthood. Structural equational model fitting was performed using Mplus. The best fitting model explained 47.8% of the variance in DA. The most prominent predictors, in order, were: early adolescent externalizing behavior, early adult criminal behavior, early adolescent internalizing behavior, early adult unemployment, early adult alcohol use disorder, and late adolescent drug use. Two major inter-connecting pathways emerged reflecting i) genetic/familial risk and ii) family dysfunction and psychosocial adversity. Generated on a first and tested on a second random half of the sample, a model from these variables predicted DA with an ROC area under the curve of 83.6%. Fifty-nine percent of DA cases arose from subjects in the top decile of risk. DA in men is a highly multifactorial syndrome with risk arising from familial-genetic, psychosocial, behavioral and psychological factors acting and interacting over development. Among the multiple predisposing factors for DA, a range of psychosocial adversities, externalizing psychopathology and lack of social constraints in early adulthood are predominant. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Antiretroviral Drug Use in a Cohort of HIV-Uninfected Women in the United States: HIV Prevention Trials Network 064.

    Directory of Open Access Journals (Sweden)

    Iris Chen

    Full Text Available Antiretroviral (ARV drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009-2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2% of 1,806 participants: 27/181 (15% in Baltimore, MD and 12/179 (7% in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1-4 drugs/sample. These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals.

  2. “Hare Krishna vs. Shiva Shiva”: Swami Agehananda Bharati, Drugs, and the Mystical State in Hindusim

    Directory of Open Access Journals (Sweden)

    Helton Christopher Jason

    2016-12-01

    Full Text Available This paper will form an overview of Swami Agehananda Bharati’s views about drugs as a catalyst for achieving the mystical state (in both a Hindu and general context, as well as his observations of the perception of drugs throughout the Hindu community, inside and outside South Asia. It will demonstrate that Bharati considered drugs a valid means toward achieving the mystical state, both as a scholar of Hinduism and as a practicing sannyasin.

  3. SC lipid model membranes designed for studying impact of ceramide species on drug diffusion and permeation--part II: diffusion and permeation of model drugs.

    Science.gov (United States)

    Ochalek, M; Podhaisky, H; Ruettinger, H-H; Wohlrab, J; Neubert, R H H

    2012-10-01

    The barrier function of two quaternary stratum corneum (SC) lipid model membranes, which were previously characterized with regard to the lipid organization, was investigated based on diffusion studies of model drugs with varying lipophilicities. Diffusion experiments of a hydrophilic drug, urea, and more lipophilic drugs than urea (i.e. caffeine, diclofenac sodium) were conducted using Franz-type diffusion cells. The amount of permeated drug was analyzed using either HPLC or CE technique. The subjects of interest in the present study were the investigation of the influence of physicochemical properties of model drugs on their diffusion and permeation through SC lipid model membranes, as well as the study of the impact of the constituents of these artificial systems (particularly ceramide species) on their barrier properties. The diffusion through both SC lipid model membranes and the human SC of the most hydrophilic model drug, urea, was faster than the permeation of the more lipophilic drugs. The slowest rate of permeation through SC lipid systems occurred in the case of caffeine. The composition of SC lipid model membranes has a significant impact on their barrier function. Model drugs diffused and permeated faster through Membrane II (presence of Cer [EOS]). In terms of the barrier properties, Membrane II is much more similar to the human SC than Membrane I. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Markov state models of protein misfolding

    Science.gov (United States)

    Sirur, Anshul; De Sancho, David; Best, Robert B.

    2016-02-01

    Markov state models (MSMs) are an extremely useful tool for understanding the conformational dynamics of macromolecules and for analyzing MD simulations in a quantitative fashion. They have been extensively used for peptide and protein folding, for small molecule binding, and for the study of native ensemble dynamics. Here, we adapt the MSM methodology to gain insight into the dynamics of misfolded states. To overcome possible flaws in root-mean-square deviation (RMSD)-based metrics, we introduce a novel discretization approach, based on coarse-grained contact maps. In addition, we extend the MSM methodology to include "sink" states in order to account for the irreversibility (on simulation time scales) of processes like protein misfolding. We apply this method to analyze the mechanism of misfolding of tandem repeats of titin domains, and how it is influenced by confinement in a chaperonin-like cavity.

  5. Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug

    Directory of Open Access Journals (Sweden)

    Tatyana Dyakonov

    2012-01-01

    Full Text Available The objective of this proof-of-concept study was to develop a platform for controlled drug delivery based on silk fibroin (SF and to explore the feasibility of using SF in oral drug delivery. The SF-containing matrixes were prepared via spray-drying and film casting, and the release profile of the model drug naproxen sodium was evaluated. Attenuated total reflectance Fourier transform infrared spectroscopy (FTIR has been used to observe conformational changes in SF- and drug-containing compositions. SF-based films, spray-dried microparticles, and matrixes loaded with naproxen were prepared. Both FTIR spectra and in vitro dissolution data demonstrated that SF β-sheet conformation regulates the release profile of naproxen. The controlled release characteristics of the SF-containing compositions were evaluated as a function of SF concentration, temperature, and exposure to dehydrating solvents. The results suggest that SF may be an attractive polymer for use in controlled drug delivery systems.

  6. Heroin delay discounting: Modulation by pharmacological state, drug-use impulsivity, and intelligence.

    Science.gov (United States)

    Stoltman, Jonathan J K; Woodcock, Eric A; Lister, Jamey J; Lundahl, Leslie H; Greenwald, Mark K

    2015-12-01

    Delay discounting (DD) refers to how rapidly an individual devalues goods based on delays to receipt. DD usually is considered a trait variable but can be state dependent, yet few studies have assessed commodity valuation at short, naturalistically relevant time intervals that might enable state-dependent analysis. This study aimed to determine whether drug-use impulsivity and intelligence influence heroin DD at short (ecologically relevant) delays during two pharmacological states (heroin satiation and withdrawal). Out-of-treatment, intensive heroin users (n = 170; 53.5% African American; 66.7% male) provided complete DD data during imagined heroin satiation and withdrawal. Delays were 3, 6, 12, 24, 48, 72, and 96 hours; maximum delayed heroin amount was thirty $10 bags. Indifference points were used to calculate area under the curve (AUC). We also assessed drug-use impulsivity (subscales from the Impulsive Relapse Questionnaire [IRQ]) and estimated intelligence (Shipley IQ) as predictors of DD. Heroin discounting was greater (smaller AUC) during withdrawal than satiation. In regression analyses, lower intelligence and IRQ Capacity for Delay as well as higher IRQ Speed (to return to drug use) predicted greater heroin discounting in the satiation condition. Lower intelligence and higher IRQ Speed predicted greater discounting in the withdrawal condition. Sex, race, substance use variables, and other IRQ subscales were not significantly related to the withdrawal or satiation DD behavior. In summary, heroin discounting was temporally rapid, pharmacologically state dependent, and predicted by drug-use impulsivity and estimated intelligence. These findings highlight a novel and sensitive measure of acute DD that is easy to administer. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  7. SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling.

    Science.gov (United States)

    Shahid, Mohammad; Shahzad Cheema, Muhammad; Klenner, Alexander; Younesi, Erfan; Hofmann-Apitius, Martin

    2013-03-01

    Systems pharmacological modeling of drug mode of action for the next generation of multitarget drugs may open new routes for drug design and discovery. Computational methods are widely used in this context amongst which support vector machines (SVM) have proven successful in addressing the challenge of classifying drugs with similar features. We have applied a variety of such SVM-based approaches, namely SVM-based recursive feature elimination (SVM-RFE). We use the approach to predict the pharmacological properties of drugs widely used against complex neurodegenerative disorders (NDD) and to build an in-silico computational model for the binary classification of NDD drugs from other drugs. Application of an SVM-RFE model to a set of drugs successfully classified NDD drugs from non-NDD drugs and resulted in overall accuracy of ∼80 % with 10 fold cross validation using 40 top ranked molecular descriptors selected out of total 314 descriptors. Moreover, SVM-RFE method outperformed linear discriminant analysis (LDA) based feature selection and classification. The model reduced the multidimensional descriptors space of drugs dramatically and predicted NDD drugs with high accuracy, while avoiding over fitting. Based on these results, NDD-specific focused libraries of drug-like compounds can be designed and existing NDD-specific drugs can be characterized by a well-characterized set of molecular descriptors. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Multimedia Mapping using Continuous State Space Models

    DEFF Research Database (Denmark)

    Lehn-Schiøler, Tue

    2004-01-01

    In this paper a system that transforms speech waveforms to animated faces are proposed. The system relies on continuous state space models to perform the mapping, this makes it possible to ensure video with no sudden jumps and allows continuous control of the parameters in 'face space'. Simulations...... are performed on recordings of 3-5 sec. video sequences with sentences from the Timit database. The model is able to construct an image sequence from an unknown noisy speech sequence fairly well even though the number of training examples are limited....

  9. A Triaxial Characteristic State Model for Sand

    DEFF Research Database (Denmark)

    Krenk, S.; Borup, M.; Hedegaard, J.

    the loading surfaces approach the zero-tension planes asymptotically, generating a nearly triangular contour in the deviator ic stress plane. The gradient of the flow potential is generated directly from the gradient of the loading potential by scaling of the mean stress component. Two hardening rules...... that permit ultimate stress states beyond the characteristic line have been proposed. Results from drained triaxial tests show good agreement with the model, usi ng a weighted work hardening rule....

  10. A Critical Subset Model Provides a Conceptual Basis for the High Antiviral Activity of Major HIV Drugs**

    Science.gov (United States)

    Shen, Lin; Rabi, S. Alireza; Sedaghat, Ahmad R.; Shan, Liang; Lai, Jun; Xing, Sifei; Siliciano, Robert F.

    2012-01-01

    Control of HIV-1 replication was first achieved with regimens that included a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI); however, an explanation for the high antiviral activity of these drugs has been lacking. Indeed, conventional pharmacodynamic measures like IC50 (drug concentration causing 50% inhibition) do not differentiate NNRTIs and PIs from less active nucleoside reverse transcriptase inhibitors (NRTIs). Drug inhibitory potential depends on the slope of the dose-response curve (m), which represents how inhibition increases as a function of increasing drug concentration and is related to the Hill coefficient, a measure of intramolecular cooperativity in ligand binding to a multivalent receptor. Although NNRTIs and PIs bind univalent targets, they unexpectedly exhibit cooperative dose-response curves (m > 1). We show that this cooperative inhibition can be explained by a model in which infectivity requires participation of multiple copies of a drug target in an individual life cycle stage. A critical subset of these target molecules must be in the unbound state. Consistent with experimental observations, this model predicts m > 1 for NNRTIs and PIs and m = 1 in situations where a single drug target/virus mediates a step in the life cycle, as is the case with NRTIs and integrase strand transfer inhibitors. This model was tested experimentally by modulating the number of functional drug targets per virus, and dose-response curves for modulated virus populations fit model predictions. This model explains the high antiviral activity of two drug classes important for successful HIV-1 treatment and defines a characteristic of good targets for antiviral drugs in general, namely, intermolecular cooperativity. PMID:21753122

  11. Modeling Patient-Specific Magnetic Drug Targeting Within the Intracranial Vasculature.

    Science.gov (United States)

    Patronis, Alexander; Richardson, Robin A; Schmieschek, Sebastian; Wylie, Brian J N; Nash, Rupert W; Coveney, Peter V

    2018-01-01

    Drug targeting promises to substantially enhance future therapies, for example through the focussing of chemotherapeutic drugs at the site of a tumor, thus reducing the exposure of healthy tissue to unwanted damage. Promising work on the steering of medication in the human body employs magnetic fields acting on nanoparticles made of paramagnetic materials. We develop a computational tool to aid in the optimization of the physical parameters of these particles and the magnetic configuration, estimating the fraction of particles reaching a given target site in a large patient-specific vascular system for different physiological states (heart rate, cardiac output, etc.). We demonstrate the excellent computational performance of our model by its application to the simulation of paramagnetic-nanoparticle-laden flows in a circle of Willis geometry obtained from an MRI scan. The results suggest a strong dependence of the particle density at the target site on the strength of the magnetic forcing and the velocity of the background fluid flow.

  12. MRI study of hydrophilic xanthan tablets with incorporated model drug

    OpenAIRE

    Mikac, Urša; Baumgartner, Saša; Sepe, Ana; Kristl, Julijana

    2015-01-01

    Magnetic resonance imaging was used to study swelling dynamics and hydrogel formation of xanthan tablets with or without Pentoxifylline drug in water and HCl pH 1.2 media at two different ionic strengths. Significant changes were observed only in the erosion front positions leading to different hydrogel thicknesses. The impact of the drug on the hydrogel thickness was found to be dependent on the medium conditions at high enough drug amount. The drug does not change the hydrogel thickness ...

  13. Pharmaceutical companies vs. the State: who is responsible for post-trial provision of drugs in Brazil?

    Science.gov (United States)

    Wang, Daniel Wei L; Ferraz, Octavio Luiz Motta

    2012-01-01

    This paper discusses the post-trial access to drugs for patients who participated in clinical trials in Brazil. The ethical guidance for clinical trials in Brazil is arguably one of the clearest in the world in attributing to research sponsors the responsibility for providing post-trial drugs to patients who participated in their experiments. The Federal Constitution recognizes health as a fundamental right to be fulfilled by the State. Based on the Brazilian constitution and on the National Health Council resolutions, courts have been accepting patients' claims and ordering the State and the pharmaceutical companies to provide these patients with the tested treatment in the quantity and duration they need it. This generous interpretation of the duties of the pharmaceutical companies and the State makes the Brazilian model for post-trial access unique when compared to the experience of other countries and thus should be followed with attention by future research in order to assess its consequences for patients, research sponsors, and the public health system. © 2012 American Society of Law, Medicine & Ethics, Inc.

  14. Increased Incidence of Spinal Abscess and Substance Abuse after Implementation of State Mandated Prescription Drug Legislation.

    Science.gov (United States)

    Nagar, Vittal R; Springer, Joe E; Salles, Sara

    2015-10-01

    To investigate the incidence of spinal abscess and substance abuse in a tertiary care hospital after state legislation titled "House Bill 1" (HB1) mandated stricter regulation of prescription drugs of abuse in Kentucky in 2012. A retrospective case series study design was used to review the incidence of spinal abscess and drug abuse diagnoses admissions from 2010 to 2014. Variances in the incidence of spinal abscess and substance abuse were plotted across this time frame. The incidence of intraspinal abscess increased 1.56-fold in 2011 (n = 26) and 2012 (n = 25) relative to 2010 (n = 16). However, in 2013, the year following implementation of HB1 legislation, the incidence of intraspinal abscess increased 2.38-fold (n = 38) and then 4.19-fold (n = 67) in 2014. The incidence of intraspinal abscess in subjects with drug abuse diagnosis remained constant between 2010 (n = 3) and 2012 (n = 3). However, it increased twofold (n = 7) in 2013 and then ninefold (n = 27) in 2014. A correlation coefficient (rSAD ) of 0.775 revealed a strong association between the increase incidence of intraspinal abscess and diagnosis of drug abuse. The results of this retrospective study demonstrate an increased incidence of intraspinal abscess associated with drug abuse after passage of HB1 legislation regulating prescriptions of controlled medications in Kentucky. This increased incidence may be related to individuals relying on nonprescription drugs of abuse due to more highly regulated access to controlled prescription medications. However, additional factors unrelated to HB1 legislation must be taken into account. Wiley Periodicals, Inc.

  15. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

    Science.gov (United States)

    Carhart-Harris, Robin L.; Leech, Robert; Hellyer, Peter J.; Shanahan, Murray; Feilding, Amanda; Tagliazucchi, Enzo; Chialvo, Dante R.; Nutt, David

    2014-01-01

    Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing

  16. Target-mediated drug disposition model for drugs with two binding sites that bind to a target with one binding site.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2017-10-01

    The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached. To illustrate properties of new equations and approximations, several variations of population PK data for mAbs with soluble (slow elimination of the complex) or membrane-bound (fast elimination of the complex) targets were simulated from a full 2-1 TMDD model and fitted to 2-1 TMDD models, to its approximations, and to the standard (1-1) QSS model. For a mAb with a soluble target, it was demonstrated that the 2-1 QSS model provided nearly identical description of the observed (simulated) free drug and total target concentrations, although there was some minor bias in predictions of unobserved free target concentrations. The standard QSS approximation also provided a good description of the observed data, but was not able to distinguish between free drug concentrations (with no target attached and both binding site free) and partially bound drug concentrations (with one of the binding sites occupied by the target). For a mAb with a membrane-bound target, the 2-1 MM approximation adequately described the data. The 2-1 QSS approximation converged 10 times faster than the full 2-1 TMDD, and its run time was comparable with the standard QSS model.

  17. Parameter and State Estimator for State Space Models

    Directory of Open Access Journals (Sweden)

    Ruifeng Ding

    2014-01-01

    Full Text Available This paper proposes a parameter and state estimator for canonical state space systems from measured input-output data. The key is to solve the system state from the state equation and to substitute it into the output equation, eliminating the state variables, and the resulting equation contains only the system inputs and outputs, and to derive a least squares parameter identification algorithm. Furthermore, the system states are computed from the estimated parameters and the input-output data. Convergence analysis using the martingale convergence theorem indicates that the parameter estimates converge to their true values. Finally, an illustrative example is provided to show that the proposed algorithm is effective.

  18. Multivariable Wind Modeling in State Space

    DEFF Research Database (Denmark)

    Sichani, Mahdi Teimouri; Pedersen, B. J.

    2011-01-01

    Turbulence of the incoming wind field is of paramount importance to the dynamic response of wind turbines. Hence reliable stochastic models of the turbulence should be available from which time series can be generated for dynamic response and structural safety analysis. In the paper an empirical...... for the vector turbulence process incorporating its phase spectrum in one stage, and its results are compared with a conventional ARMA modeling method....... the succeeding state space and ARMA modeling of the turbulence rely on the positive definiteness of the cross-spectral density matrix, the problem with the non-positive definiteness of such matrices is at first addressed and suitable treatments regarding it are proposed. From the adjusted positive definite cross...

  19. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Science.gov (United States)

    Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

    2017-01-01

    All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  20. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Directory of Open Access Journals (Sweden)

    Mohammed H Cherkaoui-Rbati

    Full Text Available All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs of new chemical entities (NCEs and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit, located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level. A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  1. Models for light QCD bound states

    International Nuclear Information System (INIS)

    LaCourse, D.P.

    1992-01-01

    After a brief overview of Regge, tower, and heavy-quark experimental data, this thesis examines two massless wave equations relevant to quark bound states. We establish general conditions on the Lorentz scalar and Lorentz vector potentials which yield arbitrary leading Regge trajectories for the case of circular classical motion. A semi-classical approximation which includes radial motion reproduces remarkably well the exact solutions. Conditions for tower structure are examined, and found to be incompatible with conditions which give a Nambu stringlike Regge slope. The author then proposes a generalization of the usual potential model of quark bound states in which the confining flux tube is a dynamical object carrying both angular momentum and energy. The Q bar Q-string system with spinless quarks is quantized using an implicit operator technique and the resulting relativistic wave equation is solved. For heavy quarks the usual Schroedinger valence-quark model is recovered. The Regge slope with light quarks agree with the classical rotating-string result and is significantly larger and the effects of short-range forces are also considered. A relativistic generalization of the quantized flux tube model predicts the glueball ground state mass to be √3/α' ≅ 1.9 GeV where α' is the normal Regge slope. The groundstate as well as excited levels like considerably above the expectations of previous models and also above various proposed experimental candidates. The glueball Regge slope is only about three-eighths that for valence quark hadrons. A semi-classical calculation of the Regge slope is in good agreement with a numerically exact value

  2. A three states sleep-waking model

    International Nuclear Information System (INIS)

    Comte, J.C.; Schatzman, M.; Ravassard, P.; Luppi, P.H.; Salin, P.A.

    2006-01-01

    The mechanisms underlying the sleep-states periodicity in animals are a mystery of biology. Recent studies identified a new neuronal population activated during the slow wave sleep (SWS) in the ventral lateral preoptic area of the hypothalamus. Interactions between this neuronal population and the others populations implicated in the vigilance states (paradoxical sleep (PS) and wake (W)) dynamics are not determined. Thus, we propose here a sleep-waking theoretical model that depicts the potential interactions between the neuronal populations responsible for the three vigilance states. First, we pooled data from previous papers regarding the neuronal populations firing rate time course and characterized statistically the experimental hypnograms. Then, we constructed a nonlinear differential equations system describing the neuronal populations activity time course. A simple rule playing the firing threshold role applied to the model allows to construct a theoretical hypnogram. A random modulation of the neuronal activity, shows that theoretical hypnograms present a dynamics close to the experimental observations. Furthermore, we show that the wake promoting neurons activity can predict the next SWS episode duration

  3. Absorbing multicultural states in the Axelrod model

    Science.gov (United States)

    Vazquez, Federico; Redner, Sidney

    2005-03-01

    We determine the ultimate fate of a limit of the Axelrod model that consists of a population of leftists, centrists, and rightists. In an elemental interaction between agents, a centrist and a leftist can both become centrists or both become leftists with equal rates (similarly for a centrist and a rightist), but leftists and rightists do not interact. This interaction is applied repeatedly until the system can no longer evolve. The constraint between extremists can lead to a frustrated final state where the system consists of only leftists and rightists. In the mean field limit, we can view the evolution of the system as the motion of a random walk in the 3-dimensional space whose coordinates correspond to the density of each species. We find the exact final state probabilities and the time to reach consensus by solving for the first-passage probability of the random walk to the corresponding absorbing boundaries. The extension to a larger number of states will be discussed. This approach is a first step towards the analytic solution of Axelrod-like models.

  4. The History of MDMA as an Underground Drug in the United States, 1960-1979.

    Science.gov (United States)

    Passie, Torsten; Benzenhöfer, Udo

    2016-01-01

    MDMA (3,4-methylenedioxy-methylamphetamine, a.k.a. "ecstasy") was first synthesized in 1912 and resynthesized more than once for pharmaceutical reasons before it became a popular recreational drug. Partially based on previously overlooked U.S. government documentation, this article reconstructs the early history of MDMA as a recreational drug in the U.S. from 1960 to 1979. According to the literature, MDMA was introduced as a street drug at the end of the 1960s. The first forensic detection of MDMA "on the street" was reported in 1970 in Chicago. It appears that MDMA was first synthesized by underground chemists in search of "legal alternatives" for the closely related and highly sought-after drug MDA, which was scheduled under the Controlled Substances Act (CSA) in 1970. Until 1974, nearly all MDMA street samples seized came from the U.S. Midwest, the first "hot region" of MDMA use. In Canada, MDMA was first detected in 1974 and scheduled in 1976. From 1975 to 1979, MDMA was found in street samples in more than 10 U.S. states, the West Coast becoming the major "hot region" of MDMA use. Recreational use of MDMA spread across the U.S. in the early 1980s, and in 1985 it was scheduled under the CSA.

  5. Personal characteristics associated with injecting drug use among Latinas in the United States of America

    Directory of Open Access Journals (Sweden)

    Jorge Delva

    1998-11-01

    Full Text Available This study examines nonmedical injecting drug use (IDU among Latinas aged 12 years and older in a nationally representative sample of U.S. households. Data from the 1990-1995 National Household Surveys on Drug Abuse disclosed 154 Latinas with self-reported histories of IDU out of 18 335 Latinas who responded. Hypotheses about correlates of IDU were tested by using the conditional form of multiple logistic regression to compare the characteristics of these IDUs with those of 602 noninjecting Latinas matched on neighborhood of residence. In the USA, an estimated 1% of Latinas age 12 years and older have injected drugs for non-medical purposes on at least one occasion. IDU was 4.6 to 6.5 times greater for adult Latinas (18-44 years old when compared to Latinas aged either 12 through 17 years (P < 0.05 or older than 44 years. IDU was an estimated 7.1 times greater for Latinas who reported marijuana use and 5.4 times greater for Latinas who reported inhalant use when compared to Latinas not using these drugs (P < 0.01. In light of recent studies indicating that IDU is a serious public health problem for Latinas in the United States, the observed associations represent first steps in an effort to understand the Latina subgroups most affected by IDU and the underlying risk factors or causes of this behavior.

  6. Patient access to new cancer drugs in the United States and Australia.

    Science.gov (United States)

    Wilson, Andrew; Cohen, Joshua

    2011-01-01

    In light of the current debate on the use value and potential impact of comparative effectiveness research on patient access, it may prove insightful to compare a health-care system that systematically bases its reimbursement decisions on comparative effectiveness evidence with the United States (US) system that hitherto has only been informed by such evidence on an ad hoc basis. For a set of 2000-2009 approved new molecular entities and biologics indicated for cancer, we compared patient access between US Medicare and Australian Pharmaceutical Benefits Scheme (PBS) beneficiaries. Here, access is defined in terms of marketing availability, payer coverage, and patient out-of-pocket costs. Although 34 drugs and biologics were approved for cancer in the US, just more than one-third (35%) were ultimately covered by the Australian PBS. The PBS also placed more restrictions on use. On the other hand, prices and patient out-of-pocket costs were greater for the US Medicare population. Our analysis points to a possible trade-off in market access to oncology drugs. Although more oncology drugs are available in the US and a higher percentage of available drugs are covered, the evidence-based approach adopted by Australia has contributed to reduced prices, thereby improving affordability for payers and patients for those medications deemed cost-effective by the reimbursement authority. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  7. Illicit drugs and the media: models of media effects for use in drug policy research.

    Science.gov (United States)

    Lancaster, Kari; Hughes, Caitlin E; Spicer, Bridget; Matthew-Simmons, Francis; Dillon, Paul

    2011-07-01

    Illicit drugs are never far from the media gaze and although identified almost a decade ago as 'a new battleground' for the alcohol and other drug (AOD) field there has been limited research examining the role of the news media and its effects on audiences and policy. This paper draws together media theories from communication literature to examine media functions. We illustrate how each function is relevant for media and drugs research by drawing upon the existing literature examining Australian media coverage during the late 1990s of escalating heroin-related problems and proposed solutions. Media can influence audiences in four key ways: by setting the agenda and defining public interest; framing issues through selection and salience; indirectly shaping individual and community attitudes towards risk; and feeding into political debate and decision making. Each has relevance for the AOD field. For example, media coverage of the escalating heroin-related problems in Australia played a strong role in generating interest in heroin overdoses, framing public discourse in terms of a health and/or criminal issue and affecting political decisions. Implications AND CONCLUSION: Media coverage in relation to illicit drugs can have multifarious effects. Incorporating media communication theories into future research and actions is critical to facilitate understanding of the short- and long-term impacts of media coverage on illicit drugs and the avenues by which the AOD field can mitigate or inform future media debates on illicit drugs. © 2010 Australasian Professional Society on Alcohol and other Drugs.

