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Sample records for accelerate drug development

  1. Improving and Accelerating Drug Development for Nervous System Disorders

    PubMed Central

    Pankevich, Diana E.; Altevogt, Bruce M.; Dunlop, John; Gage, Fred H.; Hyman, Steve E.

    2014-01-01

    Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development the Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience. PMID:25442933

  2. Development of an ADME and drug-drug interactions knowledge database for the acceleration of drug discovery and development.

    PubMed

    Petitet, François; Barberan, Olivier; Dubus, Elodie; Ijjaali, Ismail; Donlan, Mary; Ollivier, Sophie; Michel, André

    2006-12-01

    It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE(®) ADME/DDI (drug-drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug-drug interactions. PMID:23495997

  3. Repurposing pharma assets: an accelerated mechanism for strengthening the schistosomiasis drug development pipeline.

    PubMed

    Ramamoorthi, Roopa; Graef, Katy M; Dent, Jennifer

    2015-01-01

    Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis. PMID:25996066

  4. Digital technologies for cognitive assessment to accelerate drug development in Alzheimer's disease.

    PubMed

    Leurent, C; Ehlers, M D

    2015-11-01

    For many neurological and psychiatric diseases, novel therapeutics have been elusive for decades. By focusing on attention interference in Alzheimer's disease (AD), we provide a future vision on how emerging mobile, computer, and device-based cognitive tools are converting classically noisy, subjective, data-poor clinical endpoints associated with neuropsychiatric disease assessment into a richer, scalable, and objective set of measurements. Incorporation of such endpoints into clinical drug trials holds promise for more quickly and efficiently developing new medicines. PMID:26272508

  5. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

    PubMed

    Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

    2015-01-01

    For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into

  6. Accepting risk in the acceleration of drug development for rare cancers.

    PubMed

    Ashley, David; Thomas, David; Gore, Lia; Carter, Rob; Zalcberg, John R; Otmar, Renée; Savulescu, Julian

    2015-04-01

    Rare cancers collectively contribute a disproportionate fraction of the total burden of cancer. The oncology community is increasingly facing small numbers of patients with each cancer subtype, requiring cooperation and collaboration to complete multicentre trials that advance knowledge and patient care. At the same time, new insights into the biology of rare cancers have led to an explosion in knowledge and development of targeted agents. These insights and techniques are set to revolutionise the care of patients with cancer. However, drug development strategies and the availability of new agents for rare cancers are at risk of stalling owing to the ever-increasing complexity and costs of clinical trials. Finding solutions to these problems is imperative to the future of cancer care. We propose that a greater degree of risk sharing is needed than is currently accepted to enable the use of new methods with confidence, and to keep pace with scientific advancement. PMID:25846099

  7. Advanced accelerator theory development

    SciTech Connect

    Sampayan, S.E.; Houck, T.L.; Poole, B.; Tishchenko, N.; Vitello, P.A.; Wang, I.

    1998-02-09

    A new accelerator technology, the dielectric wall accelerator (DWA), is potentially an ultra compact accelerator/pulsed power driver. This new accelerator relies on three new components: the ultra-high gradient insulator, the asymmetric Blumlein and low jitter switches. In this report, we focused our attention on the first two components of the DWA system the insulators and the asymmetric Blumlein. First, we sought to develop the necessary design tools to model and scale the behavior of the high gradient insulator. To perform this task we concentrated on modeling the discharge processes (i.e., initiation and creation of the surface discharge). In addition, because these high gradient structures exhibit favorable microwave properties in certain accelerator configurations, we performed experiments and calculations to determine the relevant electromagnetic properties. Second, we performed circuit modeling to understand energy coupling to dynamic loads by the asymmetric Blumlein. Further, we have experimentally observed a non-linear coupling effect in certain asymmetric Blumlein configurations. That is, as these structures are stacked into a complete module, the output voltage does not sum linearly and a lower than expected output voltage results. Although we solved this effect experimentally, we performed calculations to understand this effect more fully to allow better optimization of this DWA pulse-forming line system.

  8. Drug Development Process

    MedlinePlus

    ... Approvals The Drug Development Process The Drug Development Process Share Tweet Linkedin Pin it More sharing options ... public. More Information More in The Drug Development Process Step 1: Discovery and Development Step 2: Preclinical ...

  9. In Vitro High-Throughput RNAi Screening to Accelerate the Process of Target Identification and Drug Development.

    PubMed

    Yin, Hongwei; Kassner, Michelle

    2016-01-01

    High-throughput RNA interference (HT-RNAi) is a powerful tool that can be used to knock down gene expression in order to identify novel genes and pathways involved in many cellular processes. It is a systematic, yet unbiased, approach to identify essential or synthetic lethal genes that promote cell survival in diseased cells as well as genes that confer resistance or sensitivity to drug treatment. This information serves as a foundation for enhancing current treatments for cancer and other diseases by identifying new drug targets, uncovering potential combination therapies, and helping clinicians match patients with the most effective treatment based on genetic information. Here, we describe the method of performing an in vitro HT-RNAi screen using chemically synthesized siRNA. PMID:27581290

  10. Animal models of efficacy to accelerate drug discovery in malaria.

    PubMed

    Jiménez-Díaz, María Belén; Viera, Sara; Fernández-Alvaro, Elena; Angulo-Barturen, Iñigo

    2014-01-01

    The emergence of resistance to artemisinins and the renewed efforts to eradicate malaria demand the urgent development of new drugs. In this endeavour, the evaluation of efficacy in animal models is often a go/no go decision assay in drug discovery. This important role relies on the capability of animal models to assess the disposition, toxicology and efficacy of drugs in a single test. Although the relative merits of each efficacy model of malaria as human surrogate have been extensively discussed, there are no critical analyses on the use of such models in current drug discovery. In this article, we intend to analyse how efficacy models are used to discover new antimalarial drugs. Our analysis indicates that testing drug efficacy is often the last assay in each discovery stage and the experimental designs utilized are not optimized to expedite decision-making and inform clinical development. In light of this analysis, we propose new ways to accelerate drug discovery using efficacy models. PMID:23789594

  11. Accelerating drug discovery via organs-on-chips

    PubMed Central

    Chan, Chung Yu; Huang, Po-Hsun; Guo, Feng; Ding, Xiaoyun; Kapur, Vivek; Mai, John D.

    2014-01-01

    Considerable advances have been made in the development of micro-physiological systems that seek to faithfully replicate the complexity and functionality of animal and human physiology in research laboratories. Sometimes referred to as “organs-on-chips”, these systems provide key insights into physiological or pathological processes associated with health maintenance and disease control, and serve as powerful platforms for new drug development and toxicity screening. In this Focus article, we review the state-of-the-art designs and examples for developing multiple “organs-on-chips”, and discuss the potential of this emerging technology to enhance our understanding of human physiology, and to transform and accelerate the drug discovery and pre-clinical testing process. This Focus article highlights some of the recent technological advances in this field, along with the challenges that must be addressed for these technologies to fully realize their potential. PMID:24193241

  12. "Precision" drug development?

    PubMed

    Woodcock, J

    2016-02-01

    The concept of precision medicine has entered broad public consciousness, spurred by a string of targeted drug approvals, highlighted by the availability of personal gene sequences, and accompanied by some remarkable claims about the future of medicine. It is likely that precision medicines will require precision drug development programs. What might such programs look like? PMID:26331240

  13. Accelerated leach test development program

    SciTech Connect

    Fuhrmann, M.; Pietrzak, R.F.; Heiser, J.; Franz, E.M.; Colombo, P.

    1990-11-01

    In FY 1989, a draft accelerated leach test for solidified waste was written. Combined test conditions that accelerate leaching were validated through experimental and modeling efforts. A computer program was developed that calculates test results and models leaching mechanisms. This program allows the user to determine if diffusion controls leaching and, if this is the case, to make projections of releases. Leaching mechanisms other than diffusion (diffusion plus source term partitioning and solubility limited leaching) are included in the program is indicators of other processes that may control leaching. Leach test data are presented and modeling results are discussed for laboratory scale waste forms composed of portland cement containing sodium sulfate salt, portland cement containing incinerator ash, and vinyl ester-styrene containing sodium sulfate. 16 refs., 38 figs., 5 tabs.

  14. Accelerator structure development for NLC

    SciTech Connect

    Hoag, H.A.; Deruyter, H.; Pearson, C.; Ruth, R.D.; Wang, J.W.; Schaefer, J.

    1993-04-01

    In the program of work directed towards the development of an X-Band Next Linear Collider accelerator structure, two different test accelerator sections have been completed, and a third is being fabricated. The first is a simple 30-cell constant-impedance section in which no special attention was given to surface finish, pumping, and alignment. The second is an 86-cell section in which the cells were precision diamond-turned by Texas Instruments Inc. The structure has internal water-cooling and vacuum pumping manifolds. Some design details are given for the third section, which is a 206-cell structure with cavities dimensioned to give a Gaussian distribution of dipole mode frequencies. It has conventional-machining surface finishes and external water and pumping manifolds. Component design, fabrication, and assembly brazing are described for the first two experimental sections.

  15. Embryonic development during chronic acceleration

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Abbott, U. K.

    1982-01-01

    Experiments carried out on chicken eggs indicate that the embryo is affected during very early development, especially over the first four days, and during hatching. In the first four days, the brain develops as well as the anlage for all other organs. In addition, the heart commences to function and the extraembryonic membranes that compartmentalize the egg contents form. The latter require an appreciable extension and folding of tissue which may be disrupted by the mechanical load. Observations of embryonic abnormalities that occur during chronic acceleration suggest an inhibition of development of the axial skeleton, which is rarely seen otherwise, a general retardation of embryonic growth, and circulatory problems. The final stages of development (after 18 days) involve the uptake of fluids, the transition to aerial respiration, and the reorientation of the embryo into a normal hatching position. At 4 G mortality is very high during this period, with a majority of embryos failing to reorient into the normal hatching position.

  16. UCLA accelerator research & development. Progress report

    SciTech Connect

    1997-09-01

    This report discusses work on advanced accelerators and beam dynamics at ANL, BNL, SLAC, UCLA and Pulse Sciences Incorporated. Discussed in this report are the following concepts: Wakefield acceleration studies; plasma lens research; high gradient rf cavities and beam dynamics studies at the Brookhaven accelerator test facility; rf pulse compression development; and buncher systems for high gradient accelerator and relativistic klystron applications.

  17. UCLA accelerator research and development

    SciTech Connect

    Cline, D.B.

    1992-01-01

    This progress report covers work supported by the above DOE grant over the period November 1, 1991 to July 31, 1992. The work is a program of experimental and theoretical studies in advanced particle accelerator research and development for high energy physics applications. The program features research at particle beam facilities in the United States and includes research on novel high power sources, novel focussing systems (e.g. plasma lens), beam monitors, novel high brightness, high current gun systems, and novel flavor factories in particular the {phi} Factory.

  18. Tuberculosis Drug Development

    PubMed Central

    Getahun, Haileyesus; Chamie, Gabriel; Lienhardt, Christian; Havlir, Diane V.

    2011-01-01

    An unprecedented number of new tuberculosis (TB) medications are currently in development, and there will be great pressure to deploy these new drugs among all populations after their efficacy is demonstrated. People living with HIV experience a large burden of TB and have a particularly pressing need for TB treatments that are shorter and less toxic. In addition, all people living with HIV now require antiretroviral therapy during TB treatment. A roadmap of the research, programmatic, and regulatory considerations includes the following: (1) inclusion of people living with HIV early in clinical trials for treatment and prevention using new TB medications, (2) prioritization of key studies of HIV–TB drug interactions and interactions between new TB agents, and (3) optimization of clinical trial infrastructure, laboratory capacity, and drug susceptibility testing. PMID:21868507

  19. Particle accelerator development: Selected examples

    NASA Astrophysics Data System (ADS)

    Wei, Jie

    2016-03-01

    About 30 years ago, I was among several students mentored by Professor Yang at Stony Brook to enter the field of particle accelerator physics. Since then, I have been fortunate to work on several major accelerator projects in USA and in China, guided and at times directly supported by Professor Yang. The field of accelerator physics is flourishing worldwide both providing indispensable tools for fundamental physics research and covering an increasingly wide spectrum of applications beneficial to our society.

  20. Particle Accelerator Development: Selected Examples

    NASA Astrophysics Data System (ADS)

    Wei, Jie

    About 30 years ago, I was among several students mentored by Professor Yang at Stony Brook to enter the field of particle accelerator physics. Since then, I have been fortunate to work on several major accelerator projects in USA and in China, guided and at times directly supported by Professor Yang. The field of accelerator physics is flourishing worldwide both providing indispensable tools for fundamental physics research and covering an increasingly wide spectrum of applications beneficial to our society.

  1. Drug development in dementia.

    PubMed

    Cunningham, Emma L; Passmore, Anthony P

    2013-11-01

    Dementia is a progressive, irreversible decline in cognition that, by definition, impacts on a patient's pre-existing level of functioning. The clinical syndrome of dementia has several aetiologies of which Alzheimer's disease (AD) is the most common. Drug development in AD is based on evolving pathophysiological theory. Disease modifying approaches include the targeting of amyloid processing, aggregation of tau, insulin signalling, neuroinflammation and neurotransmitter dysfunction, with efforts thus far yielding abandoned hopes and ongoing promise. Reflecting its dominance on the pathophysiological stage the amyloid cascade is central to many of the emerging drug therapies. The long preclinical phase of the disease requires robust biomarker means of identifying those at risk if timely intervention is to be possible. PMID:23707728

  2. Melatonergic drugs in development

    PubMed Central

    Carocci, Alessia; Catalano, Alessia; Sinicropi, Maria Stefania

    2014-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review. PMID:25258560

  3. Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

    PubMed Central

    Richey, Elizabeth A.; Lyons, E. Alison; Nebeker, Jonathan R.; Shankaran, Veena; McKoy, June M.; Luu, Thanh Ha; Nonzee, Narissa; Trifilio, Steven; Sartor, Oliver; Benson, Al B.; Carson, Kenneth R.; Edwards, Beatrice J.; Gilchrist-Scott, Douglas; Kuzel, Timothy M.; Raisch, Dennis W.; Tallman, Martin S.; West, Dennis P.; Hirschfeld, Steven; Grillo-Lopez, Antonio J.; Bennett, Charles L.

    2009-01-01

    Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs. PMID:19636013

  4. Desperately seeking cancer drugs: explaining the emergence and outcomes of accelerated pharmaceutical regulation.

    PubMed

    Davis, Courtney; Abraham, John

    2011-07-01

    Government regulators have increasingly accelerated new cancer drugs on to the market by granting them approval based on less clinical data supporting drug efficacy than permitted under standard regulations. With more lenient regulatory standards, pharmaceutical companies have keenly sought to develop cancer drugs. Focusing on the US, this article examines how the emergence and implementation of such accelerated approvals should be understood, particularly in relation to corporate bias and disease-politics theories. Drawing on longitudinal and case study data analysis, it is argued that the emergence of accelerated approval regulations for cancer drugs should be regarded primarily as part of a deregulatory regime driven by the interests of the pharmaceutical industry in partnership with all major aspects of the state, rather than as a response to patient activism in the aftermath of AIDS. Furthermore, even in cases when some patients successfully demand accelerated marketing approval of cancer drugs, such approval by regulators, while in manufacturers' interests, may not be in the interests of patients' health because the political culture of the regulatory agency is reluctant to uphold its own techno-regulatory standards of public-health protection when that would challenge the agenda-setting influence of manufacturers, including industry collaborations with patients and the medical profession. PMID:21314687

  5. Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells

    NASA Astrophysics Data System (ADS)

    Greulich, Philip; Waclaw, Bartłomiej; Allen, Rosalind J.

    2012-08-01

    Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anticancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a nonuniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combating the emergence of resistance.

  6. Drug development and manufacturing

    DOEpatents

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.

    2015-10-13

    X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.

  7. Laser-ablation-assisted microparticle acceleration for drug delivery

    NASA Astrophysics Data System (ADS)

    Menezes, V.; Takayama, K.; Ohki, T.; Gopalan, J.

    2005-10-01

    Localized drug delivery with minimal tissue damage is desired in some of the clinical procedures such as gene therapy, treatment of cancer cells, treatment of thrombosis, etc. We present an effective method for delivering drug-coated microparticles using laser ablation on a thin metal foil containing particles. A thin metal foil, with a deposition of a layer of microparticles is subjected to laser ablation on its backface such that a shock wave propagates through the foil. Due to shock wave loading, the surface of the foil containing microparticles is accelerated to very high speeds, ejecting the deposited particles at hypersonic speeds. The ejected particles have sufficient momentum to penetrate soft body tissues, and the penetration depth observed is sufficient for most of the pharmacological treatments. We have tried delivering 1μm tungsten particles into gelatin models that represent soft tissues, and liver tissues of an experimental rat. Sufficient penetration depths have been observed in these experiments with minimum target damage.

  8. Induction accelerator development for heavy ion fusion

    SciTech Connect

    Reginato, L.L.

    1993-05-01

    For approximately a decade, the Heavy Ion Fusion Accelerator Research (HIFAR) group at LBL has been exploring the use of induction accelerators with multiple beams as the driver for inertial fusion targets. Scaled experiments have investigated the transport of space charge dominated beams (SBTE), and the current amplification and transverse emittance control in induction linacs (MBE-4) with very encouraging results. In order to study many of the beam manipulations required by a driver and to further develop economically competitive technology, a proposal has been made in partnership with LLNL to build a 10 MeV accelerator and to conduct a series of experiments collectively called the Induction Linac System Experiments (ILSE). The major components critical to the ILSE accelerator are currently under development. We have constructed a full scale induction module and we have tested a number of amorphous magnetic materials developed by Allied Signal to establish an overall optimal design. The electric and magnetic quadrupoles critical to the transport and focusing of heavy ion beams are also under development The hardware is intended to be economically competitive for a driver without sacrificing any of the physics or performance requirements. This paper will concentrate on the recent developments and tests of the major components required by the ILSE accelerator.

  9. The Knowledge Accelerating the Society Development

    NASA Astrophysics Data System (ADS)

    Šmíd, Jaroslav; Sakál, Peter

    2010-01-01

    The formation of appropriate conditions can accelerate the society development. According to the existing definitions, the society can be viewed as mankind as a whole, or a state, a region or a group of businessmen. This paper extends and supplements of the contribution [1]. It deals with the knowledge accelerating the society development using the modified formal notation of the society development according to [2]. The open innovation concept [3] presents the intentional use of external knowledge flow. This paper deals with the intentional use of knowledge in time.

  10. Accelerated Leadership Development: Fast Tracking School Leaders

    ERIC Educational Resources Information Center

    Earley, Peter; Jones, Jeff

    2010-01-01

    "Accelerated Leadership Development" captures and communicates the lessons learned from successful fast-track leadership programmes in the private and public sector, and provides a model which schools can follow and customize as they plan their own leadership development strategies. As large numbers of headteachers and other senior staff retire,…

  11. Advanced Microgravity Acceleration Measurement Systems Being Developed

    NASA Technical Reports Server (NTRS)

    Sicker, Ronald J.; Kacpura, Thomas J.

    2002-01-01

    The Advanced Microgravity Acceleration Measurement Systems (AMAMS) project at the NASA Glenn Research Center is part of the Instrument Technology Development program to develop advanced sensor systems. The primary focus of the AMAMS project is to develop microelectromechanical (MEMS) acceleration sensor systems to replace existing electromechanical-sensor-based systems presently used to assess relative gravity levels aboard spacecraft. These systems are used in characterizing both vehicle and payload responses to low-gravity vibroacoustic environments. The collection of microgravity acceleration data has cross-disciplinary utility to the microgravity life and physical sciences and the structural dynamics communities. The inherent advantages of semiconductor-based systems are reduced size, mass, and power consumption, while providing enhanced stability.

  12. Acceleration in dental development: fact or fiction.

    PubMed

    Holtgrave, E A; Kretschmer, R; Müller, R

    1997-12-01

    The aim of this investigation was to determine whether an actual acceleration in dental development has taken place over the last 30 years in a European population group, as is so readily observable in relation to body height. In this study, radiographs of 1038 healthy European children, 516 boys and 522 girls, were evaluated. The methodology and norms given by Nolla (1960) for both sexes were used and compared with the tooth developmental stages in our subjects. In girls, no difference to Nolla's norms could be detected. However, in boys, dental development has accelerated. This difference was most apparent in the 3- to 9-year-old age group and was statistically significant. Thus, over the last 30 years, a small acceleration in dental development has taken place in very young males. PMID:9458603

  13. Membrane transporters in drug development

    PubMed Central

    2011-01-01

    Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling. PMID:20190787

  14. Imaging in drug development.

    PubMed

    Nairne, James; Iveson, Peter B; Meijer, Andreas

    2015-01-01

    Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised. PMID:25727706

  15. A curated and standardized adverse drug event resource to accelerate drug safety research

    PubMed Central

    Banda, Juan M.; Evans, Lee; Vanguri, Rami S.; Tatonetti, Nicholas P.; Ryan, Patrick B.; Shah, Nigam H.

    2016-01-01

    Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies. PMID:27193236

  16. A curated and standardized adverse drug event resource to accelerate drug safety research.

    PubMed

    Banda, Juan M; Evans, Lee; Vanguri, Rami S; Tatonetti, Nicholas P; Ryan, Patrick B; Shah, Nigam H

    2016-01-01

    Identification of adverse drug reactions (ADRs) during the post-marketing phase is one of the most important goals of drug safety surveillance. Spontaneous reporting systems (SRS) data, which are the mainstay of traditional drug safety surveillance, are used for hypothesis generation and to validate the newer approaches. The publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data requires substantial curation before they can be used appropriately, and applying different strategies for data cleaning and normalization can have material impact on analysis results. We provide a curated and standardized version of FAERS removing duplicate case records, applying standardized vocabularies with drug names mapped to RxNorm concepts and outcomes mapped to SNOMED-CT concepts, and pre-computed summary statistics about drug-outcome relationships for general consumption. This publicly available resource, along with the source code, will accelerate drug safety research by reducing the amount of time spent performing data management on the source FAERS reports, improving the quality of the underlying data, and enabling standardized analyses using common vocabularies. PMID:27193236

  17. Vehicle Systems Integration Laboratory Accelerates Powertrain Development

    SciTech Connect

    2014-04-15

    ORNL's Vehicle Systems Integration (VSI) Laboratory accelerates the pace of powertrain development by performing prototype research and characterization of advanced systems and hardware components. The VSI Lab is capable of accommodating a range of platforms from advanced light-duty vehicles to hybridized Class 8 powertrains with the goals of improving overall system efficiency and reducing emissions.

  18. Vehicle Systems Integration Laboratory Accelerates Powertrain Development

    ScienceCinema

    None

    2014-06-25

    ORNL's Vehicle Systems Integration (VSI) Laboratory accelerates the pace of powertrain development by performing prototype research and characterization of advanced systems and hardware components. The VSI Lab is capable of accommodating a range of platforms from advanced light-duty vehicles to hybridized Class 8 powertrains with the goals of improving overall system efficiency and reducing emissions.

  19. Chemical probe development versus drug development.

    PubMed

    Jackson, Michael R

    2013-01-01

    Phosphatases as a class of proteins have recently attracted significant attention from the pharmaceutical industry. As our knowledge of this diverse family of proteins has grown, the relationship between phosphatases and human disease has clearly been established, with model systems proving much validation for the potential of some members of this family to be candidate drug targets. This, coupled with the fact that there have been a flood of successful drug development efforts over the past 10 years targeting protein kinases, has led some to propose that phosphatases as a class of enzymes might be equally as rich a source of drug targets as kinases. However to date there remain relatively few molecules targeting protein phosphatases in clinical development. This is less a reflection of their importance in key processes associated with disease, but rather seems to reflect inherent issues with developing drugs for many members of this family. This seems especially so for intracellular phosphatases where the development of selective, potent cell penetrant molecules with good drug-like properties has proven a formidable challenge. This chapter provides a brief outline of the two major processes that have resulted in the existing armament of chemical modulators of protein phosphatases, namely, chemical probe development and drug development. These two processes initially seem to be rather similar and while they do overlap, the stated goals of the two approaches at project initiation are distinct. PMID:23860644

  20. Pediatric drug development: formulation considerations.

    PubMed

    Ali, Areeg Anwer; Charoo, Naseem Ahmad; Abdallah, Daud Baraka

    2014-10-01

    Absence of safe, effective and appropriate treatment is one of the main causes of high mortality and morbidity rates among the pediatric group. This review provides an overview of pharmacokinetic differences between pediatric and adult population and their implications in pharmaceutical development. Different pediatric dosage forms, their merits and demerits are discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical companies to perform pediatric clinical studies on new drug products. Drug development program should include additional clinical bridge studies to evaluate differences in pharmacokinetics and pharmacodynamics of drugs in adult and child populations. Additionally, pharmaceutical development should consider ease of administration, palatability, appropriate excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population is diverse with individual preferences and demand for custom made dosage formulations. Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted. PMID:24483293

  1. Adolescent Brain Development and Drugs

    ERIC Educational Resources Information Center

    Winters, Ken C.; Arria, Amelia

    2011-01-01

    Research now suggests that the human brain is still maturing during adolescence. The developing brain may help explain why adolescents sometimes make decisions that are risky and can lead to safety or health concerns, including unique vulnerabilities to drug abuse. This article explores how this new science may be put to use in our prevention and…

  2. In Vivo Target Validation Using Biological Molecules in Drug Development.

    PubMed

    Sim, Derek S; Kauser, Katalin

    2016-01-01

    Drug development is a resource-intensive process requiring significant financial and time investment. Preclinical target validation studies and in vivo testing of the therapeutic molecules in clinically relevant disease models can accelerate and significantly de-risk later stage clinical development. In this chapter, we will focus on (1) in vivo animal models and (2) pharmacological tools for target validation. PMID:26552401

  3. Live Cell in Vitro and in Vivo Imaging Applications: Accelerating Drug Discovery

    PubMed Central

    Isherwood, Beverley; Timpson, Paul; McGhee, Ewan J; Anderson, Kurt I; Canel, Marta; Serrels, Alan; Brunton, Valerie G; Carragher, Neil O

    2011-01-01

    Dynamic regulation of specific molecular processes and cellular phenotypes in live cell systems reveal unique insights into cell fate and drug pharmacology that are not gained from traditional fixed endpoint assays. Recent advances in microscopic imaging platform technology combined with the development of novel optical biosensors and sophisticated image analysis solutions have increased the scope of live cell imaging applications in drug discovery. We highlight recent literature examples where live cell imaging has uncovered novel insight into biological mechanism or drug mode-of-action. We survey distinct types of optical biosensors and associated analytical methods for monitoring molecular dynamics, in vitro and in vivo. We describe the recent expansion of live cell imaging into automated target validation and drug screening activities through the development of dedicated brightfield and fluorescence kinetic imaging platforms. We provide specific examples of how temporal profiling of phenotypic response signatures using such kinetic imaging platforms can increase the value of in vitro high-content screening. Finally, we offer a prospective view of how further application and development of live cell imaging technology and reagents can accelerate preclinical lead optimization cycles and enhance the in vitro to in vivo translation of drug candidates. PMID:24310493