  8. Generalised linear models for correlated pseudo-observations, with applications to multi-state models

    DEFF Research Database (Denmark)

    Andersen, Per Kragh; Klein, John P.; Rosthøj, Susanne

    2003-01-01

    Generalised estimating equation; Generalised linear model; Jackknife pseudo-value; Logistic regression; Markov Model; Multi-state model......Generalised estimating equation; Generalised linear model; Jackknife pseudo-value; Logistic regression; Markov Model; Multi-state model...

  9. A Model Ground State of Polyampholytes

    International Nuclear Information System (INIS)

    Wofling, S.; Kantor, Y.

    1998-01-01

    The ground state of randomly charged polyampholytes (polymers with positive and negatively charged groups along their backbone) is conjectured to have a structure similar to a necklace, made of weakly charged parts of the chain, compacting into globules, connected by highly charged stretched 'strings' attempted to quantify the qualitative necklace model, by suggesting a zero approximation model, in which the longest neutral segment of the polyampholyte forms a globule, while the remaining part will form a tail. Expanding this approximation, we suggest a specific necklace-type structure for the ground state of randomly charged polyampholyte's, where all the neutral parts of the chain compact into globules: The longest neutral segment compacts into a globule; in the remaining part of the chain, the longest neutral segment (the second longest neutral segment) compacts into a globule, then the third, and so on. A random sequence of charges is equivalent to a random walk, and a neutral segment is equivalent to a loop inside the random walk. We use analytical and Monte Carlo methods to investigate the size distribution of loops in a one-dimensional random walk. We show that the length of the nth longest neutral segment in a sequence of N monomers (or equivalently, the nth longest loop in a random walk of N steps) is proportional to N/n 2 , while the mean number of neutral segments increases as √N. The polyampholytes in the ground state within our model is found to have an average linear size proportional to dN, and an average surface area proportional to N 2/3

  10. State and Community Responses to Drug-related Violence in Mexico

    International Development Research Centre (IDRC) Digital Library (Canada)

    Violent conflict related to drug trafficking in Mexico has had a profound impact on the ... mostly due to illegal drug trafficking and the government's response to it, ... security forces and drug traffickers or in executions related to the drug trade.

  11. Modeling the drug transport in the anterior segment of the eye.

    Science.gov (United States)

    Avtar, Ram; Tandon, Deepti

    2008-10-02

    The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

  12. [Categories and characteristics of BPH drug evaluation models: a comparative study].

    Science.gov (United States)

    Huang, Dong-Yan; Wu, Jian-Hui; Sun, Zu-Yue

    2014-02-01

    Benign prostatic hyperplasia (BPH) is a worldwide common disease in men over 50 years old, and the exact cause of BPH remains largely unknown. In order to elucidate its pathogenesis and screen effective drugs for the treatment of BPH, many BPH models have been developed at home and abroad. This article presents a comprehensive analysis of the categories and characteristics of BPH drug evaluation models, highlighting the application value of each model, to provide a theoretical basis for the development of BPH drugs.

  13. The Effect of Florida Medicaid's State-Mandated Formulary Provision on Prescription Drug Use and Health Plan Costs in a Medicaid Managed Care Plan.

    Science.gov (United States)

    Munshi, Kiraat D; Mager, Douglas; Ward, Krista M; Mischel, Brian; Henderson, Rochelle R

    2018-02-01

    Formulary or preferred drug list (PDL) management is an effective strategy to ensure clinically efficient prescription drug management by managed care organizations (MCOs). Medicaid MCOs participating in Florida's Medicaid program were required to use a state-mandated PDL between May and August 2014. To examine differences in prescription drug use and plan costs between a single Florida Medicaid managed care (MMC) health plan that implemented a state-mandated PDL policy on July 1, 2014, and a comparable MMC health plan in another state without a state-mandated PDL, controlling for sociodemographic confounders. A retrospective analysis with a pre-post design was conducted using deidentified administrative claims data from a large pharmacy benefit manager. The prepolicy evaluation period was January 1 through June 30, 2014, and the postpolicy period was January 1 through June 30, 2015. Continuously eligible Florida MMC plan members were matched on sociodemographic and health characteristics to their counterparts enrolled in a comparable MMC health plan in another state without a state-mandated formulary. Outcomes were drug use, measured as the number of 30-day adjusted nonspecialty drug prescriptions per member per period, and total drug plan costs per member per period for all drugs, with separate measures for generic and brand drugs. Bivariate comparisons were conducted using t-tests. Employing a difference-in-differences (DID) analytic approach, multivariate negative binomial regression and generalized estimating equation models were used to analyze prescription drug use and costs. The final analytical sample consisted of 18,372 enrollees, evenly divided between the 2 groups. In the postpolicy evaluation period, overall and generic use declined, while brand use increased for members in the Florida health plan. Drug costs, especially for brands, significantly increased for Florida health plan members. No significant changes were observed over the same time period

  14. In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models.

    Science.gov (United States)

    Sjögren, Erik; Thörn, Helena; Tannergren, Christer

    2016-06-06

    Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and

  15. A 2-categorical state sum model

    Energy Technology Data Exchange (ETDEWEB)

    Baratin, Aristide, E-mail: abaratin@uwaterloo.ca [Department of Applied Mathematics, University of Waterloo, 200 University Ave W, Waterloo, Ontario N2L 3G1 (Canada); Freidel, Laurent, E-mail: lfreidel@perimeterinstitute.ca [Perimeter Institute for Theoretical Physics, 31 Caroline Str. N, Waterloo, Ontario N2L 2Y5 (Canada)

    2015-01-15

    It has long been argued that higher categories provide the proper algebraic structure underlying state sum invariants of 4-manifolds. This idea has been refined recently, by proposing to use 2-groups and their representations as specific examples of 2-categories. The challenge has been to make these proposals fully explicit. Here, we give a concrete realization of this program. Building upon our earlier work with Baez and Wise on the representation theory of 2-groups, we construct a four-dimensional state sum model based on a categorified version of the Euclidean group. We define and explicitly compute the simplex weights, which may be viewed a categorified analogue of Racah-Wigner 6j-symbols. These weights solve a hexagon equation that encodes the formal invariance of the state sum under the Pachner moves of the triangulation. This result unravels the combinatorial formulation of the Feynman amplitudes of quantum field theory on flat spacetime proposed in A. Baratin and L. Freidel [Classical Quantum Gravity 24, 2027–2060 (2007)] which was shown to lead after gauge-fixing to Korepanov’s invariant of 4-manifolds.

  16. Assessing the concordance between illicit drug laws on the books and drug law enforcement: Comparison of three states on the continuum from "decriminalised" to "punitive".

    Science.gov (United States)

    Belackova, Vendula; Ritter, Alison; Shanahan, Marian; Hughes, Caitlin E

    2017-03-01

    Variations in drug laws, as well as variations in enforcement practice, exist across jurisdictions. This study explored the feasibility of categorising drug laws "on the books" in terms of their punitiveness, and the extent of their concordance with "laws in practice" in a cross-national comparison. "Law on the books", classified with respect to both cannabis and other drug offences in the Czech Republic, NSW (AU) and Florida (USA) were analysed in order to establish an ordinal relationship between the three states. Indicators to assess the "laws in practice" covered both police (arrests) and court (sentencing) activity between 2002 and 2013. Parametric and non-parametric tests of equality of means, tests of stationarity and correlation analysis were used to examine the concordance between the ordinal categorisation of "laws on the books" and "laws in practice", as well as trends over time. The Czech Republic had the most lenient drug laws; Florida had the most punitive and NSW was in-between. Examining the indicators of "laws in practice", we found that the population adjusted number of individuals sentenced to prison ranked across the three states was concordant with categorisation of "laws on the books", but the average sentence length and percentage of court cases sentenced to prison were not. Also, the de jure decriminalisation of drug possession in the Czech Republic yielded a far greater share of administrative offenses than the de facto decriminalisation of cannabis use / possession in NSW. Finally, the mean value of most "laws in practice" indicators changed significantly over time although the "laws on the books" didn't change. While some indicators of "laws in practice" were concordant with the ordinal categorisation of drug laws, several indicators of "laws in practice" appeared to operate independently from the drug laws as stated. This has significant implications for drug policy analysis and means that research should not assume they are

  17. Formation, Physicochemical Characterization, and Thermodynamic Stability of the Amorphous State of Drugs and Excipients.

    Science.gov (United States)

    Martino, Piera Di; Magnoni, Federico; Peregrina, Dolores Vargas; Gigliobianco, Maria Rosa; Censi, Roberta; Malaj, Ledjan

    2016-01-01

    Drugs and excipients used for pharmaceutical applications generally exist in the solid (crystalline or amorphous) state, more rarely as liquid materials. In some cases, according to the physicochemical nature of the molecule, or as a consequence of specific technological processes, a compound may exist exclusively in the amorphous state. In other cases, as a consequence of specific treatments (freezing and spray drying, melting and co-melting, grinding and compression), the crystalline form may convert into a completely or partially amorphous form. An amorphous material shows physical and thermodynamic properties different from the corresponding crystalline form, with profound repercussions on its technological performance and biopharmaceutical properties. Several physicochemical techniques such as X-ray powder diffraction, thermal methods of analysis, spectroscopic techniques, gravimetric techniques, and inverse gas chromatography can be applied to characterize the amorphous form of a compound (drug or excipient), and to evaluate its thermodynamic stability. This review offers a survey of the technologies used to convert a crystalline solid into an amorphous form, and describes the most important techniques for characterizing the amorphous state of compounds of pharmaceutical interest.

  18. Modeling the economic outcomes of immuno-oncology drugs: alternative model frameworks to capture clinical outcomes.

    Science.gov (United States)

    Gibson, E J; Begum, N; Koblbauer, I; Dranitsaris, G; Liew, D; McEwan, P; Tahami Monfared, A A; Yuan, Y; Juarez-Garcia, A; Tyas, D; Lees, M

    2018-01-01

    Economic models in oncology are commonly based on the three-state partitioned survival model (PSM) distinguishing between progression-free and progressive states. However, the heterogeneity of responses observed in immuno-oncology (I-O) suggests that new approaches may be appropriate to reflect disease dynamics meaningfully. This study explored the impact of incorporating immune-specific health states into economic models of I-O therapy. Two variants of the PSM and a Markov model were populated with data from one clinical trial in metastatic melanoma patients. Short-term modeled outcomes were benchmarked to the clinical trial data and a lifetime model horizon provided estimates of life years and quality adjusted life years (QALYs). The PSM-based models produced short-term outcomes closely matching the trial outcomes. Adding health states generated increased QALYs while providing a more granular representation of outcomes for decision making. The Markov model gave the greatest level of detail on outcomes but gave short-term results which diverged from those of the trial (overstating year 1 progression-free survival by around 60%). Increased sophistication in the representation of disease dynamics in economic models is desirable when attempting to model treatment response in I-O. However, the assumptions underlying different model structures and the availability of data for health state mapping may be important limiting factors.

  19. The entropic brain:A theory of conscious states informed by neuroimaging research with psychedelic drugs

    Directory of Open Access Journals (Sweden)

    Robin Lester Carhart-Harris

    2014-02-01

    Full Text Available Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neural dynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of ‘primary states’ is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. It is noted that elevated entropy in this sense, is a characteristic of systems exhibiting ‘self-organised criticality’, i.e., a property of systems that gravitate towards a ‘critical’ point in a transition zone between order and disorder in which certain phenomena such as power-law scaling appear. This implies that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organised activity within the default-mode network (DMN and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled. These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as REM sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetised state.

  20. Alcohol- and Drug-Involved Driving in the United States: Methodology for the 2007 National Roadside Survey

    Science.gov (United States)

    Lacey, John H.; Kelley-Baker, Tara; Voas, Robert B.; Romano, Eduardo; Furr-Holden, C. Debra; Torres, Pedro; Berning, Amy

    2011-01-01

    This article describes the methodology used in the 2007 U.S. National Roadside Survey to estimate the prevalence of alcohol- and drug-impaired driving and alcohol- and drug-involved driving. This study involved randomly stopping drivers at 300 locations across the 48 continental U.S. states at sites selected through a stratified random sampling…

  1. Testing antidepressant compounds in a neuropsychological model of drug action

    NARCIS (Netherlands)

    Cerit, Hilal

    2015-01-01

    Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental

  2. Pitfalls in TDM of antibiotic drugs : Analytical and modelling issues

    NARCIS (Netherlands)

    Neef, C.; Touw, D. J.; Harteveld, A. R.; Eerland, J. J.; Uges, D. R. A.

    2006-01-01

    The quality assurance program of the Dutch KKGT [Association for Quality Assessment in therapeutic drug monitoring (TDM) and Clinical Toxicology] has been running for more than 25 years. One of these programs concerns TDM of the antibiotic drugs gentamicin, tobramycin, amikacin, and vancomycin. We

  3. hiv prevention among drug and alcohol users: models of ...

    African Journals Online (AJOL)

    Administrator

    The spread of HIV among drug and alcohol users, as a high-risk group, is a significant problem in Africa, as in other ... alcohol and drug addiction in many ... training in providing addiction recovery ..... because of its large scale availability and.

  4. Active State Model for Autonomous Systems

    Science.gov (United States)

    Park, Han; Chien, Steve; Zak, Michail; James, Mark; Mackey, Ryan; Fisher, Forest

    2003-01-01

    The concept of the active state model (ASM) is an architecture for the development of advanced integrated fault-detection-and-isolation (FDI) systems for robotic land vehicles, pilotless aircraft, exploratory spacecraft, or other complex engineering systems that will be capable of autonomous operation. An FDI system based on the ASM concept would not only provide traditional diagnostic capabilities, but also integrate the FDI system under a unified framework and provide mechanism for sharing of information between FDI subsystems to fully assess the overall health of the system. The ASM concept begins with definitions borrowed from psychology, wherein a system is regarded as active when it possesses self-image, self-awareness, and an ability to make decisions itself, such that it is able to perform purposeful motions and other transitions with some degree of autonomy from the environment. For an engineering system, self-image would manifest itself as the ability to determine nominal values of sensor data by use of a mathematical model of itself, and selfawareness would manifest itself as the ability to relate sensor data to their nominal values. The ASM for such a system may start with the closed-loop control dynamics that describe the evolution of state variables. As soon as this model was supplemented with nominal values of sensor data, it would possess self-image. The ability to process the current sensor data and compare them with the nominal values would represent self-awareness. On the basis of self-image and self-awareness, the ASM provides the capability for self-identification, detection of abnormalities, and self-diagnosis.

  5. Model for Microcapsule Drug Release with Ultrasound-Activated Enhancement.

    Science.gov (United States)

    Tsao, Nadia H; Hall, Elizabeth A H

    2017-11-14

    Microbubbles and microcapsules of silane-polycaprolactone (SiPCL) have been filled with a fluorescent acridium salt (lucigenin) as a model for a drug-loaded delivery vehicle. The uptake and delivery were studied and compared with similar microbubbles and microcapsules of silica/mercaptosilica (S/M/S). Positively charged lucigenin was encapsulated through an electrostatic mechanism, following a Type I Langmuir isotherm as expected, but with an additional multilayer uptake that leads to a much higher loading for the SiPCL system (∼280 μg/2.4 × 10 9 microcapsules compared with ∼135 μg/2.4 × 10 9 microcapsules for S/M/S). Whereas the lucigenin release from the S/M/S bubbles and capsules loaded below the solubility limit is consistent with diffusion from a monolithic structure, the SiPCL structures show distinct release patterns; the Weibull function predicts a general trend for diffusion from normal Euclidean space at short times tending toward diffusion out of fractal spaces with increasing time. As a slow release system, the dissolution time (T d ) increases from 1 to 2 days for the S/M/S and for the low concentration, loaded SiPCl vehicles to ∼10 days for the high loaded microcapsules. However, T d can be reduced on insonation to 2 days, indicating the potential to gain control over the local enhanced release with ultrasound. This was tested for a docetaxel model and its effect on C4-2B prostate cancer cells, showing improved cell toxicity for concentrations below the normal EC 50 in solution.

  6. The Trump Hypothesis: Testing Immigrant Populations as a Determinant of Violent and Drug-Related Crime in the United States

    OpenAIRE

    Green, David

    2016-01-01

    Objectives: To test the “Trump Hypothesis”: whether immigrants are responsible for higher levels of violent and drug-related crime in the United States, as asserted by Donald Trump in his 2015 presidential campaign announcement. This is achieved using recent crime and immigration data, thus testing the common public perception linking immigrants to crime, and providing an updated assessment of the immigrant-crime nexus. Methods: Rates of violent crime and drug arrests by state are pooled for ...

  7. Industry Perspective of Pediatric Drug Development in the United States: Involvement of the European Union Countries.

    Science.gov (United States)

    Onishi, Taku; Tsukamoto, Katsura; Matsumaru, Naoki; Waki, Takashi

    2018-01-01

    Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective. Data on US pediatric clinical trials were obtained from ClinicalTrials.gov . Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries. A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries ( P European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs.

  8. Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

    Science.gov (United States)

    Spear, Linda Patia

    2016-01-01

    Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-Methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self-administration have also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects. PMID:27484868

  9. Reliability of a Novel Model for Drug Release from 2D HPMC-Matrices

    Directory of Open Access Journals (Sweden)

    Rumiana Blagoeva

    2010-04-01

    Full Text Available A novel model of drug release from 2D-HPMC matrices is considered. Detailed mathematical description of matrix swelling and the effect of the initial drug loading are introduced. A numerical approach to solution of the posed nonlinear 2D problem is used on the basis of finite element domain approximation and time difference method. The reliability of the model is investigated in two steps: numerical evaluation of the water uptake parameters; evaluation of drug release parameters under available experimental data. The proposed numerical procedure for fitting the model is validated performing different numerical examples of drug release in two cases (with and without taking into account initial drug loading. The goodness of fit evaluated by the coefficient of determination is presented to be very good with few exceptions. The obtained results show better model fitting when accounting the effect of initial drug loading (especially for larger values.

  10. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability.

    Science.gov (United States)

    Solanki, Nayan G; Tahsin, Md; Shah, Ankita V; Serajuddin, Abu T M

    2018-01-01

    The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon ® VA64, Kollicoat ® IR, Affinsiol ™ 15 cP, and HPMCAS either individually or as binary blends (Kollidon ® VA64 + Affinisol ™ 15 cP, 1:1; Kollidon ® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon ® VA64-Affinisol ™ 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon ® VA64 and Affinisol ™ 15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Systematic synergy modeling: understanding drug synergy from a systems biology perspective.

    Science.gov (United States)

    Chen, Di; Liu, Xi; Yang, Yiping; Yang, Hongjun; Lu, Peng

    2015-09-16

    Owing to drug synergy effects, drug combinations have become a new trend in combating complex diseases like cancer, HIV and cardiovascular diseases. However, conventional synergy quantification methods often depend on experimental dose-response data which are quite resource-demanding. In addition, these methods are unable to interpret the explicit synergy mechanism. In this review, we give representative examples of how systems biology modeling offers strategies toward better understanding of drug synergy, including the protein-protein interaction (PPI) network-based methods, pathway dynamic simulations, synergy network motif recognitions, integrative drug feature calculations, and "omic"-supported analyses. Although partially successful in drug synergy exploration and interpretation, more efforts should be put on a holistic understanding of drug-disease interactions, considering integrative pharmacology and toxicology factors. With a comprehensive and deep insight into the mechanism of drug synergy, systems biology opens a novel avenue for rational design of effective drug combinations.

  12. Solid lipid particles for oral delivery of peptide and protein drugs III - the effect of fed state conditions on the in vitro release and degradation of desmopressin

    DEFF Research Database (Denmark)

    Christophersen, Philip C; Vaghela, Dimple; Müllertz, Anette

    2014-01-01

    The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles...... and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows...... that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract....

  13. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

    Science.gov (United States)

    El Rawas, Rana; Saria, Alois

    2016-03-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

  14. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    Science.gov (United States)

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  15. Effect of particle size of drug on conversion of crystals to an amorphous state in a solid dispersion with crospovidone.

    Science.gov (United States)

    Sugamura, Yuka; Fujii, Makiko; Nakanishi, Sayaka; Suzuki, Ayako; Shibata, Yusuke; Koizumi, Naoya; Watanabe, Yoshiteru

    2011-01-01

    The effect of particle size on amorphization of drugs in a solid dispersion (SD) was investigated for two drugs, indomethacin (IM) and nifedipine (NP). The SD of drugs were prepared in a mixture with crospovidone by a variety of mechanical methods, and their properties investigated by particle sizing, thermal analysis, and powder X-ray diffraction. IM, which had an initial particle size of 1 µm and tends to aggregate, was forced through a sieve to break up the particles. NP, which had a large initial particle size, was jet-milled. In both cases, reduction of the particle size of the drugs enabled transition to an amorphous state below the melting point of the drug. The reduction in particle size is considered to enable increased contact between the crospovidone and drug particles, increasing interactions between the two compounds. © 2011 Pharmaceutical Society of Japan

  16. Retrospective use of PBPK modelling to understand a clinical drug-drug interaction between dextromethorphan and GSK1034702.

    Science.gov (United States)

    Hobbs, Michael J; Bloomer, Jackie; Dear, Gordon

    2017-08-01

    1. In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702. 3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC 50  =   1.6 μM, K inact  = 3.7 h -1 and K I  = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702. 4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.

  17. Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings.

    Science.gov (United States)

    Barker, David J; Simmons, Steven J; West, Mark O

    2015-01-01

    The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals' initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures.

  18. Computing characterizations of drugs for ion channels and receptors using Markov models

    CERN Document Server

    Tveito, Aslak

    2016-01-01

    Flow of ions through voltage gated channels can be represented theoretically using stochastic differential equations where the gating mechanism is represented by a Markov model. The flow through a channel can be manipulated using various drugs, and the effect of a given drug can be reflected by changing the Markov model. These lecture notes provide an accessible introduction to the mathematical methods needed to deal with these models. They emphasize the use of numerical methods and provide sufficient details for the reader to implement the models and thereby study the effect of various drugs. Examples in the text include stochastic calcium release from internal storage systems in cells, as well as stochastic models of the transmembrane potential. Well known Markov models are studied and a systematic approach to including the effect of mutations is presented. Lastly, the book shows how to derive the optimal properties of a theoretical model of a drug for a given mutation defined in terms of a Markov model.

  19. Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.

    Science.gov (United States)

    Neuhaus, W; Mandikova, J; Pawlowitsch, R; Linz, B; Bennani-Baiti, B; Lauer, R; Lachmann, B; Noe, C R

    2012-05-01

    In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of

  20. Determination of the main solid-state form of albendazole in bulk drug, employing Raman spectroscopy coupled to multivariate analysis.

    Science.gov (United States)

    Calvo, Natalia L; Arias, Juan M; Altabef, Aída Ben; Maggio, Rubén M; Kaufman, Teodoro S

    2016-09-10

    Albendazole (ALB) is a broad-spectrum anthelmintic, which exhibits two solid-state forms (Forms I and II). The Form I is the metastable crystal at room temperature, while Form II is the stable one. Because the drug has poor aqueous solubility and Form II is less soluble than Form I, it is desirable to have a method to assess the solid-state form of the drug employed for manufacturing purposes. Therefore, a Partial Least Squares (PLS) model was developed for the determination of Form I of ALB in its mixtures with Form II. For model development, both solid-state forms of ALB were prepared and characterized by microscopic (optical and with normal and polarized light), thermal (DSC) and spectroscopic (ATR-FTIR, Raman) techniques. Mixtures of solids in different ratios were prepared by weighing and mechanical mixing of the components. Their Raman spectra were acquired, and subjected to peak smoothing, normalization, standard normal variate correction and de-trending, before performing the PLS calculations. The optimal spectral region (1396-1280cm(-1)) and number of latent variables (LV=3) were obtained employing a moving window of variable size strategy. The method was internally validated by means of the leave one out procedure, providing satisfactory statistics (r(2)=0.9729 and RMSD=5.6%) and figures of merit (LOD=9.4% and MDDC=1.4). Furthermore, the method's performance was also evaluated by analysis of two validation sets. Validation set I was used for assessment of linearity and range and Validation set II, to demonstrate accuracy and precision (Recovery=101.4% and RSD=2.8%). Additionally, a third set of spiked commercial samples was evaluated, exhibiting excellent recoveries (94.2±6.4%). The results suggest that the combination of Raman spectroscopy with multivariate analysis could be applied to the assessment of the main crystal form and its quantitation in samples of ALB bulk drug, in the routine quality control laboratory. Copyright © 2016 Elsevier B.V. All

  1. A potential model for drug screening by simulating the effect of shear stress in vivo on endothelium.

    Science.gov (United States)

    Xu, Yingqian; Wang, Bochu; Deng, Jia; Liu, Zerong; Zhu, Liancai

    2013-01-01

    The purpose of this paper was to research the potential of a dynamic cell model in drug screening by studying the influence of microvascular wall shear stress on the drug absorption of endothelial cells compared to that in the static state. The cells were grown and seeded on gelatin-coated glass slides and were pretreated with extracts of Salviae miltiorrhizae (200 μg/ml) for 1 h. Then oxidative stress damage was produced by H2O2 (300 μmol/l) for 0.5 h under the 1.5 dyn/cm2 shear stress incorporated in a parallel plate flow chamber. Morphological analysis was conducted with an inverted microscope and image analysis software, and high performance liquid chromatography-mass spectrometry was used for the detection of active compounds. We compared the drug absorption in the dynamic group with that in the static group. In the dynamic model, five compounds and two new metabolite peaks were detected. However, in the static model, four compounds were absorbed by cells, and one metabolite peak was found. This study indicated that there were some effects on the absorption and metabolism of drugs under the microvascular shear stress compared to that under stasis. We infer that shear stress in the microcirculation situation in vivo played a role in causing the differences between drug screening in vitro and in vivo.

  2. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

    2015-03-01

    Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.

  3. A reaction limited in vivo dissolution model for the study of drug absorption: Towards a new paradigm for the biopharmaceutic classification of drugs.

    Science.gov (United States)

    Macheras, Panos; Iliadis, Athanassios; Melagraki, Georgia

    2018-05-30

    The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug-reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism. Copyright © 2018. Published by Elsevier B.V.