  4. Cloud computing approaches to accelerate drug discovery value chain.

    PubMed

    Garg, Vibhav; Arora, Suchir; Gupta, Chitra

    2011-12-01

    Continued advancements in the area of technology have helped high throughput screening (HTS) evolve from a linear to parallel approach by performing system level screening. Advanced experimental methods used for HTS at various steps of drug discovery (i.e. target identification, target validation, lead identification and lead validation) can generate data of the order of terabytes. As a consequence, there is pressing need to store, manage, mine and analyze this data to identify informational tags. This need is again posing challenges to computer scientists to offer the matching hardware and software infrastructure, while managing the varying degree of desired computational power. Therefore, the potential of "On-Demand Hardware" and "Software as a Service (SAAS)" delivery mechanisms cannot be denied. This on-demand computing, largely referred to as Cloud Computing, is now transforming the drug discovery research. Also, integration of Cloud computing with parallel computing is certainly expanding its footprint in the life sciences community. The speed, efficiency and cost effectiveness have made cloud computing a 'good to have tool' for researchers, providing them significant flexibility, allowing them to focus on the 'what' of science and not the 'how'. Once reached to its maturity, Discovery-Cloud would fit best to manage drug discovery and clinical development data, generated using advanced HTS techniques, hence supporting the vision of personalized medicine. PMID:21843145

  5. Guidelines for Developing an Academic Acceleration Policy

    ERIC Educational Resources Information Center

    Colangelo, Nicholas; Assouline, Susan G.; Marron, Maureen A.; Castellano, Jaime A.; Clinkenbeard, Pamela R.; Rogers, Karen; Calvert, Eric; Malek, Rosanne; Smith, Donnajo

    2010-01-01

    As an educational intervention, acceleration is decidedly effective for high-ability students. The research support for acceleration that has accumulated over many decades is robust and consistent and allows us to confidently state that carefully planned acceleration decisions are successful. Both grade-based and content-based acceleration are…

  6. Drug Development for Metastasis Prevention.

    PubMed

    Fontebasso, Yari; Dubinett, Steven M

    2015-01-01

    Metastatic disease is responsible for 90% of death from solid tumors. However, only a minority of metastasis-specific targets has been exploited therapeutically, and effective prevention and suppression of metastatic disease is still an elusive goal. In this review, we will first summarize the current state of knowledge about the molecular features of the disease, with particular focus on steps and targets potentially amenable to therapeutic intervention. We will then discuss the reasons underlying the paucity of metastatic drugs in the current oncological arsenal and potential ways to overcome this therapeutic gap. We reason that the discovery of novel promising targets, an increased understanding of the molecular features of the disease, the effect of disruptive technologies, and a shift in the current preclinical and clinical settings have the potential to create more successful drug development endeavors. PMID:27279241

  7. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

  8. The tuberculosis drug discovery and development pipeline and emerging drug targets.

    PubMed

    Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

    2015-06-01

    The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061

  9. Pharmacokinetic/pharmacodynamic studies in drug product development.

    PubMed

    Meibohm, Bernd; Derendorf, Hartmut

    2002-01-01

    In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose-concentration-effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future. PMID:11782894

  10. Translational Bioinformatics Approaches to Drug Development

    PubMed Central

    Readhead, Ben; Dudley, Joel

    2013-01-01

    Significance A majority of therapeutic interventions occur late in the pathological process, when treatment outcome can be less predictable and effective, highlighting the need for new precise and preventive therapeutic development strategies that consider genomic and environmental context. Translational bioinformatics is well positioned to contribute to the many challenges inherent in bridging this gap between our current reactive methods of healthcare delivery and the intent of precision medicine, particularly in the areas of drug development, which forms the focus of this review. Recent Advances A variety of powerful informatics methods for organizing and leveraging the vast wealth of available molecular measurements available for a broad range of disease contexts have recently emerged. These include methods for data driven disease classification, drug repositioning, identification of disease biomarkers, and the creation of disease network models, each with significant impacts on drug development approaches. Critical Issues An important bottleneck in the application of bioinformatics methods in translational research is the lack of investigators who are versed in both biomedical domains and informatics. Efforts to nurture both sets of competencies within individuals and to increase interfield visibility will help to accelerate the adoption and increased application of bioinformatics in translational research. Future Directions It is possible to construct predictive, multiscale network models of disease by integrating genotype, gene expression, clinical traits, and other multiscale measures using causal network inference methods. This can enable the identification of the “key drivers” of pathology, which may represent novel therapeutic targets or biomarker candidates that play a more direct role in the etiology of disease. PMID:24527359

  11. Long-Term Effectiveness of Accelerated Hepatitis B Vaccination Schedule in Drug Users

    PubMed Central

    Shah, Dimpy P.; Grimes, Carolyn Z.; Nguyen, Anh T.; Lai, Dejian

    2015-01-01

    Objectives. We demonstrated the effectiveness of an accelerated hepatitis B vaccination schedule in drug users. Methods. We compared the long-term effectiveness of accelerated (0–1–2 months) and standard (0–1–6 months) hepatitis B vaccination schedules in preventing hepatitis B virus (HBV) infections and anti-hepatitis B (anti-HBs) antibody loss during 2-year follow-up in 707 drug users (HIV and HBV negative at enrollment and completed 3 vaccine doses) from February 2004 to October 2009. Results. Drug users in the accelerated schedule group had significantly lower HBV infection rates, but had a similar rate of anti-HBs antibody loss compared with the standard schedule group over 2 years of follow-up. No chronic HBV infections were observed. Hepatitis C positivity at enrollment and age younger than 40 years were independent risk factors for HBV infection and antibody loss, respectively. Conclusions. An accelerated vaccination schedule was more preferable than a standard vaccination schedule in preventing HBV infections in drug users. To overcome the disadvantages of a standard vaccination schedule, an accelerated vaccination schedule should be considered in drug users with low adherence. Our study should be repeated in different cohorts to validate our findings and establish the role of an accelerated schedule in hepatitis B vaccination guidelines for drug users. PMID:25880946

  12. Carbohydrate drugs: current status and development prospect.

    PubMed

    Zhang, Yan; Wang, Fengshan

    2015-04-01

    In recent years, there has been a great effort devoted to the investigation of the roles of carbohydrates in various essential biological processes and the development of carbohydrates to therapeutic drugs. This review summarizes the carbohydrate drugs which have been recorded in several pharmacopoeias, marketed, and under development. A prospect of the future development of carbohydrate drugs is discussed as well. PMID:25994058

  13. Supramolecular approaches for drug development.

    PubMed

    Kawakami, K; Ebara, M; Izawa, H; Sanchez-Ballester, N M; Hill, J P; Ariga, K

    2012-01-01

    Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced. PMID:22455591

  14. Accelerator System Development at High Voltage Engineering

    SciTech Connect

    Klein, M. G.; Gottdang, A.; Haitsma, R. G.; Mous, D. J. W.

    2009-03-10

    Throughout the years, HVE has continuously extended the capabilities of its accelerator systems to meet the rising demands from a diverse field of applications, among which are deep level ion implantation, micro-machining, neutron production for biomedical research, isotope production or accelerator mass spectrometry. Characteristic for HVE accelerators is the coaxial construction of the all solid state power supply around the acceleration tubes. With the use of solid state technology, the accelerators feature high stability and very low ripple. Terminal voltages range from 1 to 6 MV for HVE Singletrons and Tandetrons. The high-current versions of these accelerators can provide ion beams with powers of several kW. In the last years, several systems have been built with terminal voltages of 1.25 MV, 2 MV and 5 MV. Recently, the first system based on a 6 MV Tandetron has passed the factory tests. In this paper we describe the characteristics of the HVE accelerator systems and present as example recent systems.

  15. Technologies using accelerator-driven targets under development at BNL

    SciTech Connect

    Van Tuyle, G.J.

    1994-08-01

    Recent development work conducted at Brookhaven National Laboratory on technologies which use particle accelerator-driven targets is summarized. These efforts include development of the Spallation-Induced Lithium Conversion (SILC) Target for the Accelerator Production of Tritium (APT), the Accelerator-Driven Assembly for Plutonium Transformation (ADAPT) Target for the Accelerator-Based Conversion (ABC) of excess weapons plutonium. The PHOENIX Concept for the accelerator-driven transmutation of minor actinides and fission products from the waste stream of commercial nuclear power plants, and other potential applications.

  16. Kif14 overexpression accelerates murine retinoblastoma development.

    PubMed

    O'Hare, Michael; Shadmand, Mehdi; Sulaiman, Rania S; Sishtla, Kamakshi; Sakisaka, Toshiaki; Corson, Timothy W

    2016-10-15

    The mitotic kinesin KIF14 has an essential role in the recruitment of proteins required for the final stages of cytokinesis. Genomic gain and/or overexpression of KIF14 has been documented in retinoblastoma and a number of other cancers, such as breast, lung and ovarian carcinomas, strongly suggesting its role as an oncogene. Despite evidence of oncogenic properties in vitro and in xenografts, Kif14's role in tumor progression has not previously been studied in a transgenic cancer model. Using a novel Kif14 overexpressing, simian virus 40 large T-antigen retinoblastoma (TAg-RB) double transgenic mouse model, we aimed to determine Kif14's role in promoting retinal tumor formation. Tumor initiation and development in double transgenics and control TAg-RB littermates were documented in vivo over a time course by optical coherence tomography, with subsequent ex vivo quantification of tumor burden. Kif14 overexpression led to an accelerated initiation of tumor formation in the TAg-RB model and a significantly decreased tumor doubling time (1.8 vs. 2.9 weeks). Moreover, overall percentage tumor burden was also increased by Kif14 overexpression. These data provide the first evidence that Kif14 can promote tumor formation in susceptible cells in vivo. PMID:27270502

  17. Accelerated Application Development: The ORNL Titan Experience

    SciTech Connect

    Joubert, Wayne; Archibald, Richard K.; Berrill, Mark A.; Brown, W. Michael; Eisenbach, Markus; Grout, Ray; Larkin, Jeff; Levesque, John; Messer, Bronson; Norman, Matthew R.; Philip, Bobby; Sankaran, Ramanan; Tharrington, Arnold N.; Turner, John A.

    2015-05-09

    The use of computational accelerators such as NVIDIA GPUs and Intel Xeon Phi processors is now widespread in the high performance computing community, with many applications delivering impressive performance gains. However, programming these systems for high performance, performance portability and software maintainability has been a challenge. In this paper we discuss experiences porting applications to the Titan system. Titan, which began planning in 2009 and was deployed for general use in 2013, was the first multi-petaflop system based on accelerator hardware. To ready applications for accelerated computing, a preparedness effort was undertaken prior to delivery of Titan. In this paper we report experiences and lessons learned from this process and describe how users are currently making use of computational accelerators on Titan.

  18. Accelerated Application Development: The ORNL Titan Experience

    DOE PAGESBeta

    Joubert, Wayne; Archibald, Richard K.; Berrill, Mark A.; Brown, W. Michael; Eisenbach, Markus; Grout, Ray; Larkin, Jeff; Levesque, John; Messer, Bronson; Norman, Matthew R.; et al

    2015-05-09

    The use of computational accelerators such as NVIDIA GPUs and Intel Xeon Phi processors is now widespread in the high performance computing community, with many applications delivering impressive performance gains. However, programming these systems for high performance, performance portability and software maintainability has been a challenge. In this paper we discuss experiences porting applications to the Titan system. Titan, which began planning in 2009 and was deployed for general use in 2013, was the first multi-petaflop system based on accelerator hardware. To ready applications for accelerated computing, a preparedness effort was undertaken prior to delivery of Titan. In this papermore » we report experiences and lessons learned from this process and describe how users are currently making use of computational accelerators on Titan.« less

  19. Orphan drug: Development trends and strategies

    PubMed Central

    Sharma, Aarti; Jacob, Abraham; Tandon, Manas; Kumar, Dushyant

    2010-01-01

    The growth of pharma industries has slowed in recent years because of various reasons such as patent expiries, generic competition, drying pipelines, and increasingly stringent regulatory guidelines. Many blockbuster drugs will loose their exclusivity in next 5 years. Therefore, the current economic situation plus the huge generic competition shifted the focus of pharmaceutical companies from the essential medicines to the new business model — niche busters, also called orphan drugs. Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs could offer an integrated healthcare solution that enables pharma companies to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and patient support. Incentives for drug development provided by governments, as well as support from the FDA and EU Commission in special protocols, are a further boost for the companies developing orphan drugs. Although there may still be challenges ahead for the pharmaceutical industry, orphan drugs seem to offer the key to recovery and stability within the market. In our study, we have compared the policies and orphan drug incentives worldwide alongwith the challenges faced by the pharmaceutical companies. Recent developments are seen in orphan drug approval, the various drugs in orphan drug pipeline, and the future prospectives for orphan drugs and diseases. PMID:21180460

  20. Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring.