  4. Sex differences and ovarian hormones in animal models of drug dependence.

    Science.gov (United States)

    Carroll, Marilyn E; Anker, Justin J

    2010-06-01

    Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies. Copyright 2009. Published by Elsevier Inc.

  5. In vitro and in vivo models for testing arrhythmogenesis in drugs.

    Science.gov (United States)

    Carlsson, L

    2006-01-01

    The steadily increasing list of drugs associated with prolongation of the QT interval and torsades de pointes (TdP) constitute a medical problem of major concern. Hence, there is a need at an early stage to identify drug candidates with an inherent capacity to induce repolarization-related proarrhythmias, avoiding exposure of large populations to potentially harmful drugs. Furthermore, the availability of clinically relevant and predictive animal models should reduce the risk that effective and potentially life-saving drugs never reach the market. This review will discuss the pros and cons of some in vivo and in vitro animal models for assessing proarrhythmia liability.

  6. Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

    Science.gov (United States)

    Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

    2018-08-14

    The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. State-to-state models of vibrational relaxation in Direct Simulation Monte Carlo (DSMC)

    Science.gov (United States)

    Oblapenko, G. P.; Kashkovsky, A. V.; Bondar, Ye A.

    2017-02-01

    In the present work, the application of state-to-state models of vibrational energy exchanges to the Direct Simulation Monte Carlo (DSMC) is considered. A state-to-state model for VT transitions of vibrational energy in nitrogen and oxygen, based on the application of the inverse Laplace transform to results of quasiclassical trajectory calculations (QCT) of vibrational energy transitions, along with the Forced Harmonic Oscillator (FHO) state-to-state model is implemented in DSMC code and applied to flows around blunt bodies. Comparisons are made with the widely used Larsen-Borgnakke model and the in uence of multi-quantum VT transitions is assessed.

  8. UAV State Estimation Modeling Techniques in AHRS

    Science.gov (United States)

    Razali, Shikin; Zhahir, Amzari

    2017-11-01

    Autonomous unmanned aerial vehicle (UAV) system is depending on state estimation feedback to control flight operation. Estimation on the correct state improves navigation accuracy and achieves flight mission safely. One of the sensors configuration used in UAV state is Attitude Heading and Reference System (AHRS) with application of Extended Kalman Filter (EKF) or feedback controller. The results of these two different techniques in estimating UAV states in AHRS configuration are displayed through position and attitude graphs.

  9. Factors associated with history of drug use among female sex workers (FSW in a high HIV prevalence state of India

    Directory of Open Access Journals (Sweden)

    Medhi Gajendra

    2012-04-01

    Full Text Available Abstract Background The intersection between illicit drug use and female commercial sex work has been identified as an important factor responsible for rising HIV prevalence among female sex workers (FSW in several northeastern states of India. But, little is know about the factors associated with the use of drugs among FSWs in this region. The objective of the paper was to describe the factors associated with history of drug use among FSWs in Dimapur, an important commercial hub of Nagaland, which is a high HIV prevalence state of India. Methods FSWs were recruited using respondent driven sampling (RDS, and were interviewed to collect data on socio-demographic characteristics and HIV risk behaviours. Biological samples were tested for HIV, syphilis gonorrhea and Chlamydia. Logistic regression analysis was performed to identify factors associated with drug use. Results Among the 426 FSWs in the study, about 25% (n = 107 reported having ever used illicit drugs. Among 107 illicit drug users, 83 (77.6% were non-injecting and 24 (22.4% were injecting drug users. Drug-using FSWs were significantly more likely to test positive for one or more STIs (59% vs. 33.5%, active syphilis (27.1% vs. 11.4% and Chlamydia infection (30% vs. 19.9% compared to their non-drug using peers. Drug-using FSWs were also significantly more likely to be currently married, widowed or separated compared with non-drug-using FSWs. In multiple logistic regression analysis, being an alcohol user, being married, having a larger volume of clients, and having sexual partners who have ever used or shared injecting drugs were found to be independently associated with illicit drug use. Conclusions Drug-using FSWs were more vulnerable to STIs including HIV compared to their non-drug using peers. Several important factors associated with being an FSW who uses drugs were identified in this study and this knowledge can be used to plan more effectively targeted harm reduction strategies

  10. Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

    Science.gov (United States)

    Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

    2018-01-01

    Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

  11. Decreased resting-state interhemispheric coordination in first-episode, drug-naive paranoid schizophrenia.

    Science.gov (United States)

    Guo, Wenbin; Xiao, Changqing; Liu, Guiying; Wooderson, Sarah C; Zhang, Zhikun; Zhang, Jian; Yu, Liuyu; Liu, Jianrong

    2014-01-03

    Dysconnectivity hypothesis posits that schizophrenia relates to abnormalities in neuronal connectivity. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (FC) in patients with paranoid schizophrenia. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric FC of the whole brain in patients with paranoid schizophrenia at rest. Forty-nine first-episode, drug-naive patients with paranoid schizophrenia and 50 age-, gender-, and education-matched healthy subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scans. An automated VMHC approach was used to analyze the data. Patients exhibited lower VMHC than healthy subjects in the precuneus (PCu), the precentral gyrus, the superior temporal gyrus (STG), the middle occipital gyrus (MOG), and the fusiform gyrus/cerebellum lobule VI. No region showed greater VMHC in the patient group than in the control group. Significantly negative correlation was observed between VMHC in the precentral gyrus and the PANSS positive/total scores, and between VMHC in the STG and the PANSS positive/negative/total scores. Our results suggest that interhemispheric resting-state FC of VMHC is reduced in paranoid schizophrenia with clinical implications for psychiatric symptomatology thus further contribute to the dysconnectivity hypothesis of schizophrenia. © 2013.

  12. Demystifying "oxi" cocaine: Chemical profiling analysis of a "new Brazilian drug" from Acre State.

    Science.gov (United States)

    da Silva Junior, Ronaldo C; Gomes, Cezar S; Goulart Júnior, Saulo S; Almeida, Fernanda V; Grobério, Tatiane S; Braga, Jez W B; Zacca, Jorge J; Vieira, Maurício L; Botelho, Elvio D; Maldaner, Adriano O

    2012-09-10

    Recent information from various sources suggests that a new illicit drug, called "oxi", is being spread across Brazil. It would be used in the smoked form and it would look like to crack cocaine: usually small yellowish or light brown stones. As fully released in the media, "oxi" would differ from crack cocaine in the sense that crack would contain carbonate or bicarbonate salts whereas "oxi" would include the addition of calcium oxide and kerosene (or gasoline). In this context, this work presents a chemical profiling comparative study between "oxi" street samples seized by the Civil Police of the State of Acre (CP/AC) and samples associated with both international and interstate drug trafficking seized by the Brazilian Federal Police in Acre (FP/AC). The outcome of this work assisted Brazilian authorities to stop inaccurate and alarmist releases on this issue. It may be of good use by the forensic community in order to better understand matters in their efforts to guide local law enforcement agencies in case such claims reach the international illicit market. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. Text mining for adverse drug events: the promise, challenges, and state of the art.

    Science.gov (United States)

    Harpaz, Rave; Callahan, Alison; Tamang, Suzanne; Low, Yen; Odgers, David; Finlayson, Sam; Jung, Kenneth; LePendu, Paea; Shah, Nigam H

    2014-10-01

    Text mining is the computational process of extracting meaningful information from large amounts of unstructured text. It is emerging as a tool to leverage underutilized data sources that can improve pharmacovigilance, including the objective of adverse drug event (ADE) detection and assessment. This article provides an overview of recent advances in pharmacovigilance driven by the application of text mining, and discusses several data sources-such as biomedical literature, clinical narratives, product labeling, social media, and Web search logs-that are amenable to text mining for pharmacovigilance. Given the state of the art, it appears text mining can be applied to extract useful ADE-related information from multiple textual sources. Nonetheless, further research is required to address remaining technical challenges associated with the text mining methodologies, and to conclusively determine the relative contribution of each textual source to improving pharmacovigilance.

  14. HIV prevention among drug and alcohol users: models of ...

    African Journals Online (AJOL)

    The spread of HIV among drug and alcohol users, as a high-risk group, is a significant problem in Africa, as in other parts of the world. Few programs have been implemented in Africa to deal specifically with this issue. Since November 2006, the AED Capable Partners Program in Kenya project has provided technical ...

  15. Dynamics of synthetic drugs transmission model with psychological addicts and general incidence rate

    Science.gov (United States)

    Ma, Mingju; Liu, Sanyang; Xiang, Hong; Li, Jun

    2018-02-01

    Synthetic drugs are replacing traditional ones and becoming the main popular ones gradually, which have given rise to serious social issues in recent years. In this paper, a synthetic drugs transmission model with psychological addicts and general contact rate is proposed. The local and global stabilities are decided by the basic reproduction number R0. By analyzing the sensitivity of parameters, we obtain that controlling psychological addiction is better than drugs treatment. These results are verified by numerical simulations.

  16. Drug and Vaccine evaluation in the Human Aotus Plasmodium falciparum Model

    Science.gov (United States)

    2011-05-01

    and phenyl ring systems is anticipated to yield a valuable new antimalarial drug (33). The antimalarial activity and pharmacology of a series of...remains essentially unchanged since 1976, viz. to ascertain the antimalarial activity of drugs against P. falciparum and P. vivax in Aotus. The...Present data on the evaluation of potential antimalarial activity of drugs in the pre-clinical model of Aotus l. lemurinus (Panamanian night

  17. Mechanistic modeling of ophthalmic drug delivery to the anterior chamber by eye drops and contact lenses.

    Science.gov (United States)

    Gause, Samuel; Hsu, Kuan-Hui; Shafor, Chancellor; Dixon, Phillip; Powell, Kristin Conrad; Chauhan, Anuj

    2016-07-01

    Ophthalmic drug for the anterior chamber diseases are delivered into tears by either eye drops or by extended release devices placed in the eyes. The instilled drug exits the eye through various routes including tear drainage into the nose through the canaliculi and transport across various ocular membranes. Understanding the mechanisms relevant to each route can be useful in predicting the dependency of ocular bioavailability on various formulation parameters, such as drug concentration, salinity, viscosity, etc. Mathematical modeling has been developed for each of the routes and validated by comparison with experiments. The individual models can be combined into a system model to predict the fraction of the instilled drug that reaches the target. This review summarizes the individual models for the transport of drugs across the cornea and conjunctiva and the canaliculi tear drainage. It also summarizes the combined tear dynamics model that can predict the ocular bioavailability of drugs instilled as eye drops. The predictions from the individual models and the combined model are in good agreement with experimental data. Both experiments and models predict that the corneal bioavailability for drugs delivered through eye drops is less than 5% due to the small area of the cornea in comparison to the conjunctiva, and the rapid clearance of the instilled solution by tear drainage. A contact lens is a natural choice for delivering drugs to the cornea due to the placement of the contact in the immediate vicinity of the cornea. The drug released by the contact towards the cornea surface is trapped in the post lens tear film for extended duration of at least 30min allowing transport of a large portion into the cornea. The model predictions backed by in vivo animal and clinical data show that the bioavailability increases to about 50% with contact lenses. This realization has encouraged considerable research towards delivering ocular drugs by contact lenses. Commercial

  18. Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach.

    Science.gov (United States)

    Qi, Sheng; McAuley, William J; Yang, Ziyi; Tipduangta, Pratchaya

    2014-07-01

    Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs.

  19. THE MODELING OF DRUG ADDICTION PREVALENCE AND ITS CONSEQUENCES IN RUSSIAN REGIONS

    Directory of Open Access Journals (Sweden)

    V.P. Sirotin

    2009-12-01

    Full Text Available The narcotization prevalence in Russia as whole and its regions is described. In order to provide the adequate models the clusters of regions on the level of their economic development are defined. For every group the regression model of drug addiction social distress is constructed. Modeling results allow to find the features of regions and the most significant factors determining the drug addiction prevalence.

  20. Mathematical model of transmission network static state estimation

    Directory of Open Access Journals (Sweden)

    Ivanov Aleksandar

    2012-01-01

    Full Text Available In this paper the characteristics and capabilities of the power transmission network static state estimator are presented. The solving process of the mathematical model containing the measurement errors and their processing is developed. To evaluate difference between the general model of state estimation and the fast decoupled state estimation model, the both models are applied to an example, and so derived results are compared.

  1. Ground states of a spin-boson model

    International Nuclear Information System (INIS)

    Amann, A.

    1991-01-01

    Phase transition with respect to ground states of a spin-boson Hamiltonian are investigated. The spin-boson model under discussion consists of one spin and infinitely many bosons with a dipole-type coupling. It is shown that the order parameter of the model vanishes with respect to arbitrary ground states if it vanishes with respect to ground states obtained as (biased) temperature to zero limits of thermic equilibrium states. The ground states of the latter special type have been investigated by H. Spohn. Spohn's respective phase diagrams are therefore valid for arbitrary ground states. Furthermore, disjointness of ground states in the broken symmetry regime is examined

  2. Mathematical model to analyze the dissolution behavior of metastable crystals or amorphous drug accompanied with a solid-liquid interface reaction.

    Science.gov (United States)

    Hirai, Daiki; Iwao, Yasunori; Kimura, Shin-Ichiro; Noguchi, Shuji; Itai, Shigeru

    2017-04-30

    Metastable crystals and the amorphous state of poorly water-soluble drugs in solid dispersions (SDs), are subject to a solid-liquid interface reaction upon exposure to a solvent. The dissolution behavior during the solid-liquid interface reaction often shows that the concentration of drugs is supersaturated, with a high initial drug concentration compared with the solubility of stable crystals but finally approaching the latter solubility with time. However, a method for measuring the precipitation rate of stable crystals and/or the potential solubility of metastable crystals or amorphous drugs has not been established. In this study, a novel mathematical model that can represent the dissolution behavior of the solid-liquid interface reaction for metastable crystals or amorphous drug was developed and its validity was evaluated. The theory for this model was based on the Noyes-Whitney equation and assumes that the precipitation of stable crystals at the solid-liquid interface occurs through a first-order reaction. Moreover, two models were developed, one assuming that the surface area of the drug remains constant because of the presence of excess drug in the bulk and the other that the surface area changes in time-dependency because of agglomeration of the drug. SDs of Ibuprofen (IB)/polyvinylpyrrolidone (PVP) were prepared and their dissolution behaviors under non-sink conditions were fitted by the models to evaluate improvements in solubility. The model assuming time-dependent surface area showed good agreement with experimental values. Furthermore, by applying the model to the dissolution profile, parameters such as the precipitation rate and the potential solubility of the amorphous drug were successfully calculated. In addition, it was shown that the improvement in solubility with supersaturation was able to be evaluated quantitatively using this model. Therefore, this mathematical model would be a useful tool to quantitatively determine the supersaturation

  3. Host-guest chemistry of dendrimer-drug complexes. 6. Fully acetylated dendrimers as biocompatible drug vehicles using dexamethasone 21-phosphate as a model drug.

    Science.gov (United States)

    Yang, Kun; Weng, Liang; Cheng, Yiyun; Zhang, Hongfeng; Zhang, Jiahai; Wu, Qinglin; Xu, Tongwen

    2011-03-17

    Fully acetylated poly(amidoamine) (PAMAM) dendrimer was proposed as a biocompatible drug vehicle using dexamethasone 21-phosphate (Dp21) as a model drug. NMR techniques including (1)H NMR and 2D NOE NMR were used to characterize the host-guest chemistry of acetylated dendrimer/Dp21 and cationic dendrimer/Dp21 complexes. The pH-dependent micellization, complexation, and inclusion behaviors of Dp21 were observed in the presence of acetylated and cationic PAMAM dendrimers. Acetylated dendrimer only encapsulates Dp21 at acidic conditions, while cationic dendrimer can host Dp21 at both acidic and neutral conditions. The orientation of Dp21 molecules in the dendrimer cavities depends on the quaternization degree of tertiary amine groups of dendrimer and the protonation ratio of phosphate group of Dp21. A distinctive pH-dependent release behavior of Dp21 from the acetylated and nonacetylated dendritic matrix was observed: Dp21 exhibits a much slower release rate from acetylated dendrimer at lower pH conditions and a much faster release rate from nonacetylated dendrimer with decreasing pH values. Cytotoxicity studies further confirmed the biocompatibility of acetylated dendrimers, which are much safer in the delivery of therapeutics for the treatment of various diseases than nonacetylated dendrimers. The dendrimer-drug binding and release mechanisms provide a new insight for the design and optimization of biocompatible dendrimer-based drug delivery systems. © 2011 American Chemical Society

  4. The paradigm shift to an “open” model in drug development

    Directory of Open Access Journals (Sweden)

    Regina Au

    2014-12-01

    Full Text Available The rising cost of healthcare, the rising cost for drug development, the patent cliff for Big pharma, shorter patent protection, decrease reimbursement, and the recession have made it more difficult for the pharmaceutical and biotechnology industry to develop drugs. Due to the unsustainable amount of time and money in developing a drug that will have a significant return on investment (ROI it has become hard to sustain a robust pipeline. The industry is transforming its business model to meet these challenges. In essence a paradigm shift is occurring; the old “closed” model is giving way to a new “open” business model.

  5. A typology of drug selling among young adults in the United States.

    Science.gov (United States)

    Vaughn, Michael G; Salas-Wright, Christopher P; DeLisi, Matt; Shook, Jeffrey J; Terzis, Lauren

    2015-02-01

    Although studies have found that young adults who sell drugs are more likely to be involved in risky behaviors than those who do not sell drugs, there has been relatively little research that has explored heterogeneity among young adults who sell drugs. Using a pooled sample of 18 to 25 year olds from the National Survey on Drug Use and Health (2006-2010) who report past-year drug selling (N = 5,373), this study employs latent profile analysis to specify latent groups and assess the correlates of group membership. Findings indicate substantial differences among young adults who sell drugs. In particular, the analysis found four groups of drug sellers: normative (49.6%), club drug users (23.6%), polysubstance users (16.0%), and criminal offenders (10.8%). Club drug users were characterized by high levels of ecstasy and hallucinogen use, polysubstance users were more likely to be depressed and anxious, White and female than the other groups. Criminal offenders were overwhelmingly male and more likely to be comprised of African-Americans and Hispanics. RESULTS indicate that drug selling in early adulthood varies substantially. Contrary to media and popular notions most drug sellers are not involved in crime and polysubstance using drug sellers are in clear need of mental health services. Further, most drug sellers in this age range are White. Findings suggest that policy efforts that operate under the assumption of homogeneity of drug selling may be misguided.

  6. A stochastic multicriteria model for evidence-based decision making in drug benefit-risk analysis

    NARCIS (Netherlands)

    Tervonen, Tommi; van Valkenhoef, Gert; Buskens, Erik; Hillege, Hans L.; Postmus, Douwe

    2011-01-01

    Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multicriteria model that fully takes into account the evidence on efficacy and adverse drug

  7. Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders.

    Science.gov (United States)

    Qi, Z; Kikuchi, S; Tretter, F; Voit, E O

    2011-05-01

    Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD. © Georg Thieme Verlag KG Stuttgart · New

  8. Macroscopic modelling of solid-state fermentation

    NARCIS (Netherlands)

    Hoogschagen, M.J.

    2007-01-01

    Solid-state fermentation is different from the more well known process of liquid fermentation because no free flowing water is present. The technique is primarily used in Asia. Well-known products are the foods tempe, soy sauce and saké. In industrial solid-state fermentation, the substrate usually

  9. A drug cost model for injuries due to road traffic accidents.

    Directory of Open Access Journals (Sweden)

    Riewpaiboon A

    2008-03-01

    Full Text Available Objective: This study aimed to develop a drug cost model for injuries due to road traffic accidents for patients receiving treatment at a regional hospital in Thailand. Methods: The study was designed as a retrospective, descriptive analysis. The cases were all from road traffic accidents receiving treatment at a public regional hospital in the fiscal year 2004. Results: Three thousand seven hundred and twenty-three road accident patients were included in the study. The mean drug cost per case was USD18.20 (SD=73.49, median=2.36. The fitted drug cost model had an adjusted R2 of 0.449. The positive significant predictor variables of drug costs were prolonged length of stay, age over 30 years old, male, Universal Health Coverage Scheme, time of accident during 18:00-24:00 o’clock, and motorcycle comparing to bus. To forecast the drug budget for 2006, there were two approaches identified, the mean drug cost and the predicted average drug cost. The predicted average drug cost was calculated based on the forecasted values of statistically significant (p<0.05 predictor variables included in the fitted model; predicted total drug cost was USD44,334. Alternatively, based on the mean cost, predicted total drug cost in 2006 was USD63,408. This was 43% higher than the figure based on the predicted cost approach.Conclusions: The planned budget of drug cost based on the mean cost and predicted average cost were meaningfully different. The application of a predicted average cost model could result in a more accurate budget planning than that of a mean statistic approach.

  10. A comparative legal analysis of social media advertising of drugs in Germany and the United States.

    Science.gov (United States)

    Buechner, Bianca

    2013-01-01

    Pharmaceutical companies use social media such as Facebook and Twitter more and more to advertise their products. Advertising of medicinal products especially in social media is a critical issue confronting patient protection, competition law and ethical concerns in direct-to-consumer advertising. Advertising in the World Wide Web must take into account national and international regulations, depending on which user from which country will have access to the information posted. Different legal requirements, if any, regulate the advertising of medicinal products. This paper discusses, challenges and compares the requirements and regulations of advertising medicinal products in social media, such as Facebook, in the United States on a federal level and the European Union with Germany as a reference Member State. Social media are very active and fast moving. Therefore, it is challenging and necessary at the same time to set guidelines and regulations for the use of social media in drug advertising. This paper is a first step toward promoting an international, consistent approach when talking about regulating advertising of medicinal products in social media.

  11. Modeling Patient-Specific Magnetic Drug Targeting Within the Intracranial Vasculature

    Directory of Open Access Journals (Sweden)

    Alexander Patronis

    2018-04-01

    Full Text Available Drug targeting promises to substantially enhance future therapies, for example through the focussing of chemotherapeutic drugs at the site of a tumor, thus reducing the exposure of healthy tissue to unwanted damage. Promising work on the steering of medication in the human body employs magnetic fields acting on nanoparticles made of paramagnetic materials. We develop a computational tool to aid in the optimization of the physical parameters of these particles and the magnetic configuration, estimating the fraction of particles reaching a given target site in a large patient-specific vascular system for different physiological states (heart rate, cardiac output, etc.. We demonstrate the excellent computational performance of our model by its application to the simulation of paramagnetic-nanoparticle-laden flows in a circle of Willis geometry obtained from an MRI scan. The results suggest a strong dependence of the particle density at the target site on the strength of the magnetic forcing and the velocity of the background fluid flow.

  12. Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening.

    Science.gov (United States)

    Smith, Alec S T; Macadangdang, Jesse; Leung, Winnie; Laflamme, Michael A; Kim, Deok-Ho

    Improved methodologies for modeling cardiac disease phenotypes and accurately screening the efficacy and toxicity of potential therapeutic compounds are actively being sought to advance drug development and improve disease modeling capabilities. To that end, much recent effort has been devoted to the development of novel engineered biomimetic cardiac tissue platforms that accurately recapitulate the structure and function of the human myocardium. Within the field of cardiac engineering, induced pluripotent stem cells (iPSCs) are an exciting tool that offer the potential to advance the current state of the art, as they are derived from somatic cells, enabling the development of personalized medical strategies and patient specific disease models. Here we review different aspects of iPSC-based cardiac engineering technologies. We highlight methods for producing iPSC-derived cardiomyocytes (iPSC-CMs) and discuss their application to compound efficacy/toxicity screening and in vitro modeling of prevalent cardiac diseases. Special attention is paid to the application of micro- and nano-engineering techniques for the development of novel iPSC-CM based platforms and their potential to advance current preclinical screening modalities. Published by Elsevier Inc.

  13. Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity.

    Science.gov (United States)

    Moeller, Scott J; London, Edythe D; Northoff, Georg

    2016-02-01

    Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Modeling the Release Kinetics of Poorly Water-Soluble Drug Molecules from Liposomal Nanocarriers

    Directory of Open Access Journals (Sweden)

    Stephan Loew

    2011-01-01

    Full Text Available Liposomes are frequently used as pharmaceutical nanocarriers to deliver poorly water-soluble drugs such as temoporfin, cyclosporine A, amphotericin B, and paclitaxel to their target site. Optimal drug delivery depends on understanding the release kinetics of the drug molecules from the host liposomes during the journey to the target site and at the target site. Transfer of drugs in model systems consisting of donor liposomes and acceptor liposomes is known from experimental work to typically exhibit a first-order kinetics with a simple exponential behavior. In some cases, a fast component in the initial transfer is present, in other cases the transfer is sigmoidal. We present and analyze a theoretical model for the transfer that accounts for two physical mechanisms, collisions between liposomes and diffusion of the drug molecules through the aqueous phase. Starting with the detailed distribution of drug molecules among the individual liposomes, we specify the conditions that lead to an apparent first-order kinetic behavior. We also discuss possible implications on the transfer kinetics of (1 high drug loading of donor liposomes, (2 attractive interactions between drug molecules within the liposomes, and (3 slow transfer of drugs between the inner and outer leaflets of the liposomes.

  15. The effect of federal and state off-label marketing investigations on drug prescribing: The case of olanzapine.

    Science.gov (United States)

    Wang, Bo; Studdert, David M; Sarpatwari, Ameet; Franklin, Jessica M; Landon, Joan; Kesselheim, Aaron S

    2017-01-01

    In the past decade, the federal government has frequently investigated and prosecuted pharmaceutical manufacturers for illegal promotion of drugs for indications not approved by the Food and Drug Administration (FDA) ("off-label" uses). State governments can choose to coordinate with the federal investigation, or pursue their own independent state investigations. One of the largest-ever off-label prosecutions relates to the atypical antipsychotic drug olanzapine (Zyprexa). In a series of settlements between 2008 and 2010, Eli Lilly paid $1.4 billion to the federal government and over $290 million to state governments. We examined the effect of these settlements on off-label prescribing of this medication, taking advantage of geographical differences in states' involvement in the investigations and the timing of the settlements. However, we did not find a reduction in off-label prescribing; rather, there were no prescribing changes among states that joined the federal investigation, those that pursued independent state investigations, and states that pursued no investigations at all. Since the settlements of state investigations of off-label prescribing do not appear to significantly impact prescribing rates, policymakers should consider alternate ways of reducing the prevalence of non-evidence-based off-label use to complement their ongoing investigations.

  16. Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models.