    PubMed

    Externbrink, Anna; Clark, Meredith R; Friend, David R; Klein, Sandra

    2013-11-01

    The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring®, a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring®, it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non

  1. Contemporary murine models in preclinical astrocytoma drug development

    PubMed Central

    McNeill, Robert S.; Vitucci, Mark; Wu, Jing; Miller, C. Ryan

    2015-01-01

    Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors. PMID:25246428

  2. High charge short electron bunches for wakefield accelerator structures development.

    SciTech Connect

    Conde, M. E.

    1998-09-25

    The Argonne Wakefield Accelerator group develops accelerating structures based on dielectric loaded waveguides. We use high charge short electron bunches to excite wakefields in dielectric loaded structures, and a second (low charge) beam to probe the wakefields left behind by the drive beam. We report measurements of beam parameters and also initial results of the dielectric loaded accelerating structures. We have studied acceleration of the probe beam in these structures and we have also made measurements on the RF pulses that are generated by the drive beam. Single drive bunches, as well as multiple bunches separated by an integer number of RF periods have been used to generate the accelerating wakefields.

  3. Accelerator development for a radioactive beam facility based on ATLAS.

    SciTech Connect

    Shepard, K. W.

    1998-01-08

    The existing superconducting linac ATLAS is in many respects an ideal secondary beam accelerator for an ISOL (Isotope separator on-line) type radioactive beam facility. Such a facility would require the addition of two major accelerator elements: a low charge state injector for the existing heavy ion linac, and a primary beam accelerator providing 220 MV of acceleration for protons and light ions. Development work for both of these elements, including the option of superconducting cavities for the primary beam accelerator is discussed.

  4. Technology development for high power induction accelerators

    SciTech Connect

    Birx, D.L.; Reginato, L.L.

    1985-06-11

    The marriage of Induction Linac technology with Nonlinear Magnetic Modulators has produced some unique capabilities. It appears possible to produce electron beams with average currents measured in amperes, at gradients exceeding 1 MeV/meter, and with power efficiencies approaching 50%. A 2 MeV, 5 kA electron accelerator has been constructed at the Lawrence Livermore National Laboratory (LLNL) to demonstrate these concepts and to provide a test facility for high brightness sources. The pulse drive for the accelerator is based on state-of-the-art magnetic pulse compressors with very high peak power capability, repetition rates exceeding a kilohertz and excellent reliability.

  5. New Zealand’s Drug Development Industry

    PubMed Central

    Lockhart, Michelle Marie; Babar, Zaheer-Ud-Din; Carswell, Christopher; Garg, Sanjay

    2013-01-01

    The pharmaceutical industry’s profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ) from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ’s clinical research industry based on a standard per participant payment to study sites and the number of industry-sponsored clinical trials approved each year. Our analyses found that NZ’s clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support. PMID:24065037

  6. [Research development of HIV drug resistance].

    PubMed

    Zou, Wen; Liu, Ying; Wang, Jian; Gao, Guo-Jian; Dong, Ji-Peng; Xian, Qing-Fei

    2013-08-01

    Highly active antiretroviral combination therapy significantly reduced the mortality, but in the high-speed copying, high genetic variation and drug selection pressure under the effect of the increasingly serious problem of drug resistance greatly weakened the role of HAART inhibit viral replication and reduce antiviral treatment. This paper reports the latest trends in HIV drug-resistance in order to develop anti-HIV drugs in clinical programs, research and development of new guidance anti-HIV-1 strategy to bring guidance. PMID:24228557

  7. Vacuum Insulator Development for the Dielectric Wall Accelerator

    SciTech Connect

    Harris, J R; Blackfield, D; Caporaso, G J; Chen, Y; Hawkins, S; Kendig, M; Poole, B; Sanders, D M; Krogh, M; Managan, J E

    2008-03-17

    At Lawrence Livermore National Laboratory, we are developing a new type of accelerator, known as a Dielectric Wall Accelerator, in which compact pulse forming lines directly apply an accelerating field to the beam through an insulating vacuum boundary. The electrical strength of this insulator may define the maximum gradient achievable in these machines. To increase the system gradient, we are using 'High Gradient Insulators' composed of alternating layers of dielectric and metal for the vacuum insulator. In this paper, we present our recent results from experiment and simulation, including the first test of a High Gradient Insulator in a functioning Dielectric Wall Accelerator cell.

  8. Arrayed Diagnostic Development on the HyperV Plasma Accelerators

    NASA Astrophysics Data System (ADS)

    Brockington, Samuel; Case, Andrew; Messer, Sarah; Bomgardner, Richard; Witherspoon, F. D.

    2008-11-01

    The sparkgap injected plasma accelerator is one of several coaxial railguns constructed at HyperV to accelerate dense plasmas to high velocities. A circumferential array of 112 high voltage tungsten electrodes ablates polyethylene to form and inject a toroidally shaped plasma into the annular breech at the rear of the accelerator. A pulse forming network then applies several hundred kiloamps to the coaxial electrodes to accelerate the plasma. A 4-chord laser deflectometer and a 32-sensor fast photodiode array are being developed to help resolve the structure, density, and velocity of the accelerated plasma jet for different accelerator parameters. We present details of the diagnostic designs and initial data. Work supported by the U.S. DOE Office of Fusion Energy Sciences.

  9. Development of a dedicated superconducting accelerator for positron production

    NASA Astrophysics Data System (ADS)

    O'Rourke, B. E.; Oshima, N.; Kuroda, R.; Suzuki, R.; Ohdaira, T.; Kinomura, A.; Hayashizaki, N.; Minehara, E.; Yamauchi, H.; Fukamizu, Y.; Shikibu, M.; Kawamoto, T.; Minehara, Y.

    2011-01-01

    We report on the current status of a project to develop a dedicated superconducting accelerator for slow positron production at AIST. Two 500 MHz, 5 cell cavities will form the basis of the new accelerator. Initial set-up and preliminary design activities are reported.

  10. Accelerated Hepatitis B Vaccine Schedule among Drug Users – A Randomized Controlled Trial

    PubMed Central

    Hwang, Lu-Yu; Grimes, Carolyn Z.; Tran, Thanh Quoc; Clark, April; Xia, Rui; Lai, Dejian; Troisi, Catherine; Williams, Mark

    2010-01-01

    Background Hepatitis B vaccine provides a model for improving uptake and completion of multi-dose vaccinations in the drug-using community. Methods DASH project conducted randomized controlled trial among not-in-treatment current drug users in two urban neighborhoods. Neighborhoods were cluster-randomized to receive a standard (HIV information) or enhanced (HBV vaccine acceptance/adherence) behavioral intervention; participants within clusters were randomized to a standard (0, 1, 6 mo) or accelerated (0, 1, 2 mo) vaccination schedule. Outcomes were completion of three-dose vaccine and HBV seroprotection. Results Of those screening negative for HIV/HBV, 77% accepted HB vaccination and 75% of those received all 3 doses. Injecting drug users (IDUs) on the accelerated schedule were significantly more likely to receive 3 doses (76%) than those on the standard schedule (66%, p=.04), although for drug users as a whole the adherence was 77% and 73%. No difference in adherence was observed between behavioral intervention groups. Predictors of adherence were older age, African American race, stable housing, and alcohol use. Cumulative HBV seroprotection (≥10 mIU/mL) was gained by 12 months by 65% of those completing. Seroprotection at 6 months was greater for the accelerated schedule group. Conclusions The accelerated vaccine schedule improves hepatitis B vaccination adherence among IDU. PMID:20936979

  11. Drug Development for Alzheimer's Disease: Recent Progress

    PubMed Central

    Ji, Wonjin

    2010-01-01

    Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351

  12. Pharmacokinetic/Pharmacodynamic-Driven Drug Development

    PubMed Central

    Gallo, James M.

    2010-01-01

    The drug discovery and development enterprise, traditionally an industrial juggernaut, has spanned into the academic arena that is partially motivated by the National Institutes of Health Roadmap highlighting translational science and medicine. Since drug discovery and development represents a pipeline of basic to clinical investigations it meshes well with the prime “bench to the bedside” directive of translational medicine. The renewed interest in drug discovery and develpoment in academia provides an opportunity to rethink the hiearchary of studies with the hope to improve the staid approaches that have been critizied for lacking innovation. One area that has received limited attention concerns the use of pharmacokinetic [PK] and pharmacodynamic [PD] studies in the drug development process. Using anticancer drug development as a focus, this review will address past and current deficencies in how PK/PD studies are conducted and offer new strategies that might bridge the gap between preclinical and clinical trials. PMID:20687184

  13. Developments in antipsychotic drugs - an update.

    PubMed

    Reynolds, G P

    1998-02-01

    Antipsychotic drug research has recently made much progress. Over the past two years several new drugs have been introduced for the treatment of schizophrenia and more compounds are shortly to be released. Pharmacological studies, improved behavioural models and modern imaging techniques have all contributed to a better understanding of the mechanisms of antipsychotic drug action. Some of the developments that have been made over the past year are reviewed here. PMID:15991957

  14. Improving the tuberculosis drug development pipeline.

    PubMed

    Evangelopoulos, Dimitrios; McHugh, Timothy D

    2015-11-01

    Mycobacterium tuberculosis is considered one of the most successful pathogens and multidrug-resistant tuberculosis, a disease that urgently requires new chemical entities to be developed for treatment. There are currently several new molecules under clinical investigation in the tuberculosis (TB) drug development pipeline. However, the complex lifestyle of M. tuberculosis within the host presents a barrier to the development of new drugs. In this review, we highlight the reasons that make TB drug discovery and development challenging as well as providing solutions, future directions and alternative approaches to new therapeutics for TB. PMID:25772393

  15. Advanced Microgravity Acceleration Measurement Systems (AMAMS) Being Developed

    NASA Technical Reports Server (NTRS)

    Sicker, Ronald J.; Kacpura, Thomas J.

    2003-01-01

    The Advanced Microgravity Acceleration Measurement Systems (AMAMS) project is part of NASA s Instrument Technology Development program to develop advanced sensor systems. The primary focus of the AMAMS project is to develop microelectromechanical systems (MEMS) for acceleration sensor systems to replace existing electromechanical sensor systems presently used to assess relative gravity levels aboard spacecraft. These systems are used to characterize both vehicle and payload responses to low-gravity vibroacoustic environments. The collection of microgravity acceleration data is useful to the microgravity life sciences, microgravity physical sciences, and structural dynamics communities. The inherent advantages of semiconductor-based systems are reduced size, mass, and power consumption, with enhanced long-term calibration stability.

  16. NIPTE: a multi-university partnership supporting academic drug development.

    PubMed

    Gurvich, Vadim J; Byrn, Stephen R

    2013-10-01

    The strategic goal of academic translational research is to accelerate translational science through the improvement and development of resources for moving discoveries across translational barriers through 'first in humans' studies. To achieve this goal, access to drug discovery resources and preclinical IND-enabling infrastructure is crucial. One potential approach of research institutions for coordinating preclinical development, based on a model from the National Institute for Pharmaceutical Technology and Education (NIPTE), can provide academic translational and medical centers with access to a wide variety of enabling infrastructure for developing small molecule clinical candidates in an efficient, cost-effective manner. PMID:23732177

  17. Long non-coding RNAs in cancer drug resistance development.

    PubMed

    Majidinia, Maryam; Yousefi, Bahman

    2016-09-01

    The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency. As such, it may not be surprising that some lncRNAs have been recently linked to carcinogenesis and drug resistance/sensitivity. Research is accelerating to decipher the exact molecular mechanism of lncRNA-regulated drug resistance and its therapeutic implications. In this article, we will review the structure, biogenesis, and mode of action of lncRNAs. Then, the involvement of lncRNAs in drug resistance will be discussed in detail. PMID:27427176

  18. Indoles - A promising scaffold for drug development.

    PubMed

    Sravanthi, T V; Manju, S L

    2016-08-25

    Generally, heterocycles occupy a prominent place in chemistry due to their wide range of applications in the fields of drug design, photochemistry, agrochemicals, dyes and so on. Among them, indole scaffolds have been found in most of the important synthetic drug molecules and paved a faithful way to develop effective targets. Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds. Among the indole class of compounds, 2-arylindoles appear to be a most promising lead for drug development. The derivatives of 2-arylindoles exhibits antibacterial, anticancer, anti-oxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis activity, etc. This article would provide a clear knowledge on the wide-ranging biological activities of 2-arylindoles over the past two decades, which would be beneficial for the designing of more potent drug targets in order to compete with the existing drugs. PMID:27237590

  19. Setting accelerated dissolution test for PLGA microspheres containing peptide, investigation of critical parameters affecting drug release rate and mechanism.

    PubMed

    Tomic, I; Vidis-Millward, A; Mueller-Zsigmondy, M; Cardot, J-M

    2016-05-30

    The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation. PMID:27025293

  20. Development of compact linear accelerator in KBSI

    SciTech Connect

    Yoon, Jang-Hee; Lee, Byoung-Seob; Choi, Seyong; Park, Jin Yong; Ok, Jung-Woo; Won, Mi-Sook

    2012-02-15

    The compact linear accelerator using a 28 GHz ECRIS is under construction in KBSI, South Korea. The main capability of this facility is the production of fast neurons for the neutron radiography. The designing of a superconducting magnet, microwave transmission system, beam extraction, and plasma chamber of ECRIS were finished. The nominal axial design fields of the magnets are 3.6 T at injection and 2.2 T at extraction; the nominal radial design field strength at the plasma chamber wall is 2.1 T. We already installed 10 kW, 28 GHz gyrotron, and tested a microwave power from gyrotron using a dummy load. The current status will be discussed in this paper.