    Science.gov (United States)

    Setlow, Barry; Mendez, Ian A; Mitchell, Marci R; Simon, Nicholas W

    2009-09-01

    Drug-addicted individuals show high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human drug users. This article reviews this literature, with a particular focus on the effects of chronic cocaine administration, which have been most thoroughly characterized. The potential mechanisms of these effects are described in terms of drug-induced neural alterations in ventral striatal and prefrontal cortical brain systems. Some implications of this research for pharmacological treatment of drug-induced increases in impulsive choice are discussed, along with suggestions for future research in this area.

  17. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

    Directory of Open Access Journals (Sweden)

    Lucianna Helene Santos

    2015-11-01

    Full Text Available Reverse transcriptase (RT is a multifunctional enzyme in the human immunodeficiency virus (HIV-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

  18. Modeling attitude towards drug treament: the role of internal motivation, external pressure, and dramatic relief.

    Science.gov (United States)

    Conner, Bradley T; Longshore, Douglas; Anglin, M Douglas

    2009-04-01

    Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) entering drug treatment indicated that internal motivation and external pressure significantly and positively predicted dramatic relief and that dramatic relief significantly predicted attitudes towards drug treatment: chi (2) = 142.20, df = 100, p relief is also likely to be high. When dramatic relief is high, attitudes towards drug treatment are likely to be positive. The findings indicate that interventions to get individuals into drug treatment should include processes that promote Dramatic Relief. Implications for addictions health services are discussed.

  19. Evaluation and modeling of the eutectic composition of various drug-polyethylene glycol solid dispersions.

    Science.gov (United States)

    Baird, Jared A; Taylor, Lynne S

    2011-06-01

    The purpose of this study was to gain a better understanding of which factors contribute to the eutectic composition of drug-polyethylene glycol (PEG) blends and to compare experimental values with predictions from the semi-empirical model developed by Lacoulonche et al. Eutectic compositions of various drug-PEG 3350 solid dispersions were predicted, assuming athermal mixing, and compared to experimentally determined eutectic points. The presence or absence of specific interactions between the drug and PEG 3350 were investigated using Fourier transform infrared (FT-IR) spectroscopy. The eutectic composition for haloperidol-PEG and loratadine-PEG solid dispersions was accurately predicted using the model, while predictions for aceclofenac-PEG and chlorpropamide-PEG were very different from those experimentally observed. Deviations in the model prediction from ideal behavior for the systems evaluated were confirmed to be due to the presence of specific interactions between the drug and polymer, as demonstrated by IR spectroscopy. Detailed analysis showed that the eutectic composition prediction from the model is interdependent on the crystal lattice energy of the drug compound (evaluated from the melting temperature and the heat of fusion) as well as the nature of the drug-polymer interactions. In conclusion, for compounds with melting points less than 200°C, the model is ideally suited for predicting the eutectic composition of systems where there is an absence of drug-polymer interactions.

  20. Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers.

    Science.gov (United States)

    Kadakia, Ekta; Shah, Lipa; Amiji, Mansoor M

    2017-07-01

    Nanoemulsions have shown potential in delivering drug across epithelial and endothelial cell barriers, which express efflux transporters. However, their transport mechanisms are not entirely understood. Our goal was to investigate the cellular permeability of nanoemulsion-encapsulated drugs and apply mathematical modeling to elucidate transport mechanisms and sensitive nanoemulsion attributes. Transport studies were performed in Caco-2 cells, using fish oil nanoemulsions and a model substrate, rhodamine-123. Permeability data was modeled using a semi-mechanistic approach, capturing the following cellular processes: endocytotic uptake of the nanoemulsion, release of rhodamine-123 from the nanoemulsion, efflux and passive permeability of rhodamine-123 in aqueous solution. Nanoemulsions not only improved the permeability of rhodamine-123, but were also less sensitive to efflux transporters. The model captured bidirectional permeability results and identified sensitive processes, such as the release of the nanoemulsion-encapsulated drug and cellular uptake of the nanoemulsion. Mathematical description of cellular processes, improved our understanding of transport mechanisms, such as nanoemulsions don't inhibit efflux to improve drug permeability. Instead, their endocytotic uptake, results in higher intracellular drug concentrations, thereby increasing the concentration gradient and transcellular permeability across biological barriers. Modeling results indicated optimizing nanoemulsion attributes like the droplet size and intracellular drug release rate, may further improve drug permeability.

  1. Mathematical modeling analysis of intratumoral disposition of anticancer agents and drug delivery systems.

    Science.gov (United States)

    Popilski, Hen; Stepensky, David

    2015-05-01

    Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies. The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed. Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients.

  2. How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction.

    Science.gov (United States)

    Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

    2016-01-01

    Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. Published by Elsevier Inc.

  3. Modeling the economic outcomes of immuno-oncology drugs: alternative model frameworks to capture clinical outcomes

    Directory of Open Access Journals (Sweden)

    Gibson EJ

    2018-03-01

    Full Text Available EJ Gibson,1 N Begum,1 I Koblbauer,1 G Dranitsaris,2 D Liew,3 P McEwan,4 AA Tahami Monfared,5,6 Y Yuan,7 A Juarez-Garcia,7 D Tyas,8 M Lees9 1Wickenstones Ltd, Didcot, UK; 2Augmentium Pharma Consulting Inc, Toronto, ON, Canada; 3Department of Epidemiology and Preventive Medicine, Alfred Hospital, Monash University, Melbourne, VIC, Australia; 4Health Economics and Outcomes Research Ltd, Cardiff, UK; 5Bristol-Myers Squibb Canada, Saint-Laurent, QC Canada; 6Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada; 7Bristol-Myers Squibb, Princeton, NJ, USA; 8Bristol-Myers Squibb, Uxbridge, UK; 9Bristol-Myers Squibb, Rueil-Malmaison, France Background: Economic models in oncology are commonly based on the three-state partitioned survival model (PSM distinguishing between progression-free and progressive states. However, the heterogeneity of responses observed in immuno-oncology (I-O suggests that new approaches may be appropriate to reflect disease dynamics meaningfully. Materials and methods: This study explored the impact of incorporating immune-specific health states into economic models of I-O therapy. Two variants of the PSM and a Markov model were populated with data from one clinical trial in metastatic melanoma patients. Short-term modeled outcomes were benchmarked to the clinical trial data and a lifetime model horizon provided estimates of life years and quality adjusted life years (QALYs. Results: The PSM-based models produced short-term outcomes closely matching the trial outcomes. Adding health states generated increased QALYs while providing a more granular representation of outcomes for decision making. The Markov model gave the greatest level of detail on outcomes but gave short-term results which diverged from those of the trial (overstating year 1 progression-free survival by around 60%. Conclusion: Increased sophistication in the representation of disease dynamics in economic models

  4. Evolution analysis of the states of the EZ model

    International Nuclear Information System (INIS)

    Qing-Hua, Chen; Yi-Ming, Ding; Hong-Guang, Dong

    2009-01-01

    Based on suitable choice of states, this paper studies the stability of the equilibrium state of the EZ model by regarding the evolution of the EZ model as a Markov chain and by showing that the Markov chain is ergodic. The Markov analysis is applied to the EZ model with small number of agents, the exact equilibrium state for N = 5 and numerical results for N = 18 are obtained. (cross-disciplinary physics and related areas of science and technology)

  5. Modeling and implementing a database on drugs into a hospital intranet.

    Science.gov (United States)

    François, M; Joubert, M; Fieschi, D; Fieschi, M

    1998-09-01

    Our objective was to develop a drug information service, implementing a database on drugs in our university hospitals information system. Thériaque is a database, maintained by a group of pharmacists and physicians, on all the drugs available in France. Before its implementation we modeled its content (chemical classes, active components, excipients, indications, contra-indications, side effects, and so on) according to an object-oriented method. Then we designed HTML pages whose appearance translates the structure of classes of objects of the model. Fields in pages are dynamically fulfilled by the results of queries to a relational database in which information on drugs is stored. This allowed a fast implementation and did not imply to port a client application on the thousands of workstations over the network. The interface provides end-users with an easy-to-use and natural way to access information related to drugs in an internet environment.

  6. [Health care models for users of alcohol and other drugs: political discourse, knowledge, and practices].

    Science.gov (United States)

    Alves, Vânia Sampaio

    2009-11-01

    This article aims to characterize health care models for users of alcohol and other drugs in the Brazilian context. Discourse analysis was performed on public drug policy in Brazil from the 1970s. This analysis was contextualized by a brief digression on the main political positions identified in several countries of the world in relation to drug use problems. Beginning in the current decade, drug policies in Brazil have been receptive to harm reduction approaches, resulting in reorientation of the health care model. In conclusion, the structuring and strengthening of a network of care for users of alcohol and other drugs and their families, based on community care and the harm reduction approach and combined with other social and health services, is now a key public health challenge for the country.

  7. Drug-sensitive reward in crayfish: an invertebrate model system for the study of SEEKING, reward, addiction, and withdrawal.

    Science.gov (United States)

    Huber, Robert; Panksepp, Jules B; Nathaniel, Thomas; Alcaro, Antonio; Panksepp, Jaak

    2011-10-01

    In mammals, rewarding properties of drugs depend on their capacity to activate appetitive motivational states. With the underlying mechanisms strongly conserved in evolution, invertebrates have recently emerged as a powerful new model in addiction research. In crayfish natural reward has proven surprisingly sensitive to human drugs of abuse, opening an unlikely avenue of research into the basic biological mechanisms of drug addiction. In a series of studies we first examined the presence of natural reward systems in crayfish, then characterized its sensitivity to a wide range of human drugs of abuse. A conditioned place preference (CPP) paradigm was used to demonstrate that crayfish seek out those environments that had previously been paired with the psychostimulants cocaine and amphetamine, and the opioid morphine. The administration of amphetamine exerted its effects at a number of sites, including the stimulation of circuits for active exploratory behaviors (i.e., SEEKING). A further study examined morphine-induced reward, extinction and reinstatement in crayfish. Repeated intra-circulatory infusions of morphine served as a reward when paired with distinct visual or tactile cues. Morphine-induced CPP was extinguished after repeated saline injections. Following this extinction phase, morphine-experienced crayfish were once again challenged with the drug. The priming injections of morphine reinstated CPP at all tested doses, suggesting that morphine-induced CPP is unrelenting. In an exploration of drug-associated behavioral sensitization in crayfish we concurrently mapped measures of locomotion and rewarding properties of morphine. Single and repeated intra-circulatory infusions of morphine resulted in persistent locomotory sensitization, even 5 days following the infusion. Moreover, a single dose of morphine was sufficient to induce long-term behavioral sensitization. CPP for morphine and context-dependent cues could not be disrupted over a drug free period of 5

  8. Modeling the development of drug addiction in male and female animals.

    Science.gov (United States)

    Lynch, Wendy J

    2018-01-01

    An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug-seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non-human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. A Multiquantum State-to-State Model for the Fundamental States of Air: The Stellar Database

    Science.gov (United States)

    Lino da Silva, M.; Lopez, B.; Guerra, V.; Loureiro, J.

    2012-12-01

    We present a detailed database of vibrationally specific heavy-impact multiquantum rates for transitions between the fundamental states of neutral air species (N2 , O2 , NO, N and O). The most up-to-date datasets for atom- diatom collisions are firstly selected from the literature, scaled to accurate vibrational levels manifolds obtained using realistic intramolecular potentials, and extrapolated to high temperatures when necessary. For diatom-diatom collisions, vibrationally specific rates are produced using the Forced Harmonic Oscillator theory. An adequate manifold of vibrational levels is obtained from an accurate intermolecular potential, and available intermolecular potentials are approximated by a simplified Morse isotropic potential, or assumed through scaling of similar potentials otherwise. The database state-specific rates are valid for a large temperature range of low to very high temperatures, making it suitable for applications such as the modeling of high-enthalpy plasma sources or atmospheric entry applications. As experimentally determined state-specific rates are scarce, specially at high temperatures, emphasis has rather been put into verifying that the obtained rates are physically consistent, and verifying that they scale within the bounds of equilibrium rates available in the literature. The STELLAR database provides a complete and adequate set of heavy-impact rates for vibrational excitation, exchange, dissociation and recombination rates which can then be coupled to more detailed datasets for the simulation of physical-chemical processes in high-temperature plasmas. An application to the dissociation and exchange processes occurring behind an hypersonic shock wave are also presented in this work.

  10. Cost-offsets of prescription drug expenditures: data analysis via a copula-based bivariate dynamic hurdle model.

    Science.gov (United States)

    Deb, Partha; Trivedi, Pravin K; Zimmer, David M

    2014-10-01

    In this paper, we estimate a copula-based bivariate dynamic hurdle model of prescription drug and nondrug expenditures to test the cost-offset hypothesis, which posits that increased expenditures on prescription drugs are offset by reductions in other nondrug expenditures. We apply the proposed methodology to data from the Medical Expenditure Panel Survey, which have the following features: (i) the observed bivariate outcomes are a mixture of zeros and continuously measured positives; (ii) both the zero and positive outcomes show state dependence and inter-temporal interdependence; and (iii) the zeros and the positives display contemporaneous association. The point mass at zero is accommodated using a hurdle or a two-part approach. The copula-based approach to generating joint distributions is appealing because the contemporaneous association involves asymmetric dependence. The paper studies samples categorized by four health conditions: arthritis, diabetes, heart disease, and mental illness. There is evidence of greater than dollar-for-dollar cost-offsets of expenditures on prescribed drugs for relatively low levels of spending on drugs and less than dollar-for-dollar cost-offsets at higher levels of drug expenditures. Copyright © 2013 John Wiley & Sons, Ltd.

  11. Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of fosamprenavir in the fasted and fed state.

    Science.gov (United States)

    Brouwers, Joachim; Tack, Jan; Augustijns, Patrick

    2007-10-01

    The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

  12. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    OpenAIRE

    N. B. Molchanova

    2015-01-01

    Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII). The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the mode...

  13. [Alcohol and illicit drug use and its influence on the sexual behavior of teenagers from Minas Gerais State, Brazil].

    Science.gov (United States)

    Bertoni, Neilane; Bastos, Francisco I; Mello, Maeve Brito de; Makuch, Maria Yolanda; Sousa, Maria Helena de; Osis, Maria José; Faúndes, Anibal

    2009-06-01

    This article summarizes the findings of a survey including 5,981 students from public schools in Minas Gerais State, Brazil. The analysis assessed the influence of drug use on sexual practices. Among the boys engaged in relationships with casual partners who stated having used illicit drugs, 55.7% reported consistent condom use, as compared to 65.4% among those not reporting such habits. Among boys engaged in relationships with stable partners who reported illicit drug use, consistent condom use was reported by 42.7%, versus 64.1% among those not reporting such habits. In the subgroup of boys engaged in stable relationships who did not report illicit drug use, consistent condom use was less frequent among those that used alcohol/cigarettes, compared to those who did not drink or smoke (60.7% vs. 71.1%). Girls were less likely than boys to use condoms consistently, regardless of the nature of their relationships, without a noticeable influence of drug use. Policies to prevent drug abuse, sexually transmitted diseases, and unplanned pregnancy should be fully integrated.

  14. Alcohol and drug policy model for the Canadian upstream petroleum industry

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2007-09-15

    This alcohol and drug policy model was developed to help employers manage and reduce the risks associated with drug and alcohol use in the workplace. The policy model outlined guidelines for establishing and implementing drug and alcohol policies, and discussed treatment programs and opportunities for re-employment. The model was developed by Enform, the upstream petroleum industry's safety and training arm, who used a previous guide developed by the Construction Owner's Association of Alberta (COAA) as a model. Enform's model provided a summary of key accountabilities across all levels of industry as well as the accepted minimum criteria for developing alcohol and drug policies. The model included guidelines and recommendations for employees, supervisors, and owners, employers, and contractors. The responsibilities of associations, organizations, and private companies were also outlined. An overview of recommended implementation plans was provided, as well as details of alcohol and drug use education programs and workplace rules. A supervisor's guide to implementation provided outlines of the causes of drug use among employees. tabs.

  15. Potential Exposure to Anti-Drug Advertising and Drug-Related Attitudes, Beliefs, and Behaviors among United States Youth, 1995-2006

    Science.gov (United States)

    Terry-McElrath, Yvonne M.; Emery, Sherry; Szczypka, Glen; Johnston, Lloyd D.

    2010-01-01

    Using nationally representative data from the Monitoring the Future Study on United States middle and high school students, we related exposure to anti-drug television advertising as measured by Nielsen Media Research ratings points to student self-reported drug-related outcomes from 1995-2006. Multivariate analyses controlling for key socio-demographics and accounting for the complex survey design included 337,918 cases. Results indicated that attitudes, beliefs, and behaviors regarding substance use were significantly related to such advertising exposure over the six months prior to the date youth were surveyed. However, the observed relationships varied by grade level, over time and by advertising tagline and marijuana focus. Findings differed markedly between middle and high school students across the study interval. One factor that may partially explain observed differences may be variation in the degree to which the ads focused on marijuana. Putting a concerted effort into increasing anti-drug advertising will likely increase the exposure to and recall of such ads among youth. However, the likelihood that such advertising will result in youth being less likely to use drugs seems to depend heavily on the type of advertising utilized and how it relates to different ages and characteristics of targeted youth. PMID:20961691

  16. The liberal state and the rogue agency: FDA’s regulation of drugs for mood disorders, 1950s–1970s☆

    Science.gov (United States)

    Shorter, Edward

    2013-01-01

    The theory of the liberal state does not generally contemplate the possibility that regulatory agencies will turn into “rogues,” regulating against the interests of their clients and, indeed, the public interest. In the years between circa 1955 and 1975 this seems to have happened to one of the prime regulatory agencies of the US federal government: the Food and Drug Administration (FDA). Intent upon transforming itself from a traditional “cop” agency to a regulatory giant, the FDA campaigned systematically to bring down some safe and effective drugs. This article concentrates on hearings in the area of psychopharmacology regarding several antianxiety drugs, namely meprobamate (Miltown), chlordiazepoxide (Librium) and diazepam (Valium). In addition, from 1967 to 1973 this regulatory vengefulness occurred on a broad scale in the Drug Efficacy Study Implementation (DESI), an administrative exercise that removed from the market almost half of the psychopharmacopoeia. The article explores possible bureaucratic motives for these actions. PMID:18343498

  17. The liberal state and the rogue agency: FDA's regulation of drugs for mood disorders, 1950s-1970s.

    Science.gov (United States)

    Shorter, Edward

    2008-01-01

    The theory of the liberal state does not generally contemplate the possibility that regulatory agencies will turn into "rogues," regulating against the interests of their clients and, indeed, the public interest. In the years between circa 1955 and 1975 this seems to have happened to one of the prime regulatory agencies of the US federal government: the Food and Drug Administration (FDA). Intent upon transforming itself from a traditional "cop" agency to a regulatory giant, the FDA campaigned systematically to bring down some safe and effective drugs. This article concentrates on hearings in the area of psychopharmacology regarding several antianxiety drugs, namely meprobamate (Miltown), chlordiazepoxide (Librium) and diazepam (Valium). In addition, from 1967 to 1973 this regulatory vengefulness occurred on a broad scale in the Drug Efficacy Study Implementation (DESI), an administrative exercise that removed from the market almost half of the psychopharmacopoeia. The article explores possible bureaucratic motives for these actions.

  18. Mining FDA drug labels using an unsupervised learning technique--topic modeling.

    Science.gov (United States)

    Bisgin, Halil; Liu, Zhichao; Fang, Hong; Xu, Xiaowei; Tong, Weida

    2011-10-18

    The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering "topics" that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that might arise from specific

  19. Mining FDA drug labels using an unsupervised learning technique - topic modeling

    Science.gov (United States)

    2011-01-01

    Background The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. Method In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering “topics” that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. Results The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that

  20. Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

    Science.gov (United States)

    Zhou, Hui-yun; Chen, Xi-guang

    2008-12-01

    In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.

  1. A New State Model of Teacher Education.

    Science.gov (United States)

    Guthrie, James W.

    1983-01-01

    A new California law, Senate Bill 813, implies sweeping changes for teacher education in that state. The law permits districts to hire college graduates without teaching credentials and train them. It also requires all teachers to renew certification periodically. Implications for schools of education are discussed. (Author/PP)

  2. Zero-inflated Poisson model based likelihood ratio test for drug safety signal detection.

    Science.gov (United States)

    Huang, Lan; Zheng, Dan; Zalkikar, Jyoti; Tiwari, Ram

    2017-02-01

    In recent decades, numerous methods have been developed for data mining of large drug safety databases, such as Food and Drug Administration's (FDA's) Adverse Event Reporting System, where data matrices are formed by drugs such as columns and adverse events as rows. Often, a large number of cells in these data matrices have zero cell counts and some of them are "true zeros" indicating that the drug-adverse event pairs cannot occur, and these zero counts are distinguished from the other zero counts that are modeled zero counts and simply indicate that the drug-adverse event pairs have not occurred yet or have not been reported yet. In this paper, a zero-inflated Poisson model based likelihood ratio test method is proposed to identify drug-adverse event pairs that have disproportionately high reporting rates, which are also called signals. The maximum likelihood estimates of the model parameters of zero-inflated Poisson model based likelihood ratio test are obtained using the expectation and maximization algorithm. The zero-inflated Poisson model based likelihood ratio test is also modified to handle the stratified analyses for binary and categorical covariates (e.g. gender and age) in the data. The proposed zero-inflated Poisson model based likelihood ratio test method is shown to asymptotically control the type I error and false discovery rate, and its finite sample performance for signal detection is evaluated through a simulation study. The simulation results show that the zero-inflated Poisson model based likelihood ratio test method performs similar to Poisson model based likelihood ratio test method when the estimated percentage of true zeros in the database is small. Both the zero-inflated Poisson model based likelihood ratio test and likelihood ratio test methods are applied to six selected drugs, from the 2006 to 2011 Adverse Event Reporting System database, with varying percentages of observed zero-count cells.

  3. Progress with modeling activity landscapes in drug discovery.

    Science.gov (United States)

    Vogt, Martin

    2018-04-19

    Activity landscapes (ALs) are representations and models of compound data sets annotated with a target-specific activity. In contrast to quantitative structure-activity relationship (QSAR) models, ALs aim at characterizing structure-activity relationships (SARs) on a large-scale level encompassing all active compounds for specific targets. The popularity of AL modeling has grown substantially with the public availability of large activity-annotated compound data sets. AL modeling crucially depends on molecular representations and similarity metrics used to assess structural similarity. Areas covered: The concepts of AL modeling are introduced and its basis in quantitatively assessing molecular similarity is discussed. The different types of AL modeling approaches are introduced. AL designs can broadly be divided into three categories: compound-pair based, dimensionality reduction, and network approaches. Recent developments for each of these categories are discussed focusing on the application of mathematical, statistical, and machine learning tools for AL modeling. AL modeling using chemical space networks is covered in more detail. Expert opinion: AL modeling has remained a largely descriptive approach for the analysis of SARs. Beyond mere visualization, the application of analytical tools from statistics, machine learning and network theory has aided in the sophistication of AL designs and provides a step forward in transforming ALs from descriptive to predictive tools. To this end, optimizing representations that encode activity relevant features of molecules might prove to be a crucial step.

  4. Implant-assisted magnetic drug targeting in permeable microvessels: Comparison of two-fluid statistical transport model with experiment

    Energy Technology Data Exchange (ETDEWEB)

    ChiBin, Zhang; XiaoHui, Lin, E-mail: lxh60@seu.edu.cn; ZhaoMin, Wang; ChangBao, Wang

    2017-03-15

    In experiments and theoretical analyses, this study examines the capture efficiency (CE) of magnetic drug carrier particles (MDCPs) for implant-assisted magnetic drug targeting (IA-MDT) in microvessels. It also proposes a three-dimensional statistical transport model of MDCPs for IA-MDT in permeable microvessels, which describes blood flow by the two-fluid (Casson and Newtonian) model. The model accounts for the permeable effect of the microvessel wall and the coupling effect between the blood flow and tissue fluid flow. The MDCPs move randomly through the microvessel, and their transport state is described by the Boltzmann equation. The regulated changes and factors affecting the CE of the MDCPs in the assisted magnetic targeting were obtained by solving the theoretical model and by experimental testing. The CE was negatively correlated with the blood flow velocity, and positively correlated with the external magnetic field intensity and microvessel permeability. The predicted CEs of the MDCPs were consistent with the experimental results. Additionally, under the same external magnetic field, the predicted CE was 5–8% higher in the IA-MDT model than in the model ignoring the permeability effect of the microvessel wall. - Highlights: • A model of MDCPs for IA-MDT in permeable microvessels was established. • An experimental device was established, the CE of MDCPs was measured. • The predicted CE of MDCPs was 5–8% higher in the IA-MDT model.

  5. From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming

    Directory of Open Access Journals (Sweden)

    Aleksander Mendyk

    2015-01-01

    Full Text Available The purpose of this work was to develop a mathematical model of the drug dissolution (Q from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs and genetic programming (GP tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1 direct modeling of Q versus extrudate diameter (d and the time variable (t and (2 indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations’ parameters. Two inputs were found important for the drug dissolution: d and t. The extrudates length (L was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE from 2.19 to 2.33. The direct mode of GP modeling of Q versus d and t resulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs’ black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies.

  6. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  7. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs: - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model.

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty; Thakur, Mansee

    2016-12-01

    model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  8. Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

    Science.gov (United States)

    Pearlstein, Robert A; McKay, Daniel J J; Hornak, Viktor; Dickson, Callum; Golosov, Andrei; Harrison, Tyler; Velez-Vega, Camilo; Duca, José

    2017-01-01

    Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, "solving" sets of coupled "molecular differential equations" (i.e. represented by populations of interacting species)via "integration" of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT. Copyright© Bentham

  9. Development of Water Quality Modeling in the United States

    Science.gov (United States)

    This presentation describes historical trends in water quality model development in the United States, reviews current efforts, and projects promising future directions. Water quality modeling has a relatively long history in the United States. While its origins lie in the work...

  10. Embedding a State Space Model Into a Markov Decision Process

    DEFF Research Database (Denmark)

    Nielsen, Lars Relund; Jørgensen, Erik; Højsgaard, Søren

    2011-01-01

    In agriculture Markov decision processes (MDPs) with finite state and action space are often used to model sequential decision making over time. For instance, states in the process represent possible levels of traits of the animal and transition probabilities are based on biological models...

  11. Dynamic State Space Partitioning for External Memory Model Checking

    DEFF Research Database (Denmark)

    Evangelista, Sami; Kristensen, Lars Michael

    2009-01-01

    We describe a dynamic partitioning scheme usable by model checking techniques that divide the state space into partitions, such as most external memory and distributed model checking algorithms. The goal of the scheme is to reduce the number of transitions that link states belonging to different...

  12. MDMA, Methylone, and MDPV: Drug-Induced Brain Hyperthermia and Its Modulation by Activity State and Environment.

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn E

    2017-01-01

    Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential

  13. Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems.

    Science.gov (United States)

    Kaunisto, Erik; Marucci, Mariagrazia; Borgquist, Per; Axelsson, Anders

    2011-10-10

    The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Binary logistic regression modelling: Measuring the probability of relapse cases among drug addict

    Science.gov (United States)

    Ismail, Mohd Tahir; Alias, Siti Nor Shadila

    2014-07-01

    For many years Malaysia faced the drug addiction issues. The most serious case is relapse phenomenon among treated drug addict (drug addict who have under gone the rehabilitation programme at Narcotic Addiction Rehabilitation Centre, PUSPEN). Thus, the main objective of this study is to find the most significant factor that contributes to relapse to happen. The binary logistic regression analysis was employed to model the relationship between independent variables (predictors) and dependent variable. The dependent variable is the status of the drug addict either relapse, (Yes coded as 1) or not, (No coded as 0). Meanwhile the predictors involved are age, age at first taking drug, family history, education level, family crisis, community support and self motivation. The total of the sample is 200 which the data are provided by AADK (National Antidrug Agency). The finding of the study revealed that age and self motivation are statistically significant towards the relapse cases..

  15. Orphan Drug Pricing: An Original Exponential Model Relating Price to the Number of Patients

    Directory of Open Access Journals (Sweden)

    Andrea Messori

    2016-10-01

    Full Text Available In managing drug prices at the national level, orphan drugs represent a special case because the price of these agents is higher than that determined according to value-based principles. A common practice is to set the orphan drug price in an inverse relationship with the number of patients, so that the price increases as the number of patients decreases. Determination of prices in this context generally has a purely empirical nature, but a theoretical basis would be needed. The present paper describes an original exponential model that manages the relationship between price and number of patients for orphan drugs. Three real examples are analysed in detail (eculizumab, bosentan, and a data set of 17 orphan drugs published in 2010. These analyses have been aimed at identifying some objective criteria to rationally inform this relationship between prices and patients and at converting these criteria into explicit quantitative rules.

  16. Drug Policy and the Ultima Ratio in A Social and Democratic State, Spain

    Directory of Open Access Journals (Sweden)

    Alison Hogg

    2013-01-01

    Full Text Available As a Member State of the UN and the EU, Spain's drug policy is heavily conditioned by these external superior ‘legal personalities’. Although, the Spanish legislature has enacted amendments to legislation on illicit substances over the last ten years to attenuate excessively punitive law, their interpretation and internal application of conventions on drug legislation has by in large overlooked the ultima ratio principle i.e. minimum intervention (Arana 2012. Spain’s criminal legislation is presented as well as the consequences of the prohibition of illicit substances in this jurisdiction. Finally, alternatives that have emerged in the Basque Autonomous Community to counter the effects of its criminalisation are briefly discussed and promoted as a means of abating external legal constraints that have serious social and legal ramifications. Como miembro de ONU y UE, la política de drogas española está fuertemente condicionada por la legislación emanada de estas entidades jurídicas. A pesar de eso, los legisladores españoles han introducido reformas en la legislación sobre sustancias ilícitas en los últimos diez años para atenuar una legislación excesivamente punitiva, su interpretación y aplicación interna de convenios sobre legislación en materia de drogas en gran parte no toma en cuenta el principio del ultimo ratio (Arana 2012. Se presenta la legislación penal española en materia de sustancias ilícitas y también los efectos que ésta tiene sobre la jurisdicción. Finalmente, las alternativas surgidas en la Comunidad Autónoma Vasca para contrarrestar los efectos de la criminalización, son brevemente discutidas y promovidas como una manera para amainar las limitaciones jurídicas que tienen importantes y serias ramificaciones sociales y legales. DOWNLOAD THIS PAPER FROM SSRN: http://ssrn.com/abstract=2200886

  17. Application of PBPK modelling in drug discovery and development at Pfizer.

    Science.gov (United States)

    Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

    2012-01-01

    Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

  18. A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours

    Directory of Open Access Journals (Sweden)

    Liu Cong

    2011-12-01

    Full Text Available Abstract Background Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side. Results We develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied. Conclusions We have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.

  19. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    NARCIS (Netherlands)

    Witte, W.E.; Wong, Y.C.; Nederpelt, I.; Heitman, L.H.; Danhof, M.; Graaf, van der P.H.; Gilissen, R.A.; de, Lange E.C.

    2016-01-01

    INTRODUCTION Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target

  20. A Multiple Indicators Multiple Causes (MIMIC) model of internal barriers to drug treatment in China.

    Science.gov (United States)

    Qi, Chang; Kelly, Brian C; Liao, Yanhui; He, Haoyu; Luo, Tao; Deng, Huiqiong; Liu, Tieqiao; Hao, Wei; Wang, Jichuan

    2015-03-01

    Although evidence exists for distinct barriers to drug abuse treatment (BDATs), investigations of their inter-relationships and the effect of individual characteristics on the barrier factors have been sparse, especially in China. A Multiple Indicators Multiple Causes (MIMIC) model is applied for this target. A sample of 262 drug users were recruited from three drug rehabilitation centers in Hunan Province, China. We applied a MIMIC approach to investigate the effect of gender, age, marital status, education, primary substance use, duration of primary drug use, and drug treatment experience on the internal barrier factors: absence of problem (AP), negative social support (NSS), fear of treatment (FT), and privacy concerns (PC). Drug users of various characteristics were found to report different internal barrier factors. Younger participants were more likely to report NSS (-0.19, p=0.038) and PC (-0.31, p<0.001). Compared to other drug users, ice users were more likely to report AP (0.44, p<0.001) and NSS (0.25, p=0.010). Drug treatment experiences related to AP (0.20, p=0.012). In addition, differential item functioning (DIF) occurred in three items when participant from groups with different duration of drug use, ice use, or marital status. Individual characteristics had significant effects on internal barriers to drug treatment. On this basis, BDAT perceived by different individuals could be assessed before tactics were utilized to successfully remove perceived barriers to drug treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Advances in simultaneous DSC-FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples.

    Science.gov (United States)

    Lin, Shan-Yang; Wang, Shun-Li

    2012-04-01

    The solid-state chemistry of drugs has seen growing importance in the pharmaceutical industry for the development of useful API (active pharmaceutical ingredients) of drugs and stable dosage forms. The stability of drugs in various solid dosage forms is an important issue because solid dosage forms are the most common pharmaceutical formulation in clinical use. In solid-state stability studies of drugs, an ideal accelerated method must not only be selected by different complicated methods, but must also detect the formation of degraded product. In this review article, an analytical technique combining differential scanning calorimetry and Fourier-transform infrared (DSC-FTIR) microspectroscopy simulates the accelerated stability test, and simultaneously detects the decomposed products in real time. The pharmaceutical dipeptides aspartame hemihydrate, lisinopril dihydrate, and enalapril maleate either with or without Eudragit E were used as testing examples. This one-step simultaneous DSC-FTIR technique for real-time detection of diketopiperazine (DKP) directly evidenced the dehydration process and DKP formation as an impurity common in pharmaceutical dipeptides. DKP formation in various dipeptides determined by different analytical methods had been collected and compiled. Although many analytical methods have been applied, the combined DSC-FTIR technique is an easy and fast analytical method which not only can simulate the accelerated drug stability testing but also at the same time enable to explore phase transformation as well as degradation due to thermal-related reactions. This technique offers quick and proper interpretations. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Modeling new XYZ states at JPAC

    Energy Technology Data Exchange (ETDEWEB)

    Pilloni, Alessandro [Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States)

    2016-12-01

    The observation of the unexpected XYZP resonances has challenged the usual heavy quarkonium framework. One of the most studied exotic states, the X(3872), happens to be copiously produced in high-energy hadron collisions. We discuss how this large prompt production cross-section, together with the comparison with light nuclei production data, disfavors a loosely-bound molecule interpretation, and calls for a new interpretation for the exotic hadron resonances. We also present the research of the Joint Physics Analysis Center in Hadron Spectroscopy.

  3. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    International Nuclear Information System (INIS)

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  4. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  5. Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium

    DEFF Research Database (Denmark)

    Birch, Ditlev; Diedrichsen, Ragna G; Christophersen, Philip C

    2018-01-01

    The absence of a surface-lining mucus layer is a major pitfall for the Caco-2 epithelial model. However, this can be alleviated by applying biosimilar mucus (BM) to the apical surface of the cell monolayer, thereby constructing a mucosa mimicking in vivo conditions. This study aims to elucidate...... the influence of BM as a barrier towards exogenic compounds such as permeation enhancers, and components of fed state simulated intestinal fluid (FeSSIF). Caco-2 cell monolayers surface-lined with BM were exposed to several compounds with distinct physicochemical properties, and the cell viability...... and permeability of the cell monolayer was compared to that of cell monolayers without BM and well-established mucus-secreting epithelial models (HT29 monolayers and HT29/Caco-2 co-culture monolayers). Exposure of BM-covered cells to constituents from FeSSIF revealed that it comprised a strong, hydrophilic barrier...

  6. Minimal model for spoof acoustoelastic surface states

    Directory of Open Access Journals (Sweden)

    J. Christensen

    2014-12-01

    Full Text Available Similar to textured perfect electric conductors for electromagnetic waves sustaining artificial or spoof surface plasmons we present an equivalent phenomena for the case of sound. Aided by a minimal model that is able to capture the complex wave interaction of elastic cavity modes and airborne sound radiation in perfect rigid panels, we construct designer acoustoelastic surface waves that are entirely controlled by the geometrical environment. Comparisons to results obtained by full-wave simulations confirm the feasibility of the model and we demonstrate illustrative examples such as resonant transmissions and waveguiding to show a few examples of many where spoof elastic surface waves are useful.

  7. Four-quark states in potential model

    International Nuclear Information System (INIS)

    Badalyan, A.M.; Kitoroage, D.I.

    1987-01-01

    The mass spectrum of S-wave q 2 q -2 mesons of u, d, s quarks is calculated in the framework of the nonrelativistic potential model and compared with the bag model predictions. The spin-spin splittings of almost all four-quark mesons with J PC = 0 ++ , 2 ++ , 1 +- are shown to coincide with an accuracy of ∼ 50 MeV in both approaches. Two exceptions are O S (9), C π S (9) mesons for which the discrepancy is ∼ 300 MeV. Calculated centers of gravity of the multiplets are systematically ∼ 120 MeV higher than the MIT bag predictions

  8. Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

    Science.gov (United States)

    Morgen, Michael; Bloom, Corey; Beyerinck, Ron; Bello, Akintunde; Song, Wei; Wilkinson, Karen; Steenwyk, Rick; Shamblin, Sheri

    2012-02-01

    To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

  9. Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research.

    Science.gov (United States)

    Li, Ming; de Graaf, Inge A M; Groothuis, Geny M M

    2016-01-01

    The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies. This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed. PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro-ex vivo-in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.

  10. Work-related injuries in a state trauma registry: relationship between industry and drug screening.

    Science.gov (United States)

    Bunn, Terry L; Slavova, Svetla; Bernard, Andrew C

    2014-08-01

    Work-related injuries exert a great financial and economic burden on the US population. The study objectives were to identify the industries and occupations associated with worker injuries and to determine the predictors for injured worker drug screening in trauma centers. Work-related injury cases were selected using three criteria (expected payer source of workers' compensation, industry-related e-codes, and work-related indicator) from the Kentucky Trauma Registry data set for years 2008 to 2012. Descriptive analyses and multiple logistic regression were performed on the work-related injury cases. The "other services" and construction industry sectors accounted for the highest number of work-related cases. Drugs were detected in 55% of all drug-screened work-related trauma cases. Higher percentages of injured workers tested positive for drugs in the natural resources and mining, transportation and public utilities, and construction industries. In comparison, higher percentages of injured workers in the other services as well as transportation and public utilities industries were drug screened. Treatment at Level I trauma centers and Glasgow Coma Scale (GCS) scores indicating a coma or severe brain injury were both significant independent predictors for being screened for drugs; industry was not a significant predictor for being drug screened. The injured worker was more likely to be drug screened if the worker had a greater than mild injury, regardless of whether the worker was an interfacility transfer. These findings indicate that there may be elevated drug use or abuse in natural resources and mining, transportation and public utilities, as well as construction industry workers; improved identification of the specific drug types in positive drug screen results of injured workers is needed to better target prevention efforts. Epidemiologic study, level III.

  11. Modelling the encapsulation of the anticancer drug cisplatin into carbon nanotubes

    International Nuclear Information System (INIS)

    Hilder, Tamsyn A; Hill, James M

    2007-01-01

    The proposed use of nanocapsules in drug delivery systems promises many advantages over current procedures. The major advantage is the potential for patients to have significantly reduced side effects from taking the drug, especially for highly toxic drugs such as those used for cancer treatments. Nanotubes have been suggested as one such carrier to deliver a drug to a specific site, giving rise to the notion of the 'magic bullet'. The aim of this paper is to determine whether a particular nanotube would accept a particular drug, and to determine the radius of the nanotube that provides the maximum uptake of the drug molecule. In particular, this paper looks at the drug cisplatin, a platinum based anticancer drug widely used in the treatment of tumours. Three orientations of cisplatin, a polar molecule, are investigated as it enters the nanotube. It is shown that, for all three orientations of cisplatin to be accepted into the carbon nanotube, the minimum radius must be at least 4.785 A, which is slightly smaller than a (9, 5) nanotube and that the maximum suction energy occurs when the carbon nanotube radius is approximately 5.3 A, which is approximately equivalent to a (11, 4) nanotube. This paper presents for the first time a calculation of this nature, and although the model represents only a first approximation, it constitutes a necessary preliminary calculation which might provide medical scientists with some overall guidelines

  12. Some Remarks on Prediction of Drug-Target Interaction with Network Models.

    Science.gov (United States)

    Zhang, Shao-Wu; Yan, Xiao-Ying

    2017-01-01

    System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict Drug-Target Interactions (DTI). In this review, we make a survey on the recent advances in predicting drug-target interaction with network-based models from the following aspects: i) Available public data sources and benchmark datasets; ii) Drug/target similarity metrics; iii) Network construction; iv) Common network algorithms; v) Performance comparison of existing network-based DTI predictors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. The Last State to Grant Nurse Practitioners DEA Licensure: An Education Improvement Initiative on the Florida Prescription Drug Monitoring Program.

    Science.gov (United States)

    Kellams, Joni R; Maye, John P

    Nurse practitioners (NPs) now have prescriptive authority for controlled substances in all 50 states in the United States. Florida, the last state to grant NPs DEA licensure, has been wrought with prescription diversion practices for a number of years as pill mills, doctor shopping, and overprescribing proliferated. Prescription Drug Monitoring Programs (PDMPs) help curb drug diversion activity and play a key role in reducing the abuse of controlled substances. The primary objective of this education improvement initiative was to increase knowledge of actively licensed NPs in the state of Florida regarding the state's PDMP. The main themes included the drug abuse problem, description and progression of the PDMP, and how to use the Florida PDMP. Upon approval from the institutional review board, this education improvement initiative gauged NP knowledge of the PDMP and main themes before and after an educational PowerPoint intervention. A pretest/posttest questionnaire was administered for assessment of all knowledge questions. One hundred forty-five NPs with active advanced registered NP licenses in Florida completed both the pretest and posttest questionnaires. Descriptive statistics and paired t tests were used for statistical significance testing. Knowledge of the PDMP and the main themes of the education improvement initiative significantly increased (p < .001) from pretest to posttest results. This education improvement initiative had positive effects for NPs on the knowledge of the Florida PDMP and the main themes. This indicated that Florida NPs are able to acquire greater comprehension of the PDMP by an education intervention.

  14. Validation of ecological state space models using the Laplace approximation

    DEFF Research Database (Denmark)

    Thygesen, Uffe Høgsbro; Albertsen, Christoffer Moesgaard; Berg, Casper Willestofte

    2017-01-01

    Many statistical models in ecology follow the state space paradigm. For such models, the important step of model validation rarely receives as much attention as estimation or hypothesis testing, perhaps due to lack of available algorithms and software. Model validation is often based on a naive...... for estimation in general mixed effects models. Implementing one-step predictions in the R package Template Model Builder, we demonstrate that it is possible to perform model validation with little effort, even if the ecological model is multivariate, has non-linear dynamics, and whether observations...... useful directions in which the model could be improved....

  15. Considerations for a business model for the effective integration of novel biomarkers into drug development.

    Science.gov (United States)

    Frueh, Felix W

    2008-11-01

    It is 10 years since the introduction of trastuzumab into the US market, and we are still waiting for a validation of the business case for biomarker-driven drug development. While many reasons for the lack of duplication of this model may exist, the need for accelerated innovation in drug development paired with the opportunity of integrating biomarker-driven research into drug development programs may lead to new and creative ways of fostering the cooperation between drug developers and test manufacturers. The rapid increase in knowledge about biomarkers and our understanding of disease and disease mechanisms open unprecedented prospects to make not only better, more informed decisions regarding patient care, but also strategic decisions during drug development. This requires that a biomarker strategy becomes an integral part of (early) drug development and that new, innovative paths are tried towards a model that combines the scientific approach with an economically feasible implementation strategy. Collaborative research, the use of new communication tools, the exploration of alternative ways to position a product in the market, and other considerations are part of such a strategy. This perspective article illustrates the current landscape and takes a look at some of these new ways for more effectively integrating biomarkers into drug development.

  16. Public/private partnerships for prescription drug coverage: policy formulation and outcomes in Quebec's universal drug insurance program, with comparisons to the Medicare prescription drug program in the United States.

    Science.gov (United States)

    Pomey, Marie-Pascale; Forest, Pierre-Gerlier; Palley, Howard A; Martin, Elisabeth

    2007-09-01

    In January 1997, the government of Quebec, Canada, implemented a public/private prescription drug program that covered the entire population of the province. Under this program, the public sector collaborates with private insurers to protect all Quebecers from the high cost of drugs. This article outlines the principal features and history of the Quebec plan and draws parallels between the factors that led to its emergence and those that led to the passage of the Medicare Prescription Drug, Improvement and Modernization Act (MMA) in the United States. It also discusses the challenges and similarities of both programs and analyzes Quebec's ten years of experience to identify adjustments that may help U.S. policymakers optimize the MMA.

  17. Estimation methods for nonlinear state-space models in ecology

    DEFF Research Database (Denmark)

    Pedersen, Martin Wæver; Berg, Casper Willestofte; Thygesen, Uffe Høgsbro

    2011-01-01

    The use of nonlinear state-space models for analyzing ecological systems is increasing. A wide range of estimation methods for such models are available to ecologists, however it is not always clear, which is the appropriate method to choose. To this end, three approaches to estimation in the theta...... logistic model for population dynamics were benchmarked by Wang (2007). Similarly, we examine and compare the estimation performance of three alternative methods using simulated data. The first approach is to partition the state-space into a finite number of states and formulate the problem as a hidden...... Markov model (HMM). The second method uses the mixed effects modeling and fast numerical integration framework of the AD Model Builder (ADMB) open-source software. The third alternative is to use the popular Bayesian framework of BUGS. The study showed that state and parameter estimation performance...

  18. Steady state modeling of desiccant wheels

    DEFF Research Database (Denmark)

    Bellemo, Lorenzo; Elmegaard, Brian; Kærn, Martin Ryhl

    2014-01-01

    Desiccant wheels are rotary desiccant dehumidifiers used in air conditioning and drying applications. The modeling of simultaneous heat and mass transfer in these components is crucial for estimating their performances, as well as for simulating and optimizing their implementation in complete...

  19. Stability Analysis of an HIV/AIDS Dynamics Model with Drug Resistance

    Directory of Open Access Journals (Sweden)

    Qianqian Li

    2012-01-01

    Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.

  20. Drug states as modulators of conditioned immobility in a latent discrimination procedure.

    NARCIS (Netherlands)

    Maes, J.H.R.; Rijn, C.M. van; Vossen, J.M.H.

    1996-01-01

    Midazolam, amphetamine, and flesinoxan were used in four rat experiments to examine the usefulness of a latent Pavlovian discrimination procedure to assess the discriminative-stimulus, or occasion-setting, properties of drugs. Experiment 1 first assessed the unconditioned effect of each of the drugs

  1. Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

    Directory of Open Access Journals (Sweden)

    Fatma E. El-Khouly

    2017-10-01

    Full Text Available Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG, patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB. We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

  2. Using a 3-d model system to screen for drugs effective on solid tumors

    OpenAIRE

    Fayad, Walid

    2011-01-01

    There is a large medical need for the development of effective anticancer agents with minimal side effects. The present thesis represents an attempt to identify potent drugs for treatment of solid tumors. We used a strategy where 3-D multicellular tumor spheroids (cancer cells grown in three dimensional culture) were utilized as in vitro models for solid tumors. Drug libraries were screened using spheroids as targets and using apoptosis induction and loss of cell viability as endpoints. The h...

  3. Modeling Attitude towards Drug Treament: The Role of Internal Motivation, External Pressure, and Dramatic Relief

    OpenAIRE

    Conner, Bradley T.; Longshore, Douglas; Anglin, M. Douglas

    2008-01-01

    Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) enter...

  4. Modelling irradiation by EM waves of multifunctionalized iron oxide nanoparticles and subsequent drug release

    International Nuclear Information System (INIS)

    Wang, Feng; Calvayrac, Florent; Montembault, Véronique; Fontaine, Laurent

    2015-01-01

    Thermal transport in the environment close to the periphery of the nanoparticle, from a few angstroms to less than a nanometer scale, is becoming increasingly important with the advent of several biomedical applications of multifunctional magnetic nanoparticles, including drug delivery, magnetic resonance imaging, and hyperthermia therapy. We present a multiscale and multiphysics model of the irradiation by electromagnetic waves of radiofrequency of iron oxide nanoparticles functionalized by drug-releasing polymers used as new multifunctional therapeutic compounds against tumors. We compute ab initio the thermal conductivity of the polymer chains as a function of the length, model the unfolding of the polymer after heat transfer from the nanoparticle by molecular mechanics, and develop a multiscale thermodynamic and heat transfer model including the surrounding medium (water) in order to model the drug release. (paper)

  5. The Association between Non-Medical Prescription Drug Use and Suicidal Behavior among United States Adolescents

    Directory of Open Access Journals (Sweden)

    Amanda L. Divin

    2014-11-01

    Full Text Available Adolescence represents a vulnerable time for the development of both drug use/abuse and mental illness. Although previous research has substantiated a relationship between drug use and suicidal behavior, little research has examined this relationship with non-medical prescription drug use. Given the growing prevalence of non-medical prescription drug use (NMPDU among adolescents, this study explored the association between NMPDU and suicidal behavior. Nationally representative data were derived from 16, 410 adolescents who completed the 2009 National Youth Risk Behavior Survey. Approximately 19.8% of participants reported lifetime NMPDU. NMPDU was associated with significantly increased odds of suicidal behavior (P < 0.01, with seriously considering attempting suicide and making a plan about attempting suicide representing the strongest correlates for males and females. Results suggest the importance of 1 continued reinforcement of drug education programs in high school begun at earlier ages and 2 mental health care and screenings among adolescents.

  6. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.

    Science.gov (United States)

    Huang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, Xinyong

    2015-12-01

    The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.

  7. Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

    Science.gov (United States)

    Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

    2017-11-15

    The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

  8. Artificial emotional model based on finite state machine

    Institute of Scientific and Technical Information of China (English)

    MENG Qing-mei; WU Wei-guo

    2008-01-01

    According to the basic emotional theory, the artificial emotional model based on the finite state machine(FSM) was presented. In finite state machine model of emotion, the emotional space included the basic emotional space and the multiple emotional spaces. The emotion-switching diagram was defined and transition function was developed using Markov chain and linear interpolation algorithm. The simulation model was built using Stateflow toolbox and Simulink toolbox based on the Matlab platform.And the model included three subsystems: the input one, the emotion one and the behavior one. In the emotional subsystem, the responses of different personalities to the external stimuli were described by defining personal space. This model takes states from an emotional space and updates its state depending on its current state and a state of its input (also a state-emotion). The simulation model realizes the process of switching the emotion from the neutral state to other basic emotions. The simulation result is proved to correspond to emotion-switching law of human beings.

  9. Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

    Science.gov (United States)

    Oláh, Julianna; Mulholland, Adrian J.; Harvey, Jeremy N.

    2011-01-01

    Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical–molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism. PMID:21444768

  10. Modelling Drug Administration Regimes for Asthma: A Romanian Experience

    Science.gov (United States)

    Andras, Szilard; Szilagyi, Judit

    2010-01-01

    In this article, we present a modelling activity, which was a part of the project DQME II (Developing Quality in Mathematics Education, for more details see http://www.dqime.uni-dortmund.de) and some general observations regarding the maladjustments and rational errors arising in such type of activities.

  11. Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

    Science.gov (United States)

    Oh, Jin Sun; Kwon, Yong Seok; Lee, Kyung Ho; Jeong, Woowon; Chung, Sang Kug; Rhee, Kyehan

    2014-01-01

    Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue. © 2013 Published by Elsevier Ltd.

  12. Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

    Science.gov (United States)

    Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

    2018-04-19

    Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

  13. Glutathione metabolism modelling: a mechanism for liver drug-robustness and a new biomarker strategy

    NARCIS (Netherlands)

    Geenen, S.; du Preez, F.B.; Snoep, J.L.; Foster, A.J.; Sarda, S.; Kenna, J.G.; Wilson, I.D.; Westerhoff, H.V.