  1. Development of compact linear accelerator in KBSI.

    PubMed

    Yoon, Jang-Hee; Lee, Byoung-Seob; Choi, Seyong; Park, Jin Yong; Ok, Jung-Woo; Won, Mi-Sook

    2012-02-01

    The compact linear accelerator using a 28 GHz ECRIS is under construction in KBSI, South Korea. The main capability of this facility is the production of fast neurons for the neutron radiography. The designing of a superconducting magnet, microwave transmission system, beam extraction, and plasma chamber of ECRIS were finished. The nominal axial design fields of the magnets are 3.6 T at injection and 2.2 T at extraction; the nominal radial design field strength at the plasma chamber wall is 2.1 T. We already installed 10 kW, 28 GHz gyrotron, and tested a microwave power from gyrotron using a dummy load. The current status will be discussed in this paper. PMID:22380162

  2. Re-engineering drug discovery and development.

    PubMed

    FitzGerald, Garret A

    2011-10-01

    The rate of new drug approvals in the US has remained essentially constant since 1950, while the costs of drug development have soared. Many commentators question the sustainability of the current model of drug development, in which large pharmaceutical companies incur markedly escalating costs to deliver the same number of products to market. This Issue Brief summarizes the problem, describes ongoing governmental efforts to influence the process, and suggests changes in regulatory science and translational medicine that may promote more successful development of safe and effective therapeutics PMID:22049582

  3. Pharmaceutical development of microbicide drug products.

    PubMed

    Friend, David R

    2010-12-01

    HIV infection rates in the developing world remain a serious problem. One potential approach to reduce infection rates is to use products known as microbicides, referred to herein as microbicide drug products (MDPs). These are drugs capable of, when administered topically to the vagina (or rectum), interfering with infection by one or more mechanisms. This review article covers the latest pharmaceutical developments in the area of microbicides dosage forms and delivery systems. These products are principally designed for use in the developing world and must therefore address cultural and societal issues generally unknown in the developed world. The first-generation microbicides evaluated clinically were principally polyanions. These drugs, administered intravaginally as gels, were found to be ineffective in preventing transmission of HIV from men to women. Second-generation drugs such as tenofovir, dapivirine, and UC781 are reverse transcriptase inhibitors developed as gels formulations and intravaginal rings (IVRs). Gels are considered coitally-related products while IVRs are coitally-independent systems designed to release the drug over a four-week period or possibly longer (up to 3 or 4 months). Other dosage forms under development include fast dissolving films, tablets/capsules, and possibly vaginal sponges. Dual protection systems are also under development. These systems include formulations capable of preventing HIV infection along with a second drug capable of preventing conception or other viral infections such as HSV. PMID:20017601

  4. Optimizing Central Nervous System Drug Development Using Molecular Imaging.

    PubMed

    Hargreaves, R J; Hoppin, J; Sevigny, J; Patel, S; Chiao, P; Klimas, M; Verma, A

    2015-07-01

    Advances in multimodality fusion imaging technologies promise to accelerate the understanding of the systems biology of disease and help in the development of new therapeutics. The use of molecular imaging biomarkers has been proven to shorten cycle times for central nervous system (CNS) drug development and thereby increase the efficiency and return on investment from research. Imaging biomarkers can be used to help select the molecules, doses, and patients most likely to test therapeutic hypotheses by stopping those that have little chance of success and accelerating those with potential to achieve beneficial clinical outcomes. CNS imaging biomarkers have the potential to drive new medical care practices for patients in the latent phases of progressive neurodegenerative disorders by enabling the detection, preventative treatment, and tracking of disease in a paradigm shift from today's approaches that have to see the overt symptoms of disease before treating it. PMID:25869938

  5. Nanodiamonds: The intersection of nanotechnology, drug development, and personalized medicine

    PubMed Central

    Ho, Dean; Wang, Chung-Huei Katherine; Chow, Edward Kai-Hua

    2015-01-01

    The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others. The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces. More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine–Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed. PMID:26601235

  6. Global aspects of drug development.

    PubMed

    Hoppu, Kalle; Hogerzeil, Hans V

    2011-01-01

    About nine million children die every year before they reach the age of 5 years, of conditions largely amendable with existing medicines. Lack of medicines is not the single most important health problem of children, but work to provide children with better access to appropriate medicines is essential for achievement of the child health goals set. Taking into consideration the global aspect in the development of paediatric medicines the benefits of the regional paediatric initiatives can be spread worldwide. This chapter provides insights in the challenges and opportunities of developing paediatric medicines for health needs of children in the developing world. The Essential Medicines List for children first made available in 2008 serves as an example of the many tools available from WHO to improve children's access to the medicines they need. PMID:21882121

  7. Regional intestinal drug permeation: biopharmaceutics and drug development.

    PubMed

    Lennernäs, Hans

    2014-06-16

    Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff>1.5×10(-4)cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested

  8. Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery

    PubMed Central

    Lee, Wen Hwa

    2015-01-01

    There is a scarcity of novel treatments to address many unmet medical needs. Industry and academia are finally coming to terms with the fact that the prevalent models and incentives for innovation in early stage drug discovery are failing to promote progress quickly enough. Here we will examine how an open model of precompetitive public–private research partnership is enabling efficient derisking and acceleration in the early stages of drug discovery, whilst also widening the range of communities participating in the process, such as patient and disease foundations. PMID:26042736

  9. Computational Tools for Accelerating Carbon Capture Process Development

    SciTech Connect

    Miller, David; Sahinidis, N V; Cozad, A; Lee, A; Kim, H; Morinelly, J; Eslick, J; Yuan, Z

    2013-06-04

    This presentation reports development of advanced computational tools to accelerate next generation technology development. These tools are to develop an optimized process using rigorous models. They include: Process Models; Simulation-Based Optimization; Optimized Process; Uncertainty Quantification; Algebraic Surrogate Models; and Superstructure Optimization (Determine Configuration).

  10. Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies.

    PubMed

    Schou-Pedersen, Anne Marie V; Østergaard, Jesper; Cornett, Claus; Hansen, Steen Honoré

    2015-05-15

    Microwave ovens have been used extensively in organic synthesis in order to accelerate reaction rates. Here, a set up comprising a microwave oven combined with silicon carbide (SiC) plates for the controlled microwave heating of model formulations has been applied in order to investigate, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. In the accelerated stability studies, a design of experiments (DoE) approach was applied in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating leading to temperatures between 150°C and 180°C as compared to accelerated stability studies performed at 40°C and 80°C using a conventional oven. Ranking of the reactivity of the excipients could be made in the DoE studies performed at 150-180°C, which was representative for the ranking obtained after storage at 40°C and 80°C. It was possible to reduce the time needed for drug-excipient compatibility testing of the three model formulations from weeks to less than an hour in the three case studies. The microwave oven is therefore considered to be an interesting alternative to conventional thermal techniques for the investigation of drug-excipient interactions during preformulation. PMID:25746946

  11. Development of stable lyophilized protein drug products.

    PubMed

    Remmele, Richard L; Krishnan, Sampathkumar; Callahan, William J

    2012-03-01

    Freeze drying, or lyophilization is widely used for biopharmaceuticals to improve the long term storage stability of labile molecules. This review examines general theory and practice of rational lyophilization of biopharmaceuticals. Formulation development involving the selection of appropriate excipients, their associated physical properties, and mechanism of action in achieving a stable drug product are primary considerations for a successful lyophilization program. There are several parameters considered critical on the basis of their relationship to lyophilization cycle development and protein product stability. This along with the importance of analytical methods to provide insight toward understanding properties of drug product stability and cake structure are discussed. Also, aspects of instability found in lyophilized biopharmaceutical products, their degradation pathways and control are elucidated. Finally, container-closure requirements and drug product handling are described in context of the caveats to avoid compromising drug product quality. PMID:22283723

  12. Drug development of intranasally delivered peptides.

    PubMed

    Campbell, Catherine; Morimoto, Bruce H; Nenciu, Daniela; Fox, Anthony W

    2012-04-01

    Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug-development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies. PMID:22834082

  13. A Drug-Centric View of Drug Development: How Drugs Spread from Disease to Disease

    PubMed Central

    Rodriguez-Esteban, Raul

    2016-01-01

    Drugs are often seen as ancillary to the purpose of fighting diseases. Here an alternative view is proposed in which they occupy a spearheading role. In this view, drugs are technologies with an inherent therapeutic potential. Once created, they can spread from disease to disease independently of the drug creator’s original intentions. Through the analysis of extensive literature and clinical trial records, it can be observed that successful drugs follow a life cycle in which they are studied at an increasing rate, and for the treatment of an increasing number of diseases, leading to clinical advancement. Such initial growth, following a power law on average, has a degree of momentum, but eventually decelerates, leading to stagnation and decay. A network model can describe the propagation of drugs from disease to disease in which diseases communicate with each other by receiving and sending drugs. Within this model, some diseases appear more prone to influence other diseases than be influenced, and vice versa. Diseases can also be organized into a drug-centric disease taxonomy based on the drugs that each adopts. This taxonomy reflects not only biological similarities across diseases, but also the level of differentiation of existing therapies. In sum, this study shows that drugs can become contagious technologies playing a driving role in the fight against disease. By better understanding such dynamics, pharmaceutical developers may be able to manage drug projects more effectively. PMID:27124390

  14. Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.

    PubMed

    Rioux, Nathalie; Waters, Nigel J

    2016-07-01

    Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field. PMID:26936973

  15. Research and development of capacitive transducer with linear acceleration

    NASA Astrophysics Data System (ADS)

    Korobova, Natalia; Kochurina, Elena; Timoshenkov, Sergey; Chaplygin, Yuriy; Anchutin, Stepan; Kosolapov, Andrey

    2015-05-01

    Paper presents the study results and modeling of functional characteristics of the linear acceleration transducers, enabling sensors creation with the specified parameters. Sensing element made for linear acceleration transducer with torsion cruciform section has been proposed on the based design and technological principles. It allows minimizing the impact of cross-acceleration and gives the maximum of center mass displacement for high sensors sensitivity in the given dimensions. The range of measured acceleration from ± 0.2g to ± 50g was provided by changing the torsion bar thickness n = 34 ÷ 56 microns. The transducers frequency range of linear acceleration 100-150 Hz depends on the gas pressure P = 700-800Pa in which the sensor element was located. Methods converting displacement of sensing element in the sensor output have been provided. On their basis the linear acceleration transducers with analog output signal having a predetermined frequency range and high linearity of the transformation (nonlinearity 0.2-1.5%) was developed. Also the linear acceleration transducers with digital signal consuming little (no more than 850 μA), low noisy (standard deviation to 0.1mg/rt-Hz) and high sensitivity (up to 0.1mg) to the accelerations was made. Errors in manufacturing process of sensitive elements and operating environment temperature affect the changes in the characteristics of the linear acceleration transducers. It has been established that different plate thickness up to 3.6% leads to the scale factor error to 4.7%. Irreproducibility of depth anisotropic etching of silicon up to 6.6% introduces an error in the output signal of 2.9 ... 13.8mg.

  16. Computational Tools to Accelerate Commercial Development

    SciTech Connect

    Miller, David C

    2013-01-01

    The goals of the work reported are: to develop new computational tools and models to enable industry to more rapidly develop and deploy new advanced energy technologies; to demonstrate the capabilities of the CCSI Toolset on non-proprietary case studies; and to deploy the CCSI Toolset to industry. Challenges of simulating carbon capture (and other) processes include: dealing with multiple scales (particle, device, and whole process scales); integration across scales; verification, validation, and uncertainty; and decision support. The tools cover: risk analysis and decision making; validated, high-fidelity CFD; high-resolution filtered sub-models; process design and optimization tools; advanced process control and dynamics; process models; basic data sub-models; and cross-cutting integration tools.

  17. Status of high temperature superconductor development for accelerator magnets

    NASA Technical Reports Server (NTRS)

    Hirabayashi, H.

    1995-01-01

    High temperature superconductors are still under development for various applications. As far as conductors for magnets are concerned, the development has just been started. Small coils wound by silver sheathed Bi-2212 and Bi-2223 oxide conductors have been reported by a few authors. Essential properties of high T(sub c) superconductors like pinning force, coherent length, intergrain coupling, weak link, thermal property, AC loss and mechanical strength are still not sufficiently understandable. In this talk, a review is given with comparison between the present achievement and the final requirement for high T(sub c) superconductors, which could be particularly used in accelerator magnets. Discussions on how to develop high T(sub c) superconductors for accelerator magnets are included with key parameters of essential properties. A proposal of how to make a prototype accelerator magnet with high T(sub c) superconductors with prospect for future development is also given.

  18. Nb3Sn accelerator magnet development around the world

    SciTech Connect

    Michael J. Lamm

    2003-06-23

    During the past 30 years superconducting magnet systems have enabled accelerators to achieve energies and luminosities that would have been impractical if not impossible with resistive magnets. By far, NbTi has been the preferred conductor for this application because of its ductility and insensitivity of Jc to mechanical strain. This is despite the fact that Nb{sub 3}Sn has a more favorable Jc vs. B dependence and can operate at much higher temperatures. Unfortunately, NbTi conductor is reaching the limit of it usefulness for high field applications. Despite incremental increases in Jc and operation at superfluid temperatures, magnets are limited to approximately a 10 T field. Improvements in conductor performance combined with future requirements for accelerator magnets to have bore fields greater than 10 T or operate in areas of large beam-induced heat loads now make Nb{sub 3}Sn look attractive. Thus, laboratories in several countries are actively engaged in programs to develop Nb{sub 3}Sn accelerator magnets for future accelerator applications. A summary of this important research activity is presented along with a brief history of Nb{sub 3}Sn accelerator magnet development and a discussion of requirements for future accelerator magnets.

  19. Accelerated larvae development of Ascaris lumbricoides eggs with ultraviolet radiation

    NASA Astrophysics Data System (ADS)

    Aladawi, M. A.; Albarodi, H.; Hammoudeh, A.; Shamma, M.; Sharabi, N.

    2006-01-01

    In order to investigate the effect of UV radiation on the development of Ascaris lumbricoides larvae, eggs were exposed to increasing UV doses. Filtered wastewater from the secondary effluent taken from the Damascus wastewater treatment plant (DWTP) was used as irradiation and incubation medium. The progressive and accelerated embryonation stages were microscopically observed and the percentages of completely developed larvae were determined weekly. Results indicated that the UV radiation accelerated the development of larvae with increasing UV dose. Preliminary information about the relationship between the UV radiation dose and rate of embryonation is also presented.

  20. Space Launch System Accelerated Booster Development Cycle

    NASA Technical Reports Server (NTRS)

    Arockiam, Nicole; Whittecar, William; Edwards, Stephen

    2012-01-01

    With the retirement of the Space Shuttle, NASA is seeking to reinvigorate the national space program and recapture the public s interest in human space exploration by developing missions to the Moon, near-earth asteroids, Lagrange points, Mars, and beyond. The would-be successor to the Space Shuttle, NASA s Constellation Program, planned to take humans back to the Moon by 2020, but due to budgetary constraints was cancelled in 2010 in search of a more "affordable, sustainable, and realistic" concept2. Following a number of studies, the much anticipated Space Launch System (SLS) was unveiled in September of 2011. The SLS core architecture consists of a cryogenic first stage with five Space Shuttle Main Engines (SSMEs), and a cryogenic second stage using a new J-2X engine3. The baseline configuration employs two 5-segment solid rocket boosters to achieve a 70 metric ton payload capability, but a new, more capable booster system will be required to attain the goal of 130 metric tons to orbit. To this end, NASA s Marshall Space Flight Center recently released a NASA Research Announcement (NRA) entitled "Space Launch System (SLS) Advanced Booster Engineering Demonstration and/or Risk Reduction." The increased emphasis on affordability is evident in the language used in the NRA, which is focused on risk reduction "leading to an affordable Advanced Booster that meets the evolved capabilities of SLS" and "enabling competition" to "enhance SLS affordability. The purpose of the work presented in this paper is to perform an independent assessment of the elements that make up an affordable and realistic path forward for the SLS booster system, utilizing advanced design methods and technology evaluation techniques. The goal is to identify elements that will enable a more sustainable development program by exploring the trade space of heavy lift booster systems and focusing on affordability, operability, and reliability at the system and subsystem levels5. For this study

  1. Can hydromorphic conditions accelerate soil development?

    NASA Astrophysics Data System (ADS)

    Ringer, Marianna; Kiss, Klaudia; Horváth-Szabó, Kata; Réka Balázs, Brigitta; Németh, Tibor; Sipos, Péter; Szabó, Máté; Jakab, Gergely; Madarász, Balázs; Szalai, Zoltán

    2016-04-01

    The formation and development of waterlogged (hydromorphic) soils are primarily determined by long-term water saturation. The presence of water in the profile can result increasing speed of soil forming processes including the accumulation of organic matter or other components and mineralogical transformations. Original papers refer more than hundreds of years for this kinds of mineral transformations. We suppose that this process could be more rapid. This study focuses on the mineralogical investigation of a sandy meadow soil (calcic, gleyic Phaeozem ferric, arenic) located in a swampy area in Central Hungary. The starting time of the soil formation is a well documented fact: the parent material deposited during an extremely heavy flood event in the 1960s. Therefore, the studied soil profile is the result of the last half century. Our aim was to explore the degree of mineral phase alteration via soil formation during a half-century under hydromorphic conditions. Routine laboratory measurements (selective dissolution methods for the determination of amorphous and crystalline Fe, and Mn content, X-ray fluorescence spectroscopy measurements for elemental composition determination, X-ray powder diffraction for mineralogical composition, and particle sizing by laser diffraction) were implemented. Morphological and chemical study of carbonate and iron nodules was carried out by electron microprobe. Simple chemical tests (eg. Fe2+ indication by dipiridil test) and morphological observations were performed on the field. Redox potential (Eh) and pH were measured in 20 cm and 40 cm depths by field monitoring station during the vegetation period. Results show that well developed horizons have emerged during fifty years in the studied soil profile. The most intense mineralogical transformations developed in the zone of the heaviest redox oscillation. Soil formation under hydromorphic conditions proceeds at higher speeds contrariwise to the century time scale reported in

  2. TRPV3 in Drug Development.

    PubMed

    Broad, Lisa M; Mogg, Adrian J; Eberle, Elizabeth; Tolley, Marcia; Li, Dominic L; Knopp, Kelly L

    2016-01-01

    Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist. PMID:27618069

  3. Advances in Statistical Approaches Oncology Drug Development

    PubMed Central

    Ivanova, Anastasia; Rosner, Gary L.; Marchenko, Olga; Parke, Tom; Perevozskaya, Inna; Wang, Yanping

    2014-01-01

    We describe some recent developments in statistical methodology and practice in oncology drug development from an academic and an industry perspective. Many adaptive designs were pioneered in oncology, and oncology is still at the forefront of novel methods to enable better and faster Go/No-Go decision making while controlling the cost. PMID:25949927

  4. Drug Repurposing Is a New Opportunity for Developing Drugs against Neuropsychiatric Disorders.

    PubMed

    Lee, Hyeong-Min; Kim, Yuna

    2016-01-01

    Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing. PMID:27073698

  5. Drug Repurposing Is a New Opportunity for Developing Drugs against Neuropsychiatric Disorders

    PubMed Central

    Lee, Hyeong-Min; Kim, Yuna

    2016-01-01

    Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing. PMID:27073698

  6. [Development of antituberculous drugs: current status and future prospects].

    PubMed

    Tomioka, Haruaki; Namba, Kenji

    2006-12-01

    and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale

  7. An accelerated fusion power development plan

    NASA Astrophysics Data System (ADS)

    Dean, Stephen O.; Baker, Charles C.; Cohn, Daniel R.; Kinkead, Susan D.

    1991-06-01

    Energy for electricity and transportation is a national issue with worldwide environmental and political implications. The world must have energy options for the next century that are not vulnerable to possible disruption for technical, environmental, public confidence, or other reasons. Growing concerns about the greenhouse effect and the safety of transporting oil may lead to reduced burning of coal and other fossil fuels, and the incidents at Three Mile Island and Chernobyl, as well as nuclear waste storage problems, have eroded public acceptance of nuclear fission. Meeting future world energy needs will require improvements in energy efficiency and conservation. However, the world will soon need new central station power plants and increasing amounts of fuel for the transportation sector. The use of fossil fuels, and possibly even fission power, will very likely be restricted because of environmental, safety, and, eventually, supply considerations. Time is running out for policymakers. New energy technologies cannot be brought to the marketplace overnight. Decades are required to bring a new energy production technology from conception to full market penetration. With the added urgency to mitigate deleterious environmental effects of energy use, policymakers must act decisively now to establish and support vigorous energy technology development programs. The U.S. has invested 8 billion over the past 40 years in fusion research and development. If the U.S. fusion program proceeds according to its present strategy, an additional 40 years, and more money, will be expended before fusion will provide commercial electricity. Such an extended schedule is neither cost-effective nor technically necessary. It is time to launch a national venture to construct and operate a fusion power pilot plant. Such a plant could be operational within 15 years of a national commitment to proceed.

  8. The Blood-Brain Barrier: Bottleneck in Brain Drug Development

    PubMed Central

    Pardridge, William M.

    2005-01-01

    Summary: The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences. PMID:15717053

  9. A bioengineered drug-Eluting scaffold accelerated cutaneous wound healing In diabetic mice.

    PubMed

    Yin, Hao; Ding, Guoshan; Shi, Xiaoming; Guo, Wenyuan; Ni, Zhijia; Fu, Hong; Fu, Zhiren

    2016-09-01

    Hyperglycemia in diabetic patients can greatly hinder the wound healing process. In this study we investigated if the engagement of F4/80(+) murine macrophages could accelerate the cutaneous wound healing in streptozotocin induced diabetic mice. To facilitate the engagement of macrophages, we engineered a drug-eluting electrospun scaffold with a payload of monocyte chemoattractant protein-1 (MCP-1). MCP-1 could be readily released from the scaffold within 3 days. The electrospun scaffold showed no cytotoxic effects on human keratinocytes in vitro. Full-thickness excisional cutaneous wound was created in diabetic mice. The wound fully recovered within 10 days in mice treated with the drug-eluting scaffold. In contrast, the wound took 14 days to fully recover in control groups. The use of drug-eluting scaffold also improved the re-epithelialization. Furthermore, we observed a larger population of F4/80(+) macrophages in the wound bed of mice treated with drug-eluting scaffolds on day 3. This marked increase of macrophages in the wound bed could have contributed to the accelerated wound healing. Our study shed new light on an immuno-engineering solution for wound healing management in diabetic patients. PMID:27187186

  10. Accelerating Leadership Development via Immersive Learning and Cognitive Apprenticeship

    ERIC Educational Resources Information Center

    Backus, Clark; Keegan, Kevin; Gluck, Charles; Gulick, Lisa M. V.

    2010-01-01

    The authors put forward an approach to leadership development that builds on the principle of accelerated learning. They argue that leadership development, particularly in a period of recession or slow economic growth, needs to deliver results more quickly and with fewer resources. Indeed, they raise the question of whether or not this is what is…

  11. No Time To Kill: Entrainment and Accelerating Courseware Development.

    ERIC Educational Resources Information Center

    Millington, Paula Crnkovich

    This paper examines the concept of time in multimedia, World Wide Web-based courseware development. The biological concept of entrainment (the alignment of rhythms within and between systems) to accelerate courseware development is explored. The discussion begins with the foundational concepts of entrainment from biological systems and social…

  12. Analytical validation of accelerator mass spectrometry for pharmaceutical development

    PubMed Central

    Keck, Bradly D; Ognibene, Ted; Vogel, John S

    2011-01-01

    The validation parameters for pharmaceutical analyses were examined for the accelerator mass spectrometry measurement of 14C/C ratio, independent of chemical separation procedures. The isotope ratio measurement was specific (owing to the 14C label), stable across samples storage conditions for at least 1 year, linear over four orders of magnitude with an analytical range from 0.1 Modern to at least 2000 Modern (instrument specific). Furthermore, accuracy was excellent (between 1 and 3%), while precision expressed as coefficient of variation was between 1 and 6% determined primarily by radiocarbon content and the time spent analyzing a sample. Sensitivity, expressed as LOD and LLOQ was 1 and 10 attomoles of 14C, respectively (which can be expressed as compound equivalents) and for a typical small molecule labeled at 10% incorporated with 14C corresponds to 30 fg equivalents. Accelerator mass spectrometry provides a sensitive, accurate and precise method of measuring drug compounds in biological matrices. PMID:21083256

  13. [Strategy for the development of dipeptide drugs].

    PubMed

    Gudasheva, T A

    2011-01-01

    The author describes an original approach to the development of dipeptide drugs based on the concept of the leading role of the beta-bend in the interaction of biologically active endogenous peptides with their receptors. The approach called "peptide-based drug design" includes both developments from the structure of a known psychotropic agent toward its topological peptide analog and developments from the active dipeptide site of a neuropeptide toward its mimetic. This strategy has been worked out at the V.V. Zakusov Research Institute of Pharmacology for 25 years. Results of investigations that discovered endogenous peptide prototypes of the known non-peptidic drugs (piracetam and sulpiride) are presented. They provided a basis for the creation of highly active non-toxic oral dipeptide preparations, such as nootrop Noopept, potential anti psychotic Dilept, and potential selective anxiolytic GB-115. PMID:21899085

  14. Separations technology development to support accelerator-driven transmutation concepts

    SciTech Connect

    Venneri, F.; Arthur, E.; Bowman, C.

    1996-10-01

    This is the final report of a one-year Laboratory-Directed Research and Development (LDRD) Project at the Los Alamos National Laboratory (LANL). This project investigated separations technology development needed for accelerator-driven transmutation technology (ADTT) concepts, particularly those associated with plutonium disposition (accelerator-based conversion, ABC) and high-level radioactive waste transmutation (accelerator transmutation of waste, ATW). Specific focus areas included separations needed for preparation of feeds to ABC and ATW systems, for example from spent reactor fuel sources, those required within an ABC/ATW system for material recycle and recovery of key long-lived radionuclides for further transmutation, and those required for reuse and cleanup of molten fluoride salts. The project also featured beginning experimental development in areas associated with a small molten-salt test loop and exploratory centrifugal separations systems.