    2013-01-01

    Background Glutathione metabolism can determine an individual's ability to detoxify drugs. To increase understanding of the dynamics of cellular glutathione homeostasis, we have developed an experiment-based mathematical model of the kinetics of the glutathione network. This model was used to

  14. Monitoring alert and drowsy states by modeling EEG source nonstationarity

    Science.gov (United States)

    Hsu, Sheng-Hsiou; Jung, Tzyy-Ping

    2017-10-01

    Objective. As a human brain performs various cognitive functions within ever-changing environments, states of the brain characterized by recorded brain activities such as electroencephalogram (EEG) are inevitably nonstationary. The challenges of analyzing the nonstationary EEG signals include finding neurocognitive sources that underlie different brain states and using EEG data to quantitatively assess the state changes. Approach. This study hypothesizes that brain activities under different states, e.g. levels of alertness, can be modeled as distinct compositions of statistically independent sources using independent component analysis (ICA). This study presents a framework to quantitatively assess the EEG source nonstationarity and estimate levels of alertness. The framework was tested against EEG data collected from 10 subjects performing a sustained-attention task in a driving simulator. Main results. Empirical results illustrate that EEG signals under alert versus drowsy states, indexed by reaction speeds to driving challenges, can be characterized by distinct ICA models. By quantifying the goodness-of-fit of each ICA model to the EEG data using the model deviation index (MDI), we found that MDIs were significantly correlated with the reaction speeds (r  =  -0.390 with alertness models and r  =  0.449 with drowsiness models) and the opposite correlations indicated that the two models accounted for sources in the alert and drowsy states, respectively. Based on the observed source nonstationarity, this study also proposes an online framework using a subject-specific ICA model trained with an initial (alert) state to track the level of alertness. For classification of alert against drowsy states, the proposed online framework achieved an averaged area-under-curve of 0.745 and compared favorably with a classic power-based approach. Significance. This ICA-based framework provides a new way to study changes of brain states and can be applied to

  15. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    Science.gov (United States)

    de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

    2016-01-01

    Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

  16. Drug development costs when financial risk is measured using the Fama-French three-factor model.

    Science.gov (United States)

    Vernon, John A; Golec, Joseph H; Dimasi, Joseph A

    2010-08-01

    In a widely cited article, DiMasi, Hansen, and Grabowski (2003) estimate the average pre-tax cost of bringing a new molecular entity to market. Their base case estimate, excluding post-marketing studies, was $802 million (in $US 2000). Strikingly, almost half of this cost (or $399 million) is the cost of capital (COC) used to fund clinical development expenses to the point of FDA marketing approval. The authors used an 11% real COC computed using the capital asset pricing model (CAPM). But the CAPM is a single factor risk model, and multi-factor risk models are the current state of the art in finance. Using the Fama-French three factor model we find that the cost of drug development to be higher than the earlier estimate. Copyright (c) 2009 John Wiley & Sons, Ltd.

  17. Connecting the Kuramoto Model and the Chimera State

    Science.gov (United States)

    Kotwal, Tejas; Jiang, Xin; Abrams, Daniel M.

    2017-12-01

    Since its discovery in 2002, the chimera state has frequently been described as a counterintuitive, puzzling phenomenon. The Kuramoto model, in contrast, has become a celebrated paradigm useful for understanding a range of phenomena related to phase transitions, synchronization, and network effects. Here we show that the chimera state can be understood as emerging naturally through a symmetry-breaking bifurcation from the Kuramoto model's partially synchronized state. Our analysis sheds light on recent observations of chimera states in laser arrays, chemical oscillators, and mechanical pendula.

  18. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  19. How modeling and simulation have enhanced decision making in new drug development.

    Science.gov (United States)

    Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

    2005-04-01

    The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug

  20. Prediction of drug terminal half-life and terminal volume of distribution after intravenous dosing based on drug clearance, steady-state volume of distribution, and physiological parameters of the body.

    Science.gov (United States)

    Berezhkovskiy, Leonid M

    2013-02-01

    The steady state, V(ss), terminal volume of distribution, V(β), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(β) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(β)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter. Copyright © 2012 Wiley Periodicals, Inc.

  1. Wave Modelling - The State of the Art

    Science.gov (United States)

    2007-09-27

    8217) - -16 C-Ax( M) (I - 2y) -N +1CgAx’(1 -y)(6y’ - 6y + 1) + O(At4), (8.2) 24OX where p is the Courant- Friedrichs -Lewy (CFL) number, j = CgxAt/Ax. Thus...attainable time step is at the best of the order of min- utes . For early third generation wave models, this was unacceptable, and methods were developed to be... Barbara Channel. In: Beal, R. (Ed.), 5th California Islands Symposium, March 29-31. Mineral Management Service, Santa Barbara , CA. Onorato, M., Osborne

  2. Mining adverse drug reactions from online healthcare forums using hidden Markov model.

    Science.gov (United States)

    Sampathkumar, Hariprasad; Chen, Xue-wen; Luo, Bo

    2014-10-23

    Adverse Drug Reactions are one of the leading causes of injury or death among patients undergoing medical treatments. Not all Adverse Drug Reactions are identified before a drug is made available in the market. Current post-marketing drug surveillance methods, which are based purely on voluntary spontaneous reports, are unable to provide the early indications necessary to prevent the occurrence of such injuries or fatalities. The objective of this research is to extract reports of adverse drug side-effects from messages in online healthcare forums and use them as early indicators to assist in post-marketing drug surveillance. We treat the task of extracting adverse side-effects of drugs from healthcare forum messages as a sequence labeling problem and present a Hidden Markov Model(HMM) based Text Mining system that can be used to classify a message as containing drug side-effect information and then extract the adverse side-effect mentions from it. A manually annotated dataset from http://www.medications.com is used in the training and validation of the HMM based Text Mining system. A 10-fold cross-validation on the manually annotated dataset yielded on average an F-Score of 0.76 from the HMM Classifier, in comparison to 0.575 from the Baseline classifier. Without the Plain Text Filter component as a part of the Text Processing module, the F-Score of the HMM Classifier was reduced to 0.378 on average, while absence of the HTML Filter component was found to have no impact. Reducing the Drug names dictionary size by half, on average reduced the F-Score of the HMM Classifier to 0.359, while a similar reduction to the side-effects dictionary yielded an F-Score of 0.651 on average. Adverse side-effects mined from http://www.medications.com and http://www.steadyhealth.com were found to match the Adverse Drug Reactions on the Drug Package Labels of several drugs. In addition, some novel adverse side-effects, which can be potential Adverse Drug Reactions, were also

  3. Computational modeling of drug-resistant bacteria. Final report

    International Nuclear Information System (INIS)

    2015-01-01

    Initial proposal summary: The evolution of antibiotic-resistant mutants among bacteria (superbugs) is a persistent and growing threat to public health. In many ways, we are engaged in a war with these microorganisms, where the corresponding arms race involves chemical weapons and biological targets. Just as advances in microelectronics, imaging technology and feature recognition software have turned conventional munitions into smart bombs, the long-term objectives of this proposal are to develop highly effective antibiotics using next-generation biomolecular modeling capabilities in tandem with novel subatomic feature detection software. Using model compounds and targets, our design methodology will be validated with correspondingly ultra-high resolution structure-determination methods at premier DOE facilities (single-crystal X-ray diffraction at Argonne National Laboratory, and neutron diffraction at Oak Ridge National Laboratory). The objectives and accomplishments are summarized.

  4. Computational modeling of drug-resistant bacteria. Final report

    Energy Technology Data Exchange (ETDEWEB)

    MacDougall, Preston [Middle Tennessee State Univ., Murfreesboro, TN (United States)

    2015-03-12

    Initial proposal summary: The evolution of antibiotic-resistant mutants among bacteria (superbugs) is a persistent and growing threat to public health. In many ways, we are engaged in a war with these microorganisms, where the corresponding arms race involves chemical weapons and biological targets. Just as advances in microelectronics, imaging technology and feature recognition software have turned conventional munitions into smart bombs, the long-term objectives of this proposal are to develop highly effective antibiotics using next-generation biomolecular modeling capabilities in tandem with novel subatomic feature detection software. Using model compounds and targets, our design methodology will be validated with correspondingly ultra-high resolution structure-determination methods at premier DOE facilities (single-crystal X-ray diffraction at Argonne National Laboratory, and neutron diffraction at Oak Ridge National Laboratory). The objectives and accomplishments are summarized.

  5. The job demands-resources model : state of the art

    NARCIS (Netherlands)

    Bakker, A.B.; Demerouti, E.

    2007-01-01

    Purpose - The purpose of this paper is to give a state-of-the art overview of the Job Demands-Resources (JD-R) model Design/methodology/approach - The strengths and weaknesses of the demand-control model and the effort-reward imbalance model regarding their predictive value for employee well being

  6. Modeling all-solid-state Li-ion batteries

    NARCIS (Netherlands)

    Danilov, D.; Niessen, R.A.H.; Notten, P.H.L.

    2011-01-01

    A mathematical model for all-solid-state Li-ion batteries is presented. The model includes the charge transfer kinetics at the electrode/electrolyte interface, diffusion of lithium in the intercalation electrode, and diffusion and migration of ions in the electrolyte. The model has been applied to

  7. Tutorial in biostatistics: competing risks and multi-state models

    NARCIS (Netherlands)

    Putter, H.; Fiocco, M.; Geskus, R. B.

    2007-01-01

    Standard survival data measure the time span from some time origin until the occurrence of one type of event. If several types of events occur, a model describing progression to each of these competing risks is needed. Multi-state models generalize competing risks models by also describing

  8. Pharmacogenetics of antidepressant drugs: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics.

    Science.gov (United States)

    Quaranta, Sylvie; Dupouey, Julien; Colle, Romain; Verstuyft, Céline

    2017-04-01

    Tailoring antidepressant drug therapy to each individual patient is a complex process because these drugs have adverse effects leading to discontinuation. Pharmacogenetics may provide useful information in routine practice for optimizing antidepressant treatment by helping limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for P450 cytochromes CYP2C19 and CYP2D6 in psychiatric patients taking antidepressants. Depending on the level of evidence, the French National Network of Pharmacogenetics (RNPGx) has issued recommendations stating that pharmacogenetic tests for CYP2D6 and CYP2C19 genes are potentially useful in psychiatric patients treated with antidepressant drugs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  9. Tumor Growth Model with PK Input for Neuroblastoma Drug Development

    Science.gov (United States)

    2015-09-01

    Your credit card order has been processed on  Tuesday  2 December 2014 at 3:05 PM. Status: Complete 12/3/2014 Oasis, The Online Abstract Submission System...pharmacokinetic models. Toxicol Ind Health, 1997. 13(4): p. 407-84. PMID: 9249929 4. Davies, B. and T. Morris , Physiological parameters in laboratory animals and humans. Pharm Res, 1993. 10(7): p. 1093-5. PMID: 8378254

  10. Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging.

    Science.gov (United States)

    Nader, Michael A; Banks, Matthew L

    2014-01-01

    The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Cognitive Enhancers for Facilitating Drug Cue Extinction: Insights from Animal Models

    Science.gov (United States)

    Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M.

    2011-01-01

    Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. PMID:21295059

  12. A stochastic multicriteria model for evidence-based decision making in drug benefit-risk analysis.

    Science.gov (United States)

    Tervonen, Tommi; van Valkenhoef, Gert; Buskens, Erik; Hillege, Hans L; Postmus, Douwe

    2011-05-30

    Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multi-criteria model that fully takes into account the evidence on efficacy and adverse drug reactions. Our approach is based on the stochastic multi-criteria acceptability analysis methodology, which allows us to compute the typical value judgments that support a decision, to quantify decision uncertainty, and to compute a comprehensive BR profile. We construct a multi-criteria model for the therapeutic group of second-generation antidepressants. We assess fluoxetine and venlafaxine together with placebo according to incidence of treatment response and three common adverse drug reactions by using data from a published study. Our model shows that there are clear trade-offs among the treatment alternatives. Copyright © 2011 John Wiley & Sons, Ltd.

  13. Modelling Illicit Drug Fate in Sewers for Wastewater-Based Epidemiology

    DEFF Research Database (Denmark)

    Ramin, Pedram

    was found during festival period as compared to normal weekdays. Wastewater-based epidemiology is a truly interdisciplinary approach in which engineering tools, including models developed and tested in this thesis, can be beneficial for the accurate estimation of drug consumption in urban areas........ Sewer systems can be considered as biological reactors, in which the concentration of organic chemicals present in wastewater can be impacted by in-sewer processes during hydraulic residence time. Illicit drug biomarkers, as trace organic chemicals in the range of nanograms to micrograms per liter...... on sorption and transformation of drug biomarkers in raw wastewater and sewer biofilms; and (ii) developing modelling tools – by combining and extending existing modelling frameworks – to predict such processes. To achieve this goal, a substantial part of this thesis was dedicated to the experimental...

  14. A Model of Consumer Response to Over-the-Counter Drug Advertising: Antecedents and Influencing Factors.

    Science.gov (United States)

    Huh, Jisu; Delorme, Denise E; Reid, Leonard N

    2016-01-01

    Given the importance of over-the-counter (OTC) drugs in the health care marketplace and lack of systematic research on OTC drug advertising (OTCA) effects, this study tested a theory-based, product category-specific OTCA effects model. Structural equation modeling analysis of data for 1 OTC drug category, analgesics, supported the proposed model, explaining the OTCA effect process from key consumer antecedents to ad involvement, from ad involvement to ad attention, from ad attention to cognitive responses, then to affective/evaluative responses, leading to the final behavioral outcome. Several noteworthy patterns also emerged: (a) Product involvement was directly linked to ad attention, rather than exerting an indirect influence through ad involvement; (b) ad attention was significantly related to both cognitive and affective/evaluative responses to different degrees, with stronger links to cognitive responses; and (c) ad-prompted actions were influenced by both ad trust and ad attitude.

  15. Drug per se laws: a review of their use in the states : traffic tech.

    Science.gov (United States)

    2010-09-01

    Research has indicated that per se laws for alcohol have been : effective in reducing alcohol-related fatalities. A difficulty : in prosecuting drivers for driving impaired by drugs other : than alcohol is that there is no scientific basis for specif...

  16. State of the art of nanocrystals technology for delivery of poorly soluble drugs

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yuqi; Du, Juan; Wang, Lulu; Wang, Yancai, E-mail: wangyancai1999@163.com [Qilu University of Technology, School of Chemistry and Pharmaceutical Engineering (China)

    2016-09-15

    Formulation of nanocrystals is a distinctive approach which can effectively improve the delivery of poorly water-soluble drugs, thus enticing the development of the nanocrystals technology. The characteristics of nanocrystals resulted in an exceptional drug delivery conductance, including saturation solubility, dissolution velocity, adhesiveness, and affinity. Nanocrystals were treated as versatile pharmaceuticals that could be delivered through almost all routes of administration. In the current review, oral, pulmonary, and intravenous routes of administration were presented. Also, the targeting of drug nanocrystals, as well as issues of efficacy and safety, were also discussed. Several methods were applied for nanocrystals production including top-down production strategy (media milling, high-pressure homogenization), bottom-up production strategy (antisolvent precipitation, supercritical fluid process, and precipitation by removal of solvent), and the combination approaches. Moreover, this review also described the evaluation and characterization of the drug nanocrystals and summarized the current commercial pharmaceutical products utilizing nanocrystals technology.

  17. Tuberculosis drug resistance isolates from pulmonary tuberculosis patients, Kassala State, Sudan

    Directory of Open Access Journals (Sweden)

    Fatima A Khalid

    2015-01-01

    This study revealed that high resistance to rifampicin was associated with various point mutations in and out of the RRDR of the rpoB gene. Molecular methods are needed for early detection of TB disease and drug resistance.

  18. Modeling of drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls to treat vulnerable plaques

    KAUST Repository

    Hossain, Shaolie S.; Hossainy, Syed F A; Bazilevs, Yuri; Calo, Victor M.; Hughes, Thomas Jr R

    2010-01-01

    The main objective of this work is to develop computational tools to support the design of a catheter-based local drug delivery system that uses nanoparticles as drug carriers in order to treat vulnerable plaques and diffuse atherosclerotic disease.

  19. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    Directory of Open Access Journals (Sweden)

    N. B. Molchanova

    2015-01-01

    Full Text Available Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII. The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the modeling of market volume we have used the data about the number of hamophilia A patients on the basis of the federal registry, Russian and international morbidity indices, and the data of a real practice about average consumption of drugs of bloodcoagulation factors and data about the drugs prescription according to the standards and protocols of assistance rendering. According to the standards of care delivery, average annual volume of FVIII drugs consumption amounted to 406 325 244 IU for children and 964 578 678 IU for adults, i.e. an average volume of a “perfect” market is equal to 1 370 903 922 IU for all patients. The market volume is 1.8 times bigger than a real volume of FVIII drugs which, according to the data of IMS marketing agency, amounted to 765 000 000 IU in 2013. The modeling conducted has shown that despite a relatively high patients’ coverage there is a potential for almost double growth.

  20. Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

    Science.gov (United States)

    Ioset, Jean-Robert; Chang, Shing

    2011-09-01

    The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

  1. State of the art in hair analysis for detection of drug and alcohol abuse.

    Science.gov (United States)

    Pragst, Fritz; Balikova, Marie A

    2006-08-01

    Hair differs from other materials used for toxicological analysis because of its unique ability to serve as a long-term storage of foreign substances with respect to the temporal appearance in blood. Over the last 20 years, hair testing has gained increasing attention and recognition for the retrospective investigation of chronic drug abuse as well as intentional or unintentional poisoning. In this paper, we review the physiological basics of hair growth, mechanisms of substance incorporation, analytical methods, result interpretation and practical applications of hair analysis for drugs and other organic substances. Improved chromatographic-mass spectrometric techniques with increased selectivity and sensitivity and new methods of sample preparation have improved detection limits from the ng/mg range to below pg/mg. These technical advances have substantially enhanced the ability to detect numerous drugs and other poisons in hair. For example, it was possible to detect previous administration of a single very low dose in drug-facilitated crimes. In addition to its potential application in large scale workplace drug testing and driving ability examination, hair analysis is also used for detection of gestational drug exposure, cases of criminal liability of drug addicts, diagnosis of chronic intoxication and in postmortem toxicology. Hair has only limited relevance in therapy compliance control. Fatty acid ethyl esters and ethyl glucuronide in hair have proven to be suitable markers for alcohol abuse. Hair analysis for drugs is, however, not a simple routine procedure and needs substantial guidelines throughout the testing process, i.e., from sample collection to results interpretation.

  2. Incentives for orphan drug research and development in the United States.

    Science.gov (United States)

    Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Szeinbach, Sheryl L; Visaria, Jay

    2008-12-16

    The Orphan Drug Act (1983) established several incentives to encourage the development of orphan drugs (ODs) to treat rare diseases and conditions. This study analyzed the characteristics of OD designations, approvals, sponsors, and evaluated the effective patent and market exclusivity life of orphan new molecular entities (NMEs) approved in the US between 1983 and 2007. Primary data sources were the FDA Orange Book, the FDA Office of Orphan Drugs Development, and the US Patent and Trademark Office. Data included all orphan designations and approvals listed by the FDA and all NMEs approved by the FDA during the study period. The FDA listed 1,793 orphan designations and 322 approvals between 1983 and 2007. Cancer was the main group of diseases targeted for orphan approvals. Eighty-three companies concentrated 67.7% of the total orphan NMEs approvals. The average time from orphan designation to FDA approval was 4.0 +/- 3.3 years (mean +/- standard deviation). The average maximum effective patent and market exclusivity life was 11.7 +/- 5.0 years for orphan NME. OD market exclusivity increased the average maximum effective patent and market exclusivity life of ODs by 0.8 years. Public programs, federal regulations, and policies support orphan drugs R&D. Grants, research design support, FDA fee waivers, tax incentives, and orphan drug market exclusivity are the main incentives for orphan drug R&D. Although the 7-year orphan drug market exclusivity provision had a positive yet relatively modest overall effect on effective patent and market exclusivity life, economic incentives and public support mechanisms provide a platform for continued orphan drug development for a highly specialized market.

  3. Deep-lying hole states in the optical model

    International Nuclear Information System (INIS)

    Klevansky, S.P.; Lemmer, R.H.

    1982-01-01

    The strength function for deep-lying hole states in an optical potential is studied by the method of Green's functions. The role of isospin is emphasized. It is shown that, while the main trends of the experimental data on hole states in isotopes of Sn and Pd can be described by an energy independent optical potential, intermediate structures in these data indicate the specific nuclear polarization effects have to be included. This is done by introducing doorway states of good isospin into the optical model potential. Such states consist of neutron hole plus proton core vibrations as well as more complicated excitations that are analog states of proton hole plus neutron core vibrations of the parent nuclear system. Specific calculations for 115 Sn and 103 Pd give satisfactory fits to the strength function data using optical model and doorway state parameters that are reasonable on physical grounds

  4. Analysis of access to hypertensive and diabetic drugs in the Family Health Strategy, State of Pernambuco, Brazil.

    Science.gov (United States)

    Barreto, Maria Nelly Sobreira de Carvalho; Cesse, Eduarda Ângela Pessoa; Lima, Rodrigo Fonseca; Marinho, Michelly Geórgia da Silva; Specht, Yuri da Silva; de Carvalho, Eduardo Maia Freese; Fontbonne, Annick

    2015-01-01

    To evaluate the access to drugs for hypertension and diabetes and the direct cost of buying them among users of the Family Health Strategy (FHS) in the state of Pernambuco, Brazil. Population-based, cross-sectional study of a systematic random sample of 785 patients with hypertension and 823 patients with diabetes mellitus who were registered in 208 randomly selected FHS teams in 35 municipalities of the state of Pernambuco. The selected municipalities were classified into three levels with probability proportional to municipality size (LS, large-sized; MS, medium-sized; SS, small-sized). To verify differences between the cities, we used the χ2 test. Pharmacological treatment was used by 91.2% patients with hypertension whereas 85.6% patients with diabetes mellitus used oral antidiabetic drugs (OADs), and 15.4% used insulin. The FHS team itself provided antihypertensive medications to 69.0% patients with hypertension, OADs to 75.0% patients with diabetes mellitus, and insulin treatment to 65.4%. The 36.9% patients with hypertension and 29.8% with diabetes mellitus that had to buy all or part of their medications reported median monthly cost of R$ 18.30, R$ 14.00, and R$ 27.61 for antihypertensive drugs, OADs, and insulin, respectively. It is necessary to increase efforts to ensure access to these drugs in the primary health care network.

  5. Analysis of access to hypertensive and diabetic drugs in the Family Health Strategy, State of Pernambuco, Brazil

    Directory of Open Access Journals (Sweden)

    Maria Nelly Sobreira de Carvalho Barreto

    2015-06-01

    Full Text Available OBJECTIVE: To evaluate the access to drugs for hypertension and diabetes and the direct cost of buying them among users of the Family Health Strategy (FHS in the state of Pernambuco, Brazil.METHODS: Population-based, cross-sectional study of a systematic random sample of 785 patients with hypertension and 823 patients with diabetes mellitus who were registered in 208 randomly selected FHS teams in 35 municipalities of the state of Pernambuco. The selected municipalities were classified into three levels with probability proportional to municipality size (LS, large-sized; MS, medium-sized; SS, small-sized. To verify differences between the cities, we used the χ2 test.RESULTS: Pharmacological treatment was used by 91.2% patients with hypertension whereas 85.6% patients with diabetes mellitus used oral antidiabetic drugs (OADs, and 15.4% used insulin. The FHS team itself provided antihypertensive medications to 69.0% patients with hypertension, OADs to 75.0% patients with diabetes mellitus, and insulin treatment to 65.4%. The 36.9% patients with hypertension and 29.8% with diabetes mellitus that had to buy all or part of their medications reported median monthly cost of R$ 18.30, R$ 14.00, and R$ 27.61 for antihypertensive drugs, OADs, and insulin, respectively.CONCLUSION: It is necessary to increase efforts to ensure access to these drugs in the primary health care network.

  6. Application of Fused Deposition Modelling (FDM) Method of 3D Printing in Drug Delivery.

    Science.gov (United States)

    Long, Jingjunjiao; Gholizadeh, Hamideh; Lu, Jun; Bunt, Craig; Seyfoddin, Ali

    2017-01-01

    Three-dimensional (3D) printing is an emerging manufacturing technology for biomedical and pharmaceutical applications. Fused deposition modelling (FDM) is a low cost extrusion-based 3D printing technique that can deposit materials layer-by-layer to create solid geometries. This review article aims to provide an overview of FDM based 3D printing application in developing new drug delivery systems. The principle methodology, suitable polymers and important parameters in FDM technology and its applications in fabrication of personalised tablets and drug delivery devices are discussed in this review. FDM based 3D printing is a novel and versatile manufacturing technique for creating customised drug delivery devices that contain accurate dose of medicine( s) and provide controlled drug released profiles. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  8. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  9. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  10. Formulating state space models in R with focus on longitudinal regression models

    DEFF Research Database (Denmark)

    Dethlefsen, Claus; Lundbye-Christensen, Søren

      We provide a language for formulating a range of state space models. The described methodology is implemented in the R -package sspir available from cran.r-project.org . A state space model is specified similarly to a generalized linear model in R , by marking the time-varying terms in the form......  We provide a language for formulating a range of state space models. The described methodology is implemented in the R -package sspir available from cran.r-project.org . A state space model is specified similarly to a generalized linear model in R , by marking the time-varying terms...

  11. Solvable model for chimera states of coupled oscillators.

    Science.gov (United States)

    Abrams, Daniel M; Mirollo, Rennie; Strogatz, Steven H; Wiley, Daniel A

    2008-08-22

    Networks of identical, symmetrically coupled oscillators can spontaneously split into synchronized and desynchronized subpopulations. Such chimera states were discovered in 2002, but are not well understood theoretically. Here we obtain the first exact results about the stability, dynamics, and bifurcations of chimera states by analyzing a minimal model consisting of two interacting populations of oscillators. Along with a completely synchronous state, the system displays stable chimeras, breathing chimeras, and saddle-node, Hopf, and homoclinic bifurcations of chimeras.

  12. Ground state energy fluctuations in the nuclear shell model

    International Nuclear Information System (INIS)

    Velazquez, Victor; Hirsch, Jorge G.; Frank, Alejandro; Barea, Jose; Zuker, Andres P.

    2005-01-01

    Statistical fluctuations of the nuclear ground state energies are estimated using shell model calculations in which particles in the valence shells interact through well-defined forces, and are coupled to an upper shell governed by random 2-body interactions. Induced ground-state energy fluctuations are found to be one order of magnitude smaller than those previously associated with chaotic components, in close agreement with independent perturbative estimates based on the spreading widths of excited states

  13. Quantum catalysis : the modelling of catalytic transition states

    NARCIS (Netherlands)

    Hall, M.B.; Margl, P.; Naray-Szabo, G.; Schramm, Vern; Truhlar, D.G.; Santen, van R.A.; Warshel, A.; Whitten, J.L.; Truhlar, D.G.; Morokuma, K.