  15. Role of Hepatic Drug Transporters in Drug Development.

    PubMed

    Liu, Houfu; Sahi, Jasminder

    2016-07-01

    Hepatic drug transporters can play an important role in pharmacokinetics and the disposition of therapeutic drugs and endogenous substances. Altered function of hepatic drug transporters due to drug-drug interactions (DDIs), genetic polymorphisms, and disease states can often result in a change in systemic and/or tissue exposure and subsequent pharmacological/toxicological effects of their substrates. Regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japan Pharmaceuticals and Medical Devices Agency have issued guidance for industry on drug interaction studies, which contain comprehensive recommendations on in vitro and in vivo study tools and cutoff values to evaluate the DDI potential of new molecular entities mediated by hepatic drug transporters. In this report we summarize the latest regulatory and scientific progress of hepatic drug transporters in clinical DDIs, pharmacogenetics, drug-induced liver injury (DILI), as well as methods for predicting transporter-mediated pharmacokinetics and DDIs. PMID:27385168

  16. Development of wide area environment accelerator operation and diagnostics method

    NASA Astrophysics Data System (ADS)

    Uchiyama, Akito; Furukawa, Kazuro

    2015-08-01

    Remote operation and diagnostic systems for particle accelerators have been developed for beam operation and maintenance in various situations. Even though fully remote experiments are not necessary, the remote diagnosis and maintenance of the accelerator is required. Considering remote-operation operator interfaces (OPIs), the use of standard protocols such as the hypertext transfer protocol (HTTP) is advantageous, because system-dependent protocols are unnecessary between the remote client and the on-site server. Here, we have developed a client system based on WebSocket, which is a new protocol provided by the Internet Engineering Task Force for Web-based systems, as a next-generation Web-based OPI using the Experimental Physics and Industrial Control System Channel Access protocol. As a result of this implementation, WebSocket-based client systems have become available for remote operation. Also, as regards practical application, the remote operation of an accelerator via a wide area network (WAN) faces a number of challenges, e.g., the accelerator has both experimental device and radiation generator characteristics. Any error in remote control system operation could result in an immediate breakdown. Therefore, we propose the implementation of an operator intervention system for remote accelerator diagnostics and support that can obviate any differences between the local control room and remote locations. Here, remote-operation Web-based OPIs, which resolve security issues, are developed.

  17. Mid-infrared Laser System Development for Dielectric Laser Accelerators

    NASA Astrophysics Data System (ADS)

    Jovanovic, Igor; Xu, Guibao; Wandel, Scott

    Laser-driven particle accelerators based on dielectric laser acceleration are under development and exhibit unique and challenging pump requirements. Operation in the mid-infrared (5 μm) range with short pulses (<1 ps FWHM), high pulse energy (>500 μJ) and good beam quality is required. We present our progress on the design and development of a novel two- stage source of mid-infrared pulses for this application, which is based on optical parametric amplification. Beta barium borate and zinc germanium phosphide crystals are used, and are pumped by a Ti:sapphire ultrashort laser and seeded by self-phase modulation and parametric generation-based sources.

  18. [Prospects for development of new antituberculous drugs].

    PubMed

    Tomioka, Haruaki

    2002-08-01

    Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. Moreover, the resurgence of TB in industrialized countries and the worldwide increase in the prevalence of Mycobacterium avium complex (MAC) infections in immunocompromised hosts have prompted the quest for new antimycobacterial drugs. In particular, the appearance of multidrug-resistant (MDR) strains of M. tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drug (usually INH and RFP) and cause intractable TB, has greatly contributed to the increased incidence of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed. In this article, I reviewed the following areas. First, I briefly reviewed some new findings (mainly reported after 2000) on the pharmacological status of rifamycin derivatives (rifabutin, rifapentine, and rifalazil), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), and new macrolides (clarithromycin, azithromycin, and roxithromycin). Second, I described other types of agents which are being developed as antimycobacterial drugs. Some of the agents discussed are already under preliminary clinical investigation, and others appear to be promising candidates for future development. In this review, the status of the development of new antimycobacterial, especially antituberculous agents including oxazolidinone (PNU-100480), 5'-nitroimidazole (CGI 17341), 2-pyridone (ABT-255), new riminophenazines, nitroimidazopyran (PA-824), new ketolides (ABT-773, telithromycin) and defensins (human neutrophil peptide-I), was examined. Third, the development of new antitubercular drugs was discussed according to the potential

  19. Pathology in drug discovery and development.

    PubMed

    Jubb, Adrian M; Koeppen, Hartmut; Reis-Filho, Jorge S

    2014-01-01

    The rapid pace of drug discovery and drug development in oncology, immunology and ophthalmology brings new challenges; the efficient and effective development of new targeted drugs will require more detailed molecular classifications of histologically homogeneous diseases that show heterogeneous clinical outcomes. To this end, single companion diagnostics for specific drugs will be replaced by multiplex diagnostics for entire therapeutic areas, preserving tissue and enabling rapid molecular taxonomy. The field will move away from the development of new molecular entities as single agents, to which resistance is common. Instead, a detailed understanding of the pathological mechanisms of resistance, in patients and in preclinical models, will be key to the validation of scientifically rational and clinically effective drug combinations. To remain at the heart of disease diagnosis and appropriate management, pathologists must evolve into translational biologists and biomarker scientists. Herein, we provide examples of where this metamorphosis has already taken place, in lung cancer and melanoma, where the transformation has yet to begin, in the use of immunotherapies for ophthalmology and oncology, and where there is fertile soil for a revolution in treatment, in efforts to classify glioblastoma and personalize treatment. The challenges of disease heterogeneity, the regulatory environment and adequate tissue are ever present, but these too are being overcome in dedicated academic centres. In summary, the tools necessary to overcome the 'whens' and 'ifs' of the molecular revolution are in the hands of pathologists today; it is a matter of standardization, training and leadership to bring these into routine practice and translate science into patient benefit. This Annual Review Issue of the Journal of Pathology highlights the central role for pathology in modern drug discovery and development. PMID:24122335

  20. DEVELOPMENT OF A COMPACT RADIOGRAPHY ACCELERATOR USING DIELECTRIC WALL ACCELERATOR TECHNOLOGY

    SciTech Connect

    Sampayan, S; Caporaso, G; Chen, Y; Hawkins, S; Holmes, C; Krogh, M; McCarrick, J; Nelson, S; Nunnally, W; Poole, B; Rhodes, M; Sanders, D; Selenes, K; Sullivan, J; Wang, L; Watson, J

    2005-06-02

    We are developing an inexpensive compact accelerator system primarily intended for pulsed radiography. Design characteristics are an 8 MeV endpoint energy, 2 kA beam current, a cell gradient of approximately 3 MV/m (for an overall accelerator length is 2-3 m), and <$1/Volt capital costs. Such designs have been made possible with the development of high specific energy dielectrics (>10J/cm{sup 3}), specialized transmission line designs and multi-gap laser triggered low jitter (<1 ns) gas switches. In this geometry, the pulse forming lines, switches, and insulator/beam pipe are fully integrated within each cell to form a compact, stand-alone, stackable unit. We detail our research and modeling to date, recent high voltage test results, and the integration concept of the cells into a radiographic system.

  1. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    PubMed

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. PMID:24733008

  2. Aptamers : The New Frontier In Drug Development?

    PubMed Central

    CARLSON, BOB

    2007-01-01

    Often called chemical antibodies, aptamers are poised to take on the monoclonal antibodies in therapeutics, diagnostics, and drug development. Stability, low toxicity and immunogenicity, and, perhaps, a higher safety profile – not to mention low-cost advantages – are drawing the attention of big pharma and biotech. PMID:23372509

  3. Drugs and development: the global impact of drug use and trafficking on social and economic development.

    PubMed

    Singer, Merrill

    2008-12-01

    Locating development efforts within the context of globalism and global drug capitalism, this article examines the significant health and social impact both legal and illegal drugs have on international development efforts. The paper takes on an issue that is generally overlooked in the development debate and is not much addressed in the current international development standard, the Millennium Development Goals, and yet is one that places serious constraints on the ability of underdeveloped nations to achieve improvement. The relationship between psychotropic or "mind/mood altering" drugs and sustainable development is rooted in the contribution that the legal and illegal drug trade makes to a set of barriers to development, including: (1) interpersonal crime and community violence; (2) the corruption of public servants and the disintegration of social institutions; (3) the emergence of new or enhanced health problems; (4) the lowering of worker productivity; (5) the ensnarement of youth in drug distribution and away from productive education or employment; (6) the skewing of economies to drug production and money laundering. The paper emphasizes the need for new approaches for diminishing the burden placed by drugs on development. PMID:19038724

  4. Accelerating Child Survival and Development in Dark Times.

    ERIC Educational Resources Information Center

    Grant, James P.

    Measures were proposed that would enable UNICEF, in association with others and despite prevailing difficult economic circumstances, to more effectively bring well-being and hope to hundreds of millions of children. Specific proposals were designed to help most countries accelerate child survival and development. Most particularly, it was…

  5. Accelerating Early Language Development with Multi-Sensory Training

    ERIC Educational Resources Information Center

    Bjorn, Piia M.; Kakkuri, Irma; Karvonen, Pirkko; Leppanen, Paavo H. T.

    2012-01-01

    This paper reports the outcome of a multi-sensory intervention on infant language skills. A programme titled "Rhyming Game and Exercise Club", which included kinaesthetic-tactile mother-child rhyming games performed in natural joint attention situations, was intended to accelerate Finnish six- to eight-month-old infants' language development. The…

  6. Development of a wireless displacement measurement system using acceleration responses.

    PubMed

    Park, Jong-Woong; Sim, Sung-Han; Jung, Hyung-Jo; Spencer, Billie F

    2013-01-01

    Displacement measurements are useful information for various engineering applications such as structural health monitoring (SHM), earthquake engineering and system identification. Most existing displacement measurement methods are costly, labor-intensive, and have difficulties particularly when applying to full-scale civil structures because the methods require stationary reference points. Indirect estimation methods converting acceleration to displacement can be a good alternative as acceleration transducers are generally cost-effective, easy to install, and have low noise. However, the application of acceleration-based methods to full-scale civil structures such as long span bridges is challenging due to the need to install cables to connect the sensors to a base station. This article proposes a low-cost wireless displacement measurement system using acceleration. Developed with smart sensors that are low-cost, wireless, and capable of on-board computation, the wireless displacement measurement system has significant potential to impact many applications that need displacement information at multiple locations of a structure. The system implements an FIR-filter type displacement estimation algorithm that can remove low frequency drifts typically caused by numerical integration of discrete acceleration signals. To verify the accuracy and feasibility of the proposed system, laboratory tests are carried out using a shaking table and on a three storey shear building model, experimentally confirming the effectiveness of the proposed system. PMID:23881123

  7. Current scenario of drug development for leishmaniasis.

    PubMed

    Croft, Simon L; Seifert, Karin; Yardley, Vanessa

    2006-03-01

    Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. Other drugs or compounds that have demonstrated activity in experimental rodent models of infection include licochalcone derivatives, quinoline derivatives, bisphosphonates and a maesabalide; further chemistry based upon these leads is warranted. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection. PMID:16778319

  8. Persistent pharmacokinetic challenges to pediatric drug development

    PubMed Central

    Sage, Daniel P.; Kulczar, Christopher; Roth, Wyatt; Liu, Wanqing; Knipp, Gregory T.

    2014-01-01

    The development of new therapeutic agents for the mitigation of pediatric disorders is largely hindered by the inability for investigators to assess pediatric pharmacokinetics (PK) in healthy patients due to substantial safety concerns. Pediatric patients are a clinical moving target for drug delivery due to changes in absorption, distribution, metabolism and excretion (ADME) and the potential for PK related toxicological (T) events to occur throughout development. These changes in ADMET can have profound effects on drug delivery, and may lead to toxic or sub-therapeutic outcomes. Ethical, economical, logistical, and technical barriers have resulted in insufficient investigation of these changes by industrial, regulatory, and academic bodies, leading to the classification of pediatric patients as therapeutic orphans. In response to these concerns, regulatory agencies have incentivized investigation into these ontogenic changes and their effects on drug delivery in pediatric populations. The intent of this review is to briefly present a synopsis of the development changes that occur in pediatric patients, discuss the effects of these changes on ADME and drug delivery strategies, highlight the hurdles that are still being faced, and present some opportunities to overcome these challenges. PMID:25221567

  9. Heterocyclic Scaffolds: Centrality in Anticancer Drug Development.

    PubMed

    Ali, Imran; Lone, Mohammad Nadeem; Al-Othman, Zeid A; Al-Warthan, Abdulrahman; Sanagi, Mohd Marsin

    2015-01-01

    Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections. PMID:25751009

  10. Parasitic diarrheal disease: drug development and targets

    PubMed Central

    Azam, Amir; Peerzada, Mudasir N.; Ahmad, Kamal

    2015-01-01

    Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active anti-parasitic agents. PMID:26617574

  11. [Development of new drugs for Alzheimer's disease].