    1999-01-01

    A review with 101 refs.; we present an introduction to the computational modeling of transition states for catalytic reactions. We consider both homogeneous catalysis and heterogeneous catalysis, including organometallic catalysts, enzymes, zeolites and metal oxides, and metal surfaces. We summarize

  14. In vitro models to evaluate the permeability of poorly soluble drug entities: Challenges and perspectives

    DEFF Research Database (Denmark)

    Buckley, S. T.; Fischer, S. M.; Fricker, G.

    2012-01-01

    The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However, in their......The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However...

  15. Effect of drugs of abuse on social behaviour: a review of animal models.

    Science.gov (United States)

    Blanco-Gandía, Maria C; Mateos-García, Ana; García-Pardo, Maria P; Montagud-Romero, Sandra; Rodríguez-Arias, Marta; Miñarro, José; Aguilar, María A

    2015-09-01

    Social behaviour is disturbed in many substance abuse and psychiatric disorders. Given the consensus that social behaviours of lower mammals may help to understand some human emotional reactions, the aim of the present work was to provide an up-to-date review of studies on the changes in social behaviour induced by drugs of abuse. Various animal models have been used to study the relationship between drugs of abuse and social behaviour. Herein, we describe the effects of different substances of abuse on the three most commonly used animal models of social behaviour: the social play test, the social interaction test and the resident-intruder paradigm. The first is the most widely used test to assess adolescent behaviour in rodents, the second is generally used to evaluate a wide repertoire of behaviours in adulthood and the latter is specific to aggressive behaviour. Throughout the review we will explore the most relevant studies carried out to date to evaluate the effects of alcohol, cocaine, opioids, 3,4-methylenedioxymethamphetamine (MDMA), cannabinoids, nicotine and other drugs of abuse on these three paradigms, taking into account the influence of different variables, such as social history, age and type of exposure. Drugs of diverse pharmacological classes induce alterations in social behaviour, although they can be contrasting depending on several factors (drug, individual differences and environmental conditions). Ethanol and nicotine increase social interaction at low doses but reduce it at high doses. Psychostimulants, MDMA and cannabinoids reduce social interaction, whereas opiates increase it. Ethanol and psychostimulants enhance aggression, whereas MDMA, opiates, cannabinoids and nicotine reduce it. Prenatal drug exposure alters social behaviour, whereas drug withdrawal decreases sociability and enhances aggression. As a whole, this evidence has improved our understanding of the social dimension of drug addiction.

  16. State Space Reduction for Model Checking Agent Programs

    NARCIS (Netherlands)

    S.-S.T.Q. Jongmans (Sung-Shik); K.V. Hindriks; M.B. van Riemsdijk; L. Dennis; O. Boissier; R.H. Bordini (Rafael)

    2012-01-01

    htmlabstractState space reduction techniques have been developed to increase the efficiency of model checking in the context of imperative programming languages. Unfortunately, these techniques cannot straightforwardly be applied to agents: the nature of states in the two programming paradigms

  17. Ground state phase diagram of extended attractive Hubbard model

    International Nuclear Information System (INIS)

    Robaszkiewicz, S.; Chao, K.A.; Micnas, R.

    1980-08-01

    The ground state phase diagram of the extended Hubbard model with intraatomic attraction has been derived in the Hartree-Fock approximation formulated in terms of the Bogoliubov variational approach. For a given value of electron density, the nature of the ordered ground state depends essentially on the sign and the strength of the nearest neighbor coupling. (author)

  18. Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

    Science.gov (United States)

    Taipale, Heidi; Tanskanen, Antti; Koponen, Marjaana; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

    2016-01-01

    Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations. PMID:27785101

  19. Quantifying the levitation picture of extended states in lattice models

    OpenAIRE

    Pereira, Ana. L. C.; Schulz, P. A.

    2002-01-01

    The behavior of extended states is quantitatively analyzed for two-dimensional lattice models. A levitation picture is established for both white-noise and correlated disorder potentials. In a continuum limit window of the lattice models we find simple quantitative expressions for the extended states levitation, suggesting an underlying universal behavior. On the other hand, these results point out that the quantum Hall phase diagrams may be disorder dependent.

  20. Application of Prognostic Mesoscale Modeling in the Southeast United States

    International Nuclear Information System (INIS)

    Buckley, R.L.

    1999-01-01

    A prognostic model is being used to provide regional forecasts for a variety of applications at the Savannah River Site (SRS). Emergency response dispersion models available at SRS use the space and time-dependent meteorological data provided by this model to supplement local and regional observations. Output from the model is also used locally to aid in forecasting at SRS, and regionally in providing forecasts of the potential time and location of hurricane landfall within the southeast United States

  1. Modelling and simulation SSM: latest state of the art technology

    CSIR Research Space (South Africa)

    Jahajeeah, N

    2005-10-01

    Full Text Available as one phase ? One Phase model ?Wider volume solid fraction 0 – 1 ? Implementation in Power Law Cut-Off Model (PLCO) of Procast Supporting the Manufacturing and Materials Industry in its quest for global competitiveness Assumptions of the PLCO Model... and Materials Industry in its quest for global competitiveness Modelling and Simulation SSM Latest state of the art technology N Jahajeeah Supporting the Manufacturing and Materials Industry in its quest for global competitiveness BEHAVIOUR OF THIXOTROPIC...

  2. In Situ Lipolysis and Synchrotron Small-Angle X-ray Scattering for the Direct Determination of the Precipitation and Solid-State Form of a Poorly Water-Soluble Drug During Digestion of a Lipid-Based Formulation

    DEFF Research Database (Denmark)

    Khan, Jamal; Hawley, Adrian; Rades, Thomas

    2016-01-01

    In situ lipolysis and synchrotron small-angle X-ray scattering (SAXS) were used to directly detect and elucidate the solid-state form of precipitated fenofibrate from the digestion of a model lipid-based formulation (LBF). This method was developed in light of recent findings that indicate variab...... on drugs, and experimental conditions, which are anticipated to produce altered solid-state forms upon the precipitation of drug (i.e., polymorphs, amorphous forms, and salts). © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci....

  3. The New York State Bird Conservation Area (BCA) Program: A Model for the United States

    Science.gov (United States)

    M. F. Burger; D. J. Adams; T. Post; L. Sommers; B. Swift

    2005-01-01

    The New York State Bird Conservation Area (BCA) Program, modeled after the National Audubon Society?s Important Bird Areas Program, is based on legislation signed by Governor Pataki in 1997. New York is the first state in the nation to enact such a program. The BCA Program seeks to provide a comprehensive, ecosystem approach to conserving birds and their habitats on...

  4. Bayesian joint modelling of benefit and risk in drug development.

    Science.gov (United States)

    Costa, Maria J; Drury, Thomas

    2018-05-01

    To gain regulatory approval, a new medicine must demonstrate that its benefits outweigh any potential risks, ie, that the benefit-risk balance is favourable towards the new medicine. For transparency and clarity of the decision, a structured and consistent approach to benefit-risk assessment that quantifies uncertainties and accounts for underlying dependencies is desirable. This paper proposes two approaches to benefit-risk evaluation, both based on the idea of joint modelling of mixed outcomes that are potentially dependent at the subject level. Using Bayesian inference, the two approaches offer interpretability and efficiency to enhance qualitative frameworks. Simulation studies show that accounting for correlation leads to a more accurate assessment of the strength of evidence to support benefit-risk profiles of interest. Several graphical approaches are proposed that can be used to communicate the benefit-risk balance to project teams. Finally, the two approaches are illustrated in a case study using real clinical trial data. Copyright © 2018 John Wiley & Sons, Ltd.

  5. Modeling per capita state health expenditure variation: state-level characteristics matter.

    Science.gov (United States)

    Cuckler, Gigi; Sisko, Andrea

    2013-01-01

    In this paper, we describe the methods underlying the econometric model developed by the Office of the Actuary in the Centers for Medicare & Medicaid Services, to explain differences in per capita total personal health care spending by state, as described in Cuckler, et al. (2011). Additionally, we discuss many alternative model specifications to provide additional insights for valid interpretation of the model. We study per capita personal health care spending as measured by the State Health Expenditures, by State of Residence for 1991-2009, produced by the Centers for Medicare & Medicaid Services' Office of the Actuary. State-level demographic, health status, economic, and health economy characteristics were gathered from a variety of U.S. government sources, such as the Census Bureau, Bureau of Economic Analysis, the Centers for Disease Control, the American Hospital Association, and HealthLeaders-InterStudy. State-specific factors, such as income, health care capacity, and the share of elderly residents, are important factors in explaining the level of per capita personal health care spending variation among states over time. However, the slow-moving nature of health spending per capita and close relationships among state-level factors create inefficiencies in modeling this variation, likely resulting in incorrectly estimated standard errors. In addition, we find that both pooled and fixed effects models primarily capture cross-sectional variation rather than period-specific variation.

  6. Influence of pH on Drug Absorption from the Gastrointestinal Tract: A Simple Chemical Model

    Science.gov (United States)

    Hickman, Raymond J. S.; Neill, Jane

    1997-07-01

    A simple model of the gastrointestinal tract is obtained by placing ethyl acetate in contact with water at pH 2 and pH 8 in separate test tubes. The ethyl acetate corresponds to the lipid material lining the tract while the water corresponds to the aqueous contents of the stomach (pH 2) and intestine (pH 8). The compounds aspirin, paracetamol and 3-aminophenol are used as exemplars of acidic, neutral and basic drugs respectively to illustrate the influence which pH has on the distribution of each class of drug between the aqueous and organic phases of the model. The relative concentration of drug in the ethyl acetate is judged by applying microlitre-sized samples of ethyl acetate to a layer of fluorescent silica which, after evaporation of the ethyl acetate, is viewed under an ultraviolet lamp. Each of the three drugs, if present in the ethyl acetate, becomes visible as a dark spot on the silica layer. The observations made in the model system correspond well to the patterns of drug absorption from the gastrointestinal tract described in pharmacology texts and these observations are convincingly explained in terms of simple acid-base chemistry.

  7. Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001.

    Science.gov (United States)

    Wysowski, Diane K; Armstrong, George; Governale, Laura

    2003-06-01

    To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

  8. A detailed aerosol mixing state model for investigating interactions between mixing state, semivolatile partitioning, and coagulation

    OpenAIRE

    J. Lu; F. M. Bowman

    2010-01-01

    A new method for describing externally mixed particles, the Detailed Aerosol Mixing State (DAMS) representation, is presented in this study. This novel method classifies aerosols by both composition and size, using a user-specified mixing criterion to define boundaries between compositional populations. Interactions between aerosol mixing state, semivolatile partitioning, and coagulation are investigated with a Lagrangian box model that incorporates the DAMS approach. Model results predict th...

  9. A State Space Model for the Wood Chip Refining Model

    Directory of Open Access Journals (Sweden)

    David Di Ruscio

    1997-07-01

    Full Text Available A detailed dynamic model of the fibre size distribution between the refiner discs, distributed along the refiner radius, is presented. Both one- and two-dimensional descriptions for the fibre or shive geometry are given. It is shown that this model may be simplified and that analytic solutions exist under non-restrictive assumptions. A direct method for the recursive estimation of unknown parameters is presented. This method is applicable to linear or linearized systems which have a triangular structure.

  10. INTEGRATING GENETIC AND STRUCTURAL DATA ON HUMAN PROTEIN KINOME IN NETWORK-BASED MODELING OF KINASE SENSITIVITIES AND RESISTANCE TO TARGETED AND PERSONALIZED ANTICANCER DRUGS.

    Science.gov (United States)

    Verkhivker, Gennady M

    2016-01-01

    The human protein kinome presents one of the largest protein families that orchestrate functional processes in complex cellular networks, and when perturbed, can cause various cancers. The abundance and diversity of genetic, structural, and biochemical data underlies the complexity of mechanisms by which targeted and personalized drugs can combat mutational profiles in protein kinases. Coupled with the evolution of system biology approaches, genomic and proteomic technologies are rapidly identifying and charactering novel resistance mechanisms with the goal to inform rationale design of personalized kinase drugs. Integration of experimental and computational approaches can help to bring these data into a unified conceptual framework and develop robust models for predicting the clinical drug resistance. In the current study, we employ a battery of synergistic computational approaches that integrate genetic, evolutionary, biochemical, and structural data to characterize the effect of cancer mutations in protein kinases. We provide a detailed structural classification and analysis of genetic signatures associated with oncogenic mutations. By integrating genetic and structural data, we employ network modeling to dissect mechanisms of kinase drug sensitivities to oncogenic EGFR mutations. Using biophysical simulations and analysis of protein structure networks, we show that conformational-specific drug binding of Lapatinib may elicit resistant mutations in the EGFR kinase that are linked with the ligand-mediated changes in the residue interaction networks and global network properties of key residues that are responsible for structural stability of specific functional states. A strong network dependency on high centrality residues in the conformation-specific Lapatinib-EGFR complex may explain vulnerability of drug binding to a broad spectrum of mutations and the emergence of drug resistance. Our study offers a systems-based perspective on drug design by unravelling

  11. Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

    Directory of Open Access Journals (Sweden)

    Millard M

    2017-10-01

    Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

  12. State-space prediction model for chaotic time series

    Science.gov (United States)

    Alparslan, A. K.; Sayar, M.; Atilgan, A. R.

    1998-08-01

    A simple method for predicting the continuation of scalar chaotic time series ahead in time is proposed. The false nearest neighbors technique in connection with the time-delayed embedding is employed so as to reconstruct the state space. A local forecasting model based upon the time evolution of the topological neighboring in the reconstructed phase space is suggested. A moving root-mean-square error is utilized in order to monitor the error along the prediction horizon. The model is tested for the convection amplitude of the Lorenz model. The results indicate that for approximately 100 cycles of the training data, the prediction follows the actual continuation very closely about six cycles. The proposed model, like other state-space forecasting models, captures the long-term behavior of the system due to the use of spatial neighbors in the state space.

  13. A Learning State-Space Model for Image Retrieval

    Directory of Open Access Journals (Sweden)

    Lee Greg C

    2007-01-01

    Full Text Available This paper proposes an approach based on a state-space model for learning the user concepts in image retrieval. We first design a scheme of region-based image representation based on concept units, which are integrated with different types of feature spaces and with different region scales of image segmentation. The design of the concept units aims at describing similar characteristics at a certain perspective among relevant images. We present the details of our proposed approach based on a state-space model for interactive image retrieval, including likelihood and transition models, and we also describe some experiments that show the efficacy of our proposed model. This work demonstrates the feasibility of using a state-space model to estimate the user intuition in image retrieval.

  14. A systematic investigation of computation models for predicting Adverse Drug Reactions (ADRs.

    Directory of Open Access Journals (Sweden)

    Qifan Kuang

    Full Text Available Early and accurate identification of adverse drug reactions (ADRs is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs.In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper.Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms.

  15. A systematic investigation of computation models for predicting Adverse Drug Reactions (ADRs).

    Science.gov (United States)

    Kuang, Qifan; Wang, MinQi; Li, Rong; Dong, YongCheng; Li, Yizhou; Li, Menglong

    2014-01-01

    Early and accurate identification of adverse drug reactions (ADRs) is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs. In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper. Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms.

  16. Zebrafish as a potential model organism for drug test against hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Cun-Bao Ding

    Full Text Available Screening and evaluating anti- hepatitis C virus (HCV drugs in vivo is difficult worldwide, mainly because of the lack of suitable small animal models. We investigate whether zebrafish could be a model organism for HCV replication. To achieve NS5B-dependent replication an HCV sub-replicon was designed and created with two vectors, one with HCV ns5b and fluorescent rfp genes, and the other containing HCV's 5'UTR, core, 3'UTR and fluorescent gfp genes. The vectors containing sub-replicons were co-injected into zebrafish zygotes. The sub-replicon amplified in liver showing a significant expression of HCV core RNA and protein. The sub-replicon amplification caused no abnormality in development and growth of zebrafish larvae, but induced gene expression change similar to that in human hepatocytes. As the amplified core fluorescence in live zebrafish was detectable microscopically, it rendered us an advantage to select those with replicating sub-replicon for drug experiments. Ribavirin and oxymatrine, two known anti-HCV drugs, inhibited sub-replicon amplification in this model showing reduced levels of HCV core RNA and protein. Technically, this method had a good reproducibility and is easy to operate. Thus, zebrafish might be a model organism to host HCV, and this zebrafish/HCV (sub-replicon system could be an animal model for anti-HCV drug screening and evaluation.

  17. Colchicine in therapy. State of the art and new perspectives for an old drug.

    Science.gov (United States)

    Famaey, J P

    1988-01-01

    Colchicine is the most specific treatment in acute gouty attacks. In several European countries, oral colchicine is still used for routine treatment of acute gout. Its selectivity is used as a diagnostic tool. It is also active in the treatment of acute crises of chondrocalcinosis and more occasionally of other arthritic crises (e.g. sarcoidosis). Colchicine appears to be the necessary adjuvant prophylactic drug when starting a hypouricemic treatment with uricosuric or uricolytic drugs for avoiding acute gouty crisis due to sudden mobilisation of the uric acid pool. Besides gout, colchicine is the drug of choice for treating familial mediterranean fever. It appears to be helpful in the treatment of Behçet's disease. It seems also useful for treating fibrosing conditions such as liver cirrhosis and scleroderma. As an adjuvant therapy, it helps treating dermatological disorders which are associated with leucocyte migration as an essential pathogenic factor (e.g. psoriasis, dermatitis herpetiformis, necrotising vasculitis ...). It has been advocated as an adjuvant therapy in malignant diseases as a support in radiotherapy and as an useful drug in various other diseases where it has been tried occasionally (e.g. Paget's disease of the bone, idiopathic thrombocytopenic purpura, disc syndrome). This very old drug remains a modern therapeutic agent.

  18. Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study.

    Science.gov (United States)

    Brady, Oliver J; Slater, Hannah C; Pemberton-Ross, Peter; Wenger, Edward; Maude, Richard J; Ghani, Azra C; Penny, Melissa A; Gerardin, Jaline; White, Lisa J; Chitnis, Nakul; Aguas, Ricardo; Hay, Simon I; Smith, David L; Stuckey, Erin M; Okiro, Emelda A; Smith, Thomas A; Okell, Lucy C

    2017-07-01

    Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission. We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration. The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest. Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing

  19. HIV Prevention and Rehabilitation Models for Women Who Inject Drugs in Russia and Ukraine

    Directory of Open Access Journals (Sweden)

    Roman Yorick

    2012-01-01

    Full Text Available Women who inject drugs require gender-specific approaches to drug rehabilitation, modification of risk behaviors, and psychosocial adaptation. Improved outcomes have been demonstrated when the specific needs of women’s subpopulations have been addressed. Special services for women include prenatal care, child care, women-only programs, supplemental workshops on women-focused topics, mental health services, and comprehensive programs that include several of the above components. To address the special needs of women injecting drug user (IDU subpopulations, such as HIV-positive pregnant women and women with young children, recently released female prisoners, and street-involved girls and young women, HealthRight International and its local partners in Russia and Ukraine have developed innovative service models. This paper presents each of these models and discusses their effectiveness and implementation challenges specific to local contexts in Russia and Ukraine.

  20. Experimental methods and transport models for drug delivery across the blood-brain barrier.

    Science.gov (United States)

    Fu, Bingmei M

    2012-06-01

    The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the micro-environment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood-born neurotoxins, however, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. This review summarized the unique structures of the BBB, described a variety of in vivo and in vitro experimental methods for determining the transport properties of the BBB, e.g., the permeability of the BBB to water, ions, and solutes including nutrients, therapeutic agents and drug carriers, and presented newly developed mathematical models which quantitatively correlate the anatomical structures of the BBB with its barrier functions. Finally, on the basis of the experimental observations and the quantitative models, several strategies for drug delivery through the BBB were proposed.

  1. Dual process interaction model of HIV-risk behaviors among drug offenders.

    Science.gov (United States)

    Ames, Susan L; Grenard, Jerry L; Stacy, Alan W

    2013-03-01

    This study evaluated dual process interaction models of HIV-risk behavior among drug offenders. A dual process approach suggests that decisions to engage in appetitive behaviors result from a dynamic interplay between a relatively automatic associative system and an executive control system. One synergistic type of interplay suggests that executive functions may dampen or block effects of spontaneously activated associations. Consistent with this model, latent variable interaction analyses revealed that drug offenders scoring higher in affective decision making were relatively protected from predictive effects of spontaneous sex associations promoting risky sex. Among drug offenders with lower levels of affective decision making ability, spontaneous sexually-related associations more strongly predicted risky sex (lack of condom use and greater number of sex partners). These findings help elucidate associative and control process effects on appetitive behaviors and are important for explaining why some individuals engage in risky sex, while others are relatively protected.

  2. What is a new drug worth? An innovative model for performance-based pricing.

    Science.gov (United States)

    Dranitsaris, G; Dorward, K; Owens, R C; Schipper, H

    2015-05-01

    This article focuses on a novel method to derive prices for new pharmaceuticals by making price a function of drug performance. We briefly review current models for determining price for a new product and discuss alternatives that have historically been favoured by various funding bodies. The progressive approach to drug pricing, proposed herein, may better address the views and concerns of multiple stakeholders in a developed healthcare system by acknowledging and incorporating input from disparate parties via comprehensive and successive negotiation stages. In proposing a valid construct for performance-based pricing, the following model seeks to achieve several crucial objectives: earlier and wider access to new treatments; improved transparency in drug pricing; multi-stakeholder involvement through phased pricing negotiations; recognition of innovative product performance and latent changes in value; an earlier and more predictable return for developers without sacrificing total return on investment (ROI); more involved and informed risk sharing by the end-user. © 2014 John Wiley & Sons Ltd.

  3. Rethinking 'flexibilities' in the international drug control system-Potential, precedents and models for reforms.

    Science.gov (United States)

    Collins, John

    2017-01-24

    Much international drug policy debate centres on, what policies are permissible under the international drug treaties, whether member states are openly 'breaching' these treaties by changing national regulatory frameworks and shifting priorities away from a 'war on drugs' approach, and what 'flexibility' exists for policy reform and experimentation at national and local levels. Orthodox interpretations hold that the current system is a US-led 'prohibition regime' that was constructed in an extremely repressive and restrictive manner with almost no flexibility for significant national deviations. This paper challenges these orthodox interpretive frameworks and suggests no absolute and clear dichotomy between strict adherence and 'breaches' of the international treaties. This paper uses historical analysis to highlight the flaws in orthodox policy analyses, which assume a uniform interpretation, implementation and set of policy trajectories towards a 'prohibition regime' in the 20th century. It challenges some existing legal interpretations of the treaties through recourse to historical precedents of flexible interpretation and policy prioritisation. It then examines the legal justifications currently being formulated by member states to explain a shift towards policies which, until recently, have been viewed as outside the permissible scope of the conventions. It then examines a functionalist framework for understanding the likely contours of drug diplomacy in the post-UN General Assembly Special Session (UNGASS) 2016 era. The paper highlights that, contrary to current policy discourses, the international control system has always been implemented in a 'flexible' manner. It demonstrates that drug control goals were repeatedly subsumed to security, development, political stability and population welfare imperatives, or what we might now refer to under the umbrella of 'development issues.' The paper further demonstrates that policy prioritisation, inherent treaty

  4. Primary and secondary anti-tuberculosis drug resistance in Hitossa District of Arsi Zone, Oromia Regional State, Central Ethiopia

    Directory of Open Access Journals (Sweden)

    Shallo Daba Hamusse

    2016-07-01

    Full Text Available Abstract Background Multidrug-resistant tuberculosis (MDR-TB drugs which is resistant to the major first-line anti-TB drugs, Isoniazid and Rifampicin, has become a major global challenge in tuberculosis (TB control programme. However, its burden at community level is not well known. Thus, the aim of study was to assess the prevalence of primary and secondary resistance to any first line anti-TB drugs and MDR TB in Hitossa District of Oromia Regional State, Central Ethiopia. Methods Population based cross- sectional study was conducted on individuals aged ≥15 years. Those with symptoms suggestive of TB were interviewed and two sputum specimens were collected from each and examined using Lowenstein-Jensen (LJ culture medium. Further, the isolates were confirmed by the Ziehl-Neelsen microscopic examination method. Drug susceptibility test (DST was also conducted on LJ medium using a simplified indirect proportion method. The resistance strains were then determined by percentage of colonies that grew on the critical concentration of Isoniazid, Streptomycin, Rifampicin and Ethambutol. Results The overall resistance of all forms of TB to any first-line anti-TB drug was 21.7 %. Of the total new and previously treated culture positive TB cases, 15.3 and 48.8 % respectively were found to be a resistant to any of the first-line anti-TB drugs. Further, of all forms of TB, the overall resistance of MDR-TB was 4.7 %. However, of the total new TB cases, 2.4 % had primary while 14.3 % had secondary MDR-TB. Resistance to any of the first-line anti-TB drugs (adjusted odd ratio (AOR, 8.1; 95 % CI: 2.26–29.30 and MDR-TB (AOR, 7.1; 95 % CI: 2.6–43.8 was found to be linked with previous history of anti-TB treatment. Conclusions The study has identified a high rate of primary and secondary resistance to any of the first-line anti-TB drugs and MDR-TB in the study area. The resistance may have resulted from sub-optimal performance of directly observed

  5. Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development

    Science.gov (United States)

    Swat, MJ; Moodie, S; Wimalaratne, SM; Kristensen, NR; Lavielle, M; Mari, A; Magni, P; Smith, MK; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, AC; Kaye, R; Keizer, R; Kloft, C; Kok, JN; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, HB; Parra-Guillen, ZP; Plan, E; Ribba, B; Smith, G; Trocóniz, IF; Yvon, F; Milligan, PA; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

    2015-01-01

    The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps. PMID:26225259

  6. Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

    Science.gov (United States)

    Swat, M J; Moodie, S; Wimalaratne, S M; Kristensen, N R; Lavielle, M; Mari, A; Magni, P; Smith, M K; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, A C; Kaye, R; Keizer, R; Kloft, C; Kok, J N; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, H B; Parra-Guillen, Z P; Plan, E; Ribba, B; Smith, G; Trocóniz, I F; Yvon, F; Milligan, P A; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

    2015-06-01

    The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

  7. Ising percolation in a three-state majority vote model

    Energy Technology Data Exchange (ETDEWEB)

    Balankin, Alexander S., E-mail: abalankin@ipn.mx [Grupo Mecánica Fractal, ESIME, Instituto Politécnico Nacional, México D.F., 07738 (Mexico); Martínez-Cruz, M.A.; Gayosso Martínez, Felipe [Grupo Mecánica Fractal, ESIME, Instituto Politécnico Nacional, México D.F., 07738 (Mexico); Mena, Baltasar [Laboratorio de Ingeniería y Procesos Costeros, Instituto de Ingeniería, Universidad Nacional Autónoma de México, Sisal, Yucatán, 97355 (Mexico); Tobon, Atalo; Patiño-Ortiz, Julián; Patiño-Ortiz, Miguel; Samayoa, Didier [Grupo Mecánica Fractal, ESIME, Instituto Politécnico Nacional, México D.F., 07738 (Mexico)

    2017-02-05

    Highlights: • Three-state non-consensus majority voter model is introduced. • Phase transition in the absorbing state non-consensus is revealed. • The percolation transition belongs to the universality class of Ising percolation. • The effect of an updating rule for a tie between voter neighbors is highlighted. - Abstract: In this Letter, we introduce a three-state majority vote model in which each voter adopts a state of a majority of its active neighbors, if exist, but the voter becomes uncommitted if its active neighbors are in a tie, or all neighbors are the uncommitted. Numerical simulations were performed on square lattices of different linear size with periodic boundary conditions. Starting from a random distribution of active voters, the model leads to a stable non-consensus state in which three opinions coexist. We found that the “magnetization” of the non-consensus state and the concentration of uncommitted voters in it are governed by an initial composition of system and are independent of the lattice size. Furthermore, we found that a configuration of the stable non-consensus state undergoes a second order percolation transition at a critical concentration of voters holding the same opinion. Numerical simulations suggest that this transition belongs to the same universality class as the Ising percolation. These findings highlight the effect of an updating rule for a tie between voter neighbors on the critical behavior of models obeying the majority vote rule whenever a strict majority exists.

  8. Ising percolation in a three-state majority vote model

    International Nuclear Information System (INIS)

    Balankin, Alexander S.; Martínez-Cruz, M.A.; Gayosso Martínez, Felipe; Mena, Baltasar; Tobon, Atalo; Patiño-Ortiz, Julián; Patiño-Ortiz, Miguel; Samayoa, Didier

    2017-01-01

    Highlights: • Three-state non-consensus majority voter model is introduced. • Phase transition in the absorbing state non-consensus is revealed. • The percolation transition belongs to the universality class of Ising percolation. • The effect of an updating rule for a tie between voter neighbors is highlighted. - Abstract: In this Letter, we introduce a three-state majority vote model in which each voter adopts a state of a majority of its active neighbors, if exist, but the voter becomes uncommitted if its active neighbors are in a tie, or all neighbors are the uncommitted. Numerical simulations were performed on square lattices of different linear size with periodic boundary conditions. Starting from a random distribution of active voters, the model leads to a stable non-consensus state in which three opinions coexist. We found that the “magnetization” of the non-consensus state and the concentration of uncommitted voters in it are governed by an initial composition of system and are independent of the lattice size. Furthermore, we found that a configuration of the stable non-consensus state undergoes a second order percolation transition at a critical concentration of voters holding the same opinion. Numerical simulations suggest that this transition belongs to the same universality class as the Ising percolation. These findings highlight the effect of an updating rule for a tie between voter neighbors on the critical behavior of models obeying the majority vote rule whenever a strict majority exists.

  9. Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.

    Science.gov (United States)

    Engleman, Eric A; Katner, Simon N; Neal-Beliveau, Bethany S

    2016-01-01

    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission

  10. Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction

    Science.gov (United States)

    Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.

    2016-01-01

    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine

  11. Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier.

    Science.gov (United States)

    Blundell, Cassidy; Yi, Yoon-Suk; Ma, Lin; Tess, Emily R; Farrell, Megan J; Georgescu, Andrei; Aleksunes, Lauren M; Huh, Dongeun

    2018-01-01

    The current lack of knowledge about the effect of maternally administered drugs on the developing fetus is a major public health concern worldwide. The first critical step toward predicting the safety of medications in pregnancy is to screen drug compounds for their ability to cross the placenta. However, this type of preclinical study has been hampered by the limited capacity of existing in vitro and ex vivo models to mimic physiological drug transport across the maternal-fetal interface in the human placenta. Here the proof-of-principle for utilizing a microengineered model of the human placental barrier to simulate and investigate drug transfer from the maternal to the fetal circulation is demonstrated. Using the gestational diabetes drug glyburide as a model compound, it is shown that the microphysiological system is capable of reconstituting efflux transporter-mediated active transport function of the human placental barrier to limit fetal exposure to maternally administered drugs. The data provide evidence that the placenta-on-a-chip may serve as a new screening platform to enable more accurate prediction of drug transport in the human placenta. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Prohibited or regulated? LSD psychotherapy and the United States Food and Drug Administration.

    Science.gov (United States)

    Oram, Matthew

    2016-09-01

    Over the 1950s and early 1960s, the use of the hallucinogenic drug lysergic acid diethylamide (LSD) to facilitate psychotherapy was a promising field of psychiatric research in the USA. However, during the 1960s, research began to decline, before coming to a complete halt in the mid-1970s. This has commonly been explained through the increase in prohibitive federal regulations during the 1960s that aimed to curb the growing recreational use of the drug. However, closely examining the Food and Drug Administration's regulation of LSD research in the 1960s will reveal that not only was LSD research never prohibited, but that the administration supported research to a greater degree than has been recognized. Instead, the decline in research reflected more complex changes in the regulation of pharmaceutical research and development. © The Author(s) 2016.

  13. Drugs of abuse: the highs and lows of altered mental states in the emergency department.

    Science.gov (United States)

    Meehan, Timothy J; Bryant, Sean M; Aks, Steven E

    2010-08-01

    The diagnosis and management of poisoned patients presenting with alterations in mental status can be challenging, as patients are often unable (or unwilling) to provide an adequate history. Several toxidromes exist. Recognition hinges upon vital signs and the physical examination. Understanding these "toxic syndromes" may guide early therapy and management, providing insight into the patient's underlying medical problem. Despite toxidrome recognition guiding antidotal therapy, the fundamental aspect of managing these patients involves meticulous supportive care. The authors begin with a discussion of various toxidromes and then delve into the drugs responsible for each syndrome. They conclude with a discussion on drug-facilitated sexual assault ("date rape"), which is both an underrecognized problem in the emergency department (ED) and representative of the drug-related problems faced in a modern ED. Copyright 2010. Published by Elsevier Inc.

  14. The current state of GPCR-based drug discovery to treat metabolic disease.

    Science.gov (United States)

    Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S

    2018-02-02

    One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.

  15. Lipid-Based Formulations Can Enable the Model Poorly Water-Soluble Weakly Basic Drug Cinnarizine to Precipitate in an Amorphous-Salt Form during in Vitro Digestion

    DEFF Research Database (Denmark)

    Khan, Jamal; Rades, Thomas; Boyd, Ben J

    2016-01-01

    The tendency for poorly water-soluble weakly basic drugs to precipitate in a noncrystalline form during the in vitro digestion of lipid-based formulations (LBFs) was linked to an ionic interaction between drug and fatty acid molecules produced upon lipid digestion. Cinnarizine was chosen as a model...... from the starting free base crystalline material to the hydrochloride salt, thus supporting the case that ionic interactions between weak bases and fatty acid molecules during digestion are responsible for producing amorphous-salts upon precipitation. The conclusion has wide implications...... weakly basic drug and was dissolved in a medium-chain (MC) LBF, which was subject to in vitro lipolysis experiments at various pH levels above and below the reported pKa value of cinnarizine (7.47). The solid-state form of the precipitated drug was analyzed using X-ray diffraction (XRD), Fourier...

  16. Methodologies Related to Computational models in View of Developing Anti-Alzheimer Drugs: An Overview.

    Science.gov (United States)

    Baheti, Kirtee; Kale, Mayura Ajay

    2018-04-17

    Since last two decades, there has been more focus on the development strategies related to Anti-Alzheimer's drug research. This may be attributed to the fact that most of the Alzheimer's cases are still mostly unknown except for a few cases, where genetic differences have been identified. With the progress of the disease, the symptoms involve intellectual deterioration, memory impairment, abnormal personality and behavioural patterns, confusion, aggression, mood swings, irritability Current therapies available for this disease give only symptomatic relief and do not focus on manipulations of biololecular processes. Nearly all the therapies to treat Alzheimer's disease, target to change the amyloid cascade which is considered to be an important in AD pathogenesis. New drug regimens are not able to keep pace with the ever-increasing understanding about dementia at molecular level. Looking into these aggravated problems, we though to put forth molecular modeling as a drug discovery approach for developing novel drugs to treat Alzheimer disease. The disease is incurable and it gets worst as it advances and finally causes death. Due to this, the design of drugs to treat this disease has become an utmost priority for research. One of the most important emerging technologies applied for this has been Computer-assisted drug design (CADD). It is a research tool that employs large scale computing strategies in an attempt to develop a model receptor site which can be used for designing of an anti-Alzheimer drug. The various models of amyloid-based calcium channels have been computationally optimized. Docking and De novo evolution are used to design the compounds. These are further subjected to absorption, distribution, metabolism, excretion and toxicity (ADMET) studies to finally bring about active compounds that are able to cross BBB. Many novel compounds have been designed which might be promising ones for the treatment of AD. The present review describes the research

  17. Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

    Directory of Open Access Journals (Sweden)

    Charles H. Williams

    2011-04-01

    Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

  18. Ontology and modeling patterns for state-based behavior representation

    Science.gov (United States)

    Castet, Jean-Francois; Rozek, Matthew L.; Ingham, Michel D.; Rouquette, Nicolas F.; Chung, Seung H.; Kerzhner, Aleksandr A.; Donahue, Kenneth M.; Jenkins, J. Steven; Wagner, David A.; Dvorak, Daniel L.; hide

    2015-01-01

    This paper provides an approach to capture state-based behavior of elements, that is, the specification of their state evolution in time, and the interactions amongst them. Elements can be components (e.g., sensors, actuators) or environments, and are characterized by state variables that vary with time. The behaviors of these elements, as well as interactions among them are represented through constraints on state variables. This paper discusses the concepts and relationships introduced in this behavior ontology, and the modeling patterns associated with it. Two example cases are provided to illustrate their usage, as well as to demonstrate the flexibility and scalability of the behavior ontology: a simple flashlight electrical model and a more complex spacecraft model involving instruments, power and data behaviors. Finally, an implementation in a SysML profile is provided.

  19. Analysis of West African Drug Trafficking: The Dynamics of Interdiction and State Capacity

    Science.gov (United States)

    2011-03-01

    Trouble Ahead: The Cocaleros of Peru .” Current History 105, no. 688 (Feb, 2006): 79–83 15Senlis Council. Impact Assessment of Crop Eradication in...WORLD/africa/09/21/africa.drug.cartels/index.html. Brown, Vanda. “Trouble Ahead: The Cocaleros of Peru .” Current History 105, no. 688 (February, 2006...Studies 2, no. 1 (March 1964): 118–120. Clay , Cane. “Drug Cartels Find New Home in West Africa.” The Jacksonville Free Press, September 24, 2009

  20. Thermodynamic state ensemble models of cis-regulation.

    Directory of Open Access Journals (Sweden)

    Marc S Sherman

    Full Text Available A major goal in computational biology is to develop models that accurately predict a gene's expression from its surrounding regulatory DNA. Here we present one class of such models, thermodynamic state ensemble models. We describe the biochemical derivation of the thermodynamic framework in simple terms, and lay out the mathematical components that comprise each model. These components include (1 the possible states of a promoter, where a state is defined as a particular arrangement of transcription factors bound to a DNA promoter, (2 the binding constants that describe the affinity of the protein-protein and protein-DNA interactions that occur in each state, and (3 whether each state is capable of transcribing. Using these components, we demonstrate how to compute a cis-regulatory function that encodes the probability of a promoter being active. Our intention is to provide enough detail so that readers with little background in thermodynamics can compose their own cis-regulatory functions. To facilitate this goal, we also describe a matrix form of the model that can be easily coded in any programming language. This formalism has great flexibility, which we show by illustrating how phenomena such as competition between transcription factors and cooperativity are readily incorporated into these models. Using this framework, we also demonstrate that Michaelis-like functions, another class of cis-regulatory models, are a subset of the thermodynamic framework with specific assumptions. By recasting Michaelis-like functions as thermodynamic functions, we emphasize the relationship between these models and delineate the specific circumstances representable by each approach. Application of thermodynamic state ensemble models is likely to be an important tool in unraveling the physical basis of combinatorial cis-regulation and in generating formalisms that accurately predict gene expression from DNA sequence.

  1. Hyperstate matrix models : extending demographic state spaces to higher dimensions

    NARCIS (Netherlands)

    Roth, G.; Caswell, H.

    2016-01-01

    1. Demographic models describe population dynamics in terms of the movement of individuals among states (e.g. size, age, developmental stage, parity, frailty, physiological condition). Matrix population models originally classified individuals by a single characteristic. This was enlarged to two

  2. Kinematic Cosmology & a new ``Steady State'' Model of Continued Creation

    Science.gov (United States)

    Wegener, Mogens

    2006-03-01

    Only a new "steady state" model justifies the observations of fully mature galaxies at ever increasing distances. The basic idea behind the world model presented here, which is a synthesis of the cosmologies of Parmenides and Herakleitos, is that the invariant structure of the infinite contents of a universe in flux may be depicted as a finite hyperbolic pseudo-sphere.

  3. Information Sharing In Shipbuilding based on the Product State Model

    DEFF Research Database (Denmark)

    Larsen, Michael Holm

    1999-01-01

    The paper provides a review of product modelling technologies and the overall architecture for the Product State Model (PSM) environment as a basis for how dynamically updated product data can improve control of production activities. Especially, the paper focuses on the circumstances prevailing...

  4. Hyperon polarizabilities in the bound-state soliton model

    International Nuclear Information System (INIS)

    Gobbi, C.; Scoccola, N.N.

    1996-01-01

    A detailed calculation of electric and magnetic static polarizabilities of octet hyperons is presented in the framework of the bound-state soliton model. Both seagull and dispersive contributions are considered, and the results are compared with different model predictions. (orig.)

  5. Funding Models of Community Colleges in 10 Midwest States

    Science.gov (United States)

    Kenton, Carol Piper; Schuh, John H.; Huba, Mary E.; Shelley, Mack C., II

    2004-01-01

    The extent to which community colleges in 10 Midwest states relied on 12 current funds revenue sources between 1990 and 2000 is presented in this study. Four models of funding were identified and evaluated. All models generated revenue in excess of the change in the Higher Education Price Index (HEPI), a measure of inflation over the period…

  6. 3 QP plus rotor model and high spin states

    International Nuclear Information System (INIS)

    Mathur, Tripti

    1995-01-01

    Nuclear models are approximate methods to describe certain properties of a large number of nuclei. In this paper details of 3 QP (three quasi particle) plus rotor model and high spin state are discussed. The band head energies for the 3 QP rotational bands for 157 Ho and 159 Tm are also given. 5 refs., 8 figs

  7. Ground states of the massless Derezinski-Gerard model

    International Nuclear Information System (INIS)

    Ohkubo, Atsushi

    2009-01-01

    We consider the massless Derezinski-Gerard model introduced by Derezinski and Gerard in 1999. We give a sufficient condition for the existence of a ground state of the massless Derezinski-Gerard model without the assumption that the Hamiltonian of particles has compact resolvent.

  8. A Modified Microfinance Model Proposed for the United States

    Directory of Open Access Journals (Sweden)

    Eldon H Bernstein

    2014-07-01

    While the goal in the traditional model in developing markets is the elimination of poverty, we show how those critical conditions help to explain the lack of success in the United States.  We propose a modified model whose goal is the creation of an entrepreneurial venture or improving the performance of an existing small enterprise.

  9. A model of directional selection applied to the evolution of drug resistance in HIV-1.

    Science.gov (United States)

    Seoighe, Cathal; Ketwaroo, Farahnaz; Pillay, Visva; Scheffler, Konrad; Wood, Natasha; Duffet, Rodger; Zvelebil, Marketa; Martinson, Neil; McIntyre, James; Morris, Lynn; Hide, Winston

    2007-04-01

    Understanding how pathogens acquire resistance to drugs is important for the design of treatment strategies, particularly for rapidly evolving viruses such as HIV-1. Drug treatment can exert strong selective pressures and sites within targeted genes that confer resistance frequently evolve far more rapidly than the neutral rate. Rapid evolution at sites that confer resistance to drugs can be used to help elucidate the mechanisms of evolution of drug resistance and to discover or corroborate novel resistance mutations. We have implemented standard maximum likelihood methods that are used to detect diversifying selection and adapted them for use with serially sampled reverse transcriptase (RT) coding sequences isolated from a group of 300 HIV-1 subtype C-infected women before and after single-dose nevirapine (sdNVP) to prevent mother-to-child transmission. We have also extended the standard models of codon evolution for application to the detection of directional selection. Through simulation, we show that the directional selection model can provide a substantial improvement in sensitivity over models of diversifying selection. Five of the sites within the RT gene that are known to harbor mutations that confer resistance to nevirapine (NVP) strongly supported the directional selection model. There was no evidence that other mutations that are known to confer NVP resistance were selected in this cohort. The directional selection model, applied to serially sampled sequences, also had more power than the diversifying selection model to detect selection resulting from factors other than drug resistance. Because inference of selection from serial samples is unlikely to be adversely affected by recombination, the methods we describe may have general applicability to the analysis of positive selection affecting recombining coding sequences when serially sampled data are available.

  10. Bayesian state space models for dynamic genetic network construction across multiple tissues.

    Science.gov (United States)

    Liang, Yulan; Kelemen, Arpad

    2016-08-01

    Construction of gene-gene interaction networks and potential pathways is a challenging and important problem in genomic research for complex diseases while estimating the dynamic changes of the temporal correlations and non-stationarity are the keys in this process. In this paper, we develop dynamic state space models with hierarchical Bayesian settings to tackle this challenge for inferring the dynamic profiles and genetic networks associated with disease treatments. We treat both the stochastic transition matrix and the observation matrix time-variant and include temporal correlation structures in the covariance matrix estimations in the multivariate Bayesian state space models. The unevenly spaced short time courses with unseen time points are treated as hidden state variables. Hierarchical Bayesian approaches with various prior and hyper-prior models with Monte Carlo Markov Chain and Gibbs sampling algorithms are used to estimate the model parameters and the hidden state variables. We apply the proposed Hierarchical Bayesian state space models to multiple tissues (liver, skeletal muscle, and kidney) Affymetrix time course data sets following corticosteroid (CS) drug administration. Both simulation and real data analysis results show that the genomic changes over time and gene-gene interaction in response to CS treatment can be well captured by the proposed models. The proposed dynamic Hierarchical Bayesian state space modeling approaches could be expanded and applied to other large scale genomic data, such as next generation sequence (NGS) combined with real time and time varying electronic health record (EHR) for more comprehensive and robust systematic and network based analysis in order to transform big biomedical data into predictions and diagnostics for precision medicine and personalized healthcare with better decision making and patient outcomes.

  11. Nanoporous materials modified with biodegradable polymers as models for drug delivery applications

    DEFF Research Database (Denmark)

    Gruber, Mathias F; Schulte, Lars; Ndoni, Sokol

    2013-01-01

    of principle for a system combining these two encapsulation methods and consisting of a nanoporous polymer (NP) with the pores filled with a degradable polymer mixed with a drug model. Rhodamine 6G (R6G) mixed with Poly(l-Lactic Acid) (PLLA) were confined within the 14nm pores of a NP with gyroid morphology...

  12. PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties.

    Science.gov (United States)

    Borrel, Alexandre; Regad, Leslie; Xhaard, Henri; Petitjean, Michel; Camproux, Anne-Claude

    2015-04-27

    Predicting protein druggability is a key interest in the target identification phase of drug discovery. Here, we assess the pocket estimation methods' influence on druggability predictions by comparing statistical models constructed from pockets estimated using different pocket estimation methods: a proximity of either 4 or 5.5 Å to a cocrystallized ligand or DoGSite and fpocket estimation methods. We developed PockDrug, a robust pocket druggability model that copes with uncertainties in pocket boundaries. It is based on a linear discriminant analysis from a pool of 52 descriptors combined with a selection of the most stable and efficient models using different pocket estimation methods. PockDrug retains the best combinations of three pocket properties which impact druggability: geometry, hydrophobicity, and aromaticity. It results in an average accuracy of 87.9% ± 4.7% using a test set and exhibits higher accuracy (∼5-10%) than previous studies that used an identical apo set. In conclusion, this study confirms the influence of pocket estimation on pocket druggability prediction and proposes PockDrug as a new model that overcomes pocket estimation variability.

  13. Formulating state space models in R with focus on longitudinal regression models

    DEFF Research Database (Denmark)

    Dethlefsen, Claus; Lundbye-Christensen, Søren

    2006-01-01

    We provide a language for formulating a range of state space models with response densities within the exponential family. The described methodology is implemented in the R-package sspir. A state space model is specified similarly to a generalized linear model in R, and then the time-varying terms...

  14. Hindered disulfide bonds to regulate release rate of model drug from mesoporous silica.

    Science.gov (United States)

    Nadrah, Peter; Maver, Uroš; Jemec, Anita; Tišler, Tatjana; Bele, Marjan; Dražić, Goran; Benčina, Mojca; Pintar, Albin; Planinšek, Odon; Gaberšček, Miran

    2013-05-01

    With the advancement of drug delivery systems based on mesoporous silica nanoparticles (MSNs), a simple and efficient method regulating the drug release kinetics is needed. We developed redox-responsive release systems with three levels of hindrance around the disulfide bond. A model drug (rhodamine B dye) was loaded into MSNs' mesoporous voids. The pore opening was capped with β-cyclodextrin in order to prevent leakage of drug. Indeed, in absence of a reducing agent the systems exhibited little leakage, while the addition of dithiothreitol cleaved the disulfide bonds and enabled the release of cargo. The release rate and the amount of released dye were tuned by the level of hindrance around disulfide bonds, with the increased hindrance causing a decrease in the release rate as well as in the amount of released drug. Thus, we demonstrated the ability of the present mesoporous systems to intrinsically control the release rate and the amount of the released cargo by only minor structural variations. Furthermore, an in vivo experiment on zebrafish confirmed that the present model delivery system is nonteratogenic.

  15. Advanced progress of microencapsulation technologies: in vivo and in vitro models for studying oral and transdermal drug deliveries.

    Science.gov (United States)

    Lam, P L; Gambari, R

    2014-03-28

    This review provides an overall discussion of microencapsulation systems for both oral and transdermal drug deliveries. Clinically, many drugs, especially proteins and peptides, are susceptible to the gastrointestinal tract and the first-pass metabolism after oral administration while some drugs exhibit low skin permeability through transdermal delivery route. Medicated microcapsules as oral and transdermal drug delivery vehicles are believed to offer an extended drug effect at a relatively low dose and provide a better patient compliance. The polymeric microcapsules can be produced by different microencapsulation methods and the drug microencapsulation technology provides the quality preservation for drug stabilization. The release of the entrapped drug is controlled and prolonged for specific usages. Some recent studies have focused on the evaluation of drug containing microcapsules on potential biological and therapeutic applications. For the oral delivery, in vivo animal models were used for evaluating possible treatment effects of drug containing microcapsules. For the transdermal drug delivery, skin delivery models were introduced to investigate the potential skin delivery of medicated microcapsules. Finally, the challenges and limitations of drug microencapsulation in real life are discussed and the commercially available drug formulations using microencapsulation technology for oral and transdermal applications are shown. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. [Pediatric drug development: ICH harmonized tripartite guideline E11 within the United States of America, the European Union, and Japan].

    Science.gov (United States)

    Pflieger, M; Bertram, D

    2014-10-01

    To address the lack of appropriate pediatric drugs available on the global market, in 2000 the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH E11 guideline regarding the Clinical Investigation of Medicinal Products in the Pediatric Population. This guideline considerably changes the environment of drug development for children. It has been written specifically to harmonize, promote, and facilitate high-quality and ethical clinical research for children within the ICH regions, i.e., the United States of America (USA), the European Union (EU), and Japan. This article details the various regulations applicable in each ICH region following the publication of the guideline. The framework of rewards, incentives, and obligations for pharmaceutical companies established for the development of pediatric drugs are compared. It appears that the USA and the EU have both developed specific regulations for pediatric drug development while Japan has not. However, in Japan, pharmaceutical companies (PCs) are encouraged to develop pediatric drugs voluntarily, and they may be granted additional months of market exclusivity or the postponement of the drug re-examination deadline. In both the USA and the EU, regulations aimed to increase the number of clinical studies conducted in children, in order to ensure that the necessary data are generated, determining the conditions in which a drug may be authorized to treat the pediatric population. PCs are encouraged to develop pediatric assessment, including pediatric clinical trials, which is described in a pediatric plan submitted to the relevant authorities. A system of rewards for PCs submitting an application for marketing authorization containing pediatric use information has been put in place to cover the additional investment for testing drugs in children. Subject to conditions, these rewards consist in a 6-month extension of the patent or

  17. A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2015-01-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

  18. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Fault Diagnosis of Nonlinear Systems Using Structured Augmented State Models

    Institute of Scientific and Technical Information of China (English)

    Jochen Aβfalg; Frank Allg(o)wer

    2007-01-01

    This paper presents an internal model approach for modeling and diagnostic functionality design for nonlinear systems operating subject to single- and multiple-faults. We therefore provide the framework of structured augmented state models. Fault characteristics are considered to be generated by dynamical exosystems that are switched via equality constraints to overcome the augmented state observability limiting the number of diagnosable faults. Based on the proposed model, the fault diagnosis problem is specified as an optimal hybrid augmented state estimation problem. Sub-optimal solutions are motivated and exemplified for the fault diagnosis of the well-known three-tank benchmark. As the considered class of fault diagnosis problems is large, the suggested approach is not only of theoretical interest but also of high practical relevance.

  20. THE EUROPEAN MODEL OF STATE REGULATION OF TOURISM ACTIVITIES

    Directory of Open Access Journals (Sweden)

    О. Davydova

    2013-11-01

    Full Text Available In the article the existing model of state regulation of the development of tourism. Expediency of the European model of state regulation of tourism development in Ukraine. It is noted that the European model of state regulation of tourism activities based on the coordination of marketing activities and the development of cooperation between the public and private sectors. The basic forms of public-private partnerships and the advantages of using cluster model of development of tourism, namely, contracts, production sharing agreement, lease, joint venture. Promising areas of application of the PPP identified the transport sector, housing and utilities, energy and tourism sector. The features of cluster formations in the country and the prospects for tourism clusters.