    PubMed

    Tabira, Takeshi

    2010-07-01

    Currently, only donepezil is available for the treatment of Alzheimer disease (AD) in Japan. Clinical trials of galantamine, rivastigmine, and memantine have been completed in Japan, and patients are awaiting government approval for the use of these drugs. The herbal medicine yokukansan was found to be effective for behavioral and psychological symptoms of dementia (BPSD) in patients, and juzentaihoto was found to reduce AD pathology in a mouse model. In addition, muscarinic and nicotinic acetylcholine receptor agonists, serotonergic agonists, other drugs are being developed. These medicines have little effect on the improvement of cognitive functions. The anti-histamine dimebolin was expected to have a significant effect on the improvement of cognitive functions, but unfortunately, it was rejected during phase III clinical trials. Disease modifying drugs such as alpha-secretase activators, beta- and gamma-secretase inhibitors or modulators, inhibitors of Abeta and tau aggregation, enhancers of Abeta degradation, immunotherapies to remove Abeta oligomers and fibrils, and neurotrophic factors are being developed. Some of these drugs are in phase III clinical trials and are expected to be available for clinical use in the near future. PMID:20675883

  12. Drugs in development for relapsing multiple sclerosis.

    PubMed

    Ali, Rehiana; Nicholas, Richard St John; Muraro, Paolo Antonio

    2013-05-01

    Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development. The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice. Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market? Are they safer or better tolerated? Do they offer any practical advantages over current treatments? Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route. However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema. Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy. The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable. Other monoclonal antibodies are in various phases of development. Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity. Its once-yearly administration, however, seems particularly advantageous. Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising. Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing. There are new oral

  13. 75 FR 32482 - Investigational New Drug Applications; Co-development of Investigational Drugs

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-08

    ... HUMAN SERVICES Food and Drug Administration Investigational New Drug Applications; Co-development of Investigational Drugs AGENCY: Food and Drug Administration, HHS. ACTION: Notice; establishment of docket; request for comments. SUMMARY: The Food and Drug Administration (FDA) is establishing a public docket...

  14. A Case for Developing Community Drug Indicators

    ERIC Educational Resources Information Center

    Loughran, Hilda; McCann, Mary Ellen

    2011-01-01

    The EU Action Plan on Drugs (2005-2008) calls for member states of the European Union to provide information on five key epidemiological indicators. These are: general population surveys, prevalence and patterns of problem drug use, drug related infectious diseases, drug related deaths and mortality of drug users, and demand for drug treatment.…

  15. Development of an artificial climatic complex accelerated corrosion tester and investigation of complex accelerated corrosion test methods

    SciTech Connect

    Li, J.; Li, M.; Sun, Z. )

    1999-05-01

    During recent decades, accelerated corrosion test equipment and methods simulating atmospheric corrosion have been developed to incorporate the many factors involved in complex accelerated corrosion. A new accelerated corrosion tester was developed to simulate various kinds of atmospheric corrosion environments. The equipment can be used to simulate various types of atmospheric corrosion environments with up to eight factors and can be used to carry out 18 kinds of standard corrosion and environmental tasks.

  16. Alcohol and Drug Use and the Developing Brain.

    PubMed

    Squeglia, Lindsay M; Gray, Kevin M

    2016-05-01

    Adolescence is an important neurodevelopmental period marked by rapidly escalating rates of alcohol and drug use. Over the past decade, research has attempted to disentangle pre- and post-substance use effects on brain development by using sophisticated longitudinal designs. This review focuses on recent, prospective studies and addresses the following important questions: (1) what neuropsychological and neural features predate adolescent substance use, making youth more vulnerable to engage in heavy alcohol or drug use, and (2) how does heavy alcohol and drug use affect normal neural development and cognitive functioning? Findings suggest that pre-existing neural features that relate to increased substance use during adolescence include poorer neuropsychological functioning on tests of inhibition and working memory, smaller gray and white matter volume, changes in white matter integrity, and altered brain activation during inhibition, working memory, reward, and resting state. After substance use is initiated, alcohol and marijuana use are associated with poorer cognitive functioning on tests of verbal memory, visuospatial functioning, psychomotor speed, working memory, attention, cognitive control, and overall IQ. Heavy alcohol use during adolescence is related to accelerated decreases in gray matter and attenuated increases in white matter volume, as well as increased brain activation during tasks of inhibition and working memory, relative to controls. Larger longitudinal studies with more diverse samples are needed to better understand the interactive effects of alcohol, marijuana, and other substances, as well as the role of sex, co-occurring psychopathology, genetics, sleep, and age of initiation on substance use. PMID:26984684

  17. Malaria drug resistance: new observations and developments

    PubMed Central

    Sá, Juliana M.; Chong, Jason L.; Wellems, Thomas E.

    2012-01-01

    Drug-resistant micro-organisms became widespread in the 20th Century, often with devastating consequences, in response to widespread use of natural and synthetic drugs against infectious diseases. Antimalarial resistance provides one of the earliest examples, following the introduction of new medicines that filled important needs for prophylaxis and treatment around the globe. In the present chapter, we offer a brief synopsis of major antimalarial developments from two natural remedies, the qinghaosu and cinchona bark infusions, and of synthetic drugs inspired by the active components of these remedies. We review some contributions that early efficacy studies of antimalarial treatment brought to clinical pharmacology, including convincing documentation of atebrine-resistant malaria in the 1940s, prior to the launching of what soon became first-choice antimalarials, chloroquine and amodiaquine. Finally, we discuss some new observations on the molecular genetics of drug resistance, including delayed parasite clearances that have been increasingly observed in response to artemisinin derivatives in regions of South-East Asia. PMID:22023447

  18. Application of accelerators for the research and development of scintillators.

    PubMed

    Shibuya, Kengo; Koshimizu, Masanori; Asai, Keisuke; Muroya, Yusa; Katsumura, Yosuke; Inadama, Naoko; Yoshida, Eiji; Nishikido, Fumihiko; Yamaya, Taiga; Murayama, Hideo

    2007-08-01

    We introduce experimental systems which use accelerators to evaluate scintillation properties such as scintillation intensity, wavelength, and lifetime. A single crystal of good optical quality is often unavailable during early stages in the research and development (R&D) of new scintillator materials. Because of their beams' high excitation power and/or low penetration depth, accelerators facilitate estimation of the properties of early samples which may only be available as powders, thin films, and very small crystals. We constructed a scintillation spectrum measurement system that uses a Van de Graaff accelerator and an optical multichannel analyzer to estimate the relative scintillation intensity. In addition, we constructed a scintillation time profile measurement system that uses an electron linear accelerator and a femtosecond streak camera or a microchannel plate photomultiplier tube followed by a digital oscilloscope to determine the scintillation lifetimes. The time resolution is approximately 10 ps. The scintillation spectra or time profiles can be obtained in a significantly shorter acquisition time in comparison with that required by conventional measuring systems. The advantages of the systems described in this study can significantly promote the R&D of novel scintillator materials. PMID:17764319

  19. WIPO Re:Search: Accelerating anthelmintic development through cross-sector partnerships

    PubMed Central

    Ramamoorthi, Roopa; Graef, Katy M.; Dent, Jennifer

    2014-01-01

    Neglected tropical diseases (NTDs), malaria, and tuberculosis have a devastating effect on an estimated 1.6 billion people worldwide. The World Intellectual Property Organization (WIPO) Re:Search consortium accelerates the development of new drugs, vaccines, and diagnostics for these diseases by connecting the assets and resources of pharmaceutical companies, such as compound libraries and expertise, to academic or nonprofit researchers with novel product discovery or development ideas. As the WIPO Re:Search Partnership Hub Administrator, BIO Ventures for Global Health (BVGH) fields requests from researchers, identifies Member organizations able to fulfill these requests, and helps forge mutually beneficial collaborations. Since its inception in October 2011, WIPO Re:Search membership has expanded to more than 90 institutions, including leading pharmaceutical companies, universities, nonprofit research institutions, and product development partnerships from around the world. To date, WIPO Re:Search has facilitated over 70 research agreements between Consortium Members, including 11 collaborations focused on anthelmintic drug discovery. PMID:25516832

  20. Advances in Parallel Electromagnetic Codes for Accelerator Science and Development

    SciTech Connect

    Ko, Kwok; Candel, Arno; Ge, Lixin; Kabel, Andreas; Lee, Rich; Li, Zenghai; Ng, Cho; Rawat, Vineet; Schussman, Greg; Xiao, Liling; /SLAC

    2011-02-07

    Over a decade of concerted effort in code development for accelerator applications has resulted in a new set of electromagnetic codes which are based on higher-order finite elements for superior geometry fidelity and better solution accuracy. SLAC's ACE3P code suite is designed to harness the power of massively parallel computers to tackle large complex problems with the increased memory and solve them at greater speed. The US DOE supports the computational science R&D under the SciDAC project to improve the scalability of ACE3P, and provides the high performance computing resources needed for the applications. This paper summarizes the advances in the ACE3P set of codes, explains the capabilities of the modules, and presents results from selected applications covering a range of problems in accelerator science and development important to the Office of Science.

  1. Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

    PubMed

    Phillips, Anthony George; Hongaard-Andersen, Peter; Moscicki, Richard A; Sahakian, Barbara; Quirion, Rémi; Krishnan, K Ranga Rama; Race, Tim

    2015-02-01

    Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in

  2. Proceedings of the 2013 CINP Summit: Innovative Partnerships to Accelerate CNS Drug Discovery for Improved Patient Care

    PubMed Central

    Hongaard-Andersen, Peter; Moscicki, Richard A.; Sahakian, Barbara; Quirion, Rémi; Krishnan, K. Ranga Rama; Race, Tim

    2015-01-01

    Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21st century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues,Prevention, early diagnosis, and treatment,Linking science and regulation,Patient involvement in trial design, definition of endpoints, etc.,Novel trial design,Reproduction and confirmation of data,Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority),Large-scale, global patient registries,Editorials on nomenclature, biomarkers, and diagnostic tools, andPublic awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos

  3. Drug Development of Therapeutic Monoclonal Antibodies.

    PubMed

    Mould, Diane R; Meibohm, Bernd

    2016-08-01

    Monoclonal antibodies (MAbs) have become a substantial part of many pharmaceutical company portfolios. However, the development process of MAbs for clinical use is quite different than for small-molecule drugs. MAb development programs require careful interdisciplinary evaluations to ensure the pharmacology of both the MAb and the target antigen are well-understood. Selection of appropriate preclinical species must be carefully considered and the potential development of anti-drug antibodies (ADA) during these early studies can limit the value and complicate the performance and possible duration of preclinical studies. In human studies, many of the typical pharmacology studies such as renal or hepatic impairment evaluations may not be needed but the pharmacokinetics and pharmacodynamics of these agents is complex, often necessitating more comprehensive evaluation of clinical data and more complex bioanalytical assays than might be used for small molecules. This paper outlines concerns and strategies for development of MAbs from the early in vitro assessments needed through preclinical and clinical development. This review focuses on how to develop, submit, and comply with regulatory requirements for MAb therapeutics. PMID:27342605

  4. Development of X-Band Dielectric-Loaded Accelerating Structures

    SciTech Connect

    Gold, S. H.; Jing, C.; Kanareykin, A.; Gai, W.; Konecny, R.; Power, J. G.; Kinkead, A. K.

    2010-11-04

    This paper presents a progress report on the development and testing of X-band dielectric-loaded accelerating structures. Recent tests on several quartz DLA structures with different inner diameters are reported. Designs for gap-free DLA structures are presented. Also, planned new experiments are discussed, including higher gradient traveling-wave and standing-wave structures and special grooved structures for multipactor suppression.

  5. Extracellular proteases as targets for drug development.

    PubMed

    Cudic, Mare; Fields, Gregg B

    2009-08-01

    Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addition to directly blocking the activity of a targeted protease, one can take advantage of differential expression in disease states to selectively deliver therapeutic or imaging agents. Recent studies in targeted drug development for the metalloproteases (matrix metalloproteinases, adamalysins, pappalysins, neprilysin, angiotensin-converting enzyme, metallocarboxypeptidases, and glutamate carboxypeptidase II), serine proteases (elastase, coagulation factors, tissue/urokinase plasminogen activator system, kallikreins, tryptase, dipeptidyl peptidase IV) and cysteine proteases (cathepsin B) are discussed herein. PMID:19689354

  6. Developments in Laser and Plasma-Based Accelerators

    NASA Astrophysics Data System (ADS)

    Downer, Michael

    2001-04-01

    The explosive growth of multiterawatt laser technology combined with the increasing size and cost of conventional RF particle accelerators has driven intense research into more compact laser-driven and/or plasma based acceleration concepts. Although schemes for direct laser acceleration without plasmas or, conversely, plasma acceleration without lasers have been studied, the greatest recent progress has been made with concepts that combine lasers and plasmas [1]. Tajima and Dawson [2] proposed in 1979 that a sufficiently intense single laser pulse of duration t ω_p-1, or a pair of laser pulses with Δω ω_p, could be efficiently drive a longitudinal electron plasma wave with phase velocity approaching c via the ponderomotive force. Charged particles that "surf" such waves experience accelerating gradients (E 10^9 V/cm) as much as a thousand times greater than conventional RF accelerators. Numerous experiments have now demonstrated acceleration of up to 10^9 electrons per laser pulse to energies exceeding 100 MeV, with wide energy spread, but competitive beam emittance. Such sources have proven useful for nuclear activation analysis in their current form. However for such accelerators to be useful to a wider community, including high energy physics, key challenges must be addressed. These include: 1) Guiding terawatt laser pulses. Achieving useful laser intensities requires focusing, thus limiting interaction length to < 1 mm, whereas interaction lengths of several cm are needed to use laser energy efficiently and reach GeV acceleration in a single stage. Several groups are now developing high-throughput plasma "fibers" that have supported peak powers near a terawatt over > 1 cm without distortion [3]. 2) Phased injection. Since plasma waves with useful gradients have wavelengths of micron dimensions, charged particles must be injected with unprecedented spatial and temporal precision to achieve a monochromatic output beam. Several groups are developing new laser

  7. In vitro testing of drug absorption for drug 'developability' assessment: forming an interface between in vitro preclinical data and clinical outcome.

    PubMed

    Sun, Duxin; Yu, Lawrence X; Hussain, Munir A; Wall, Doris A; Smith, Ronald L; Amidon, Gordon L

    2004-01-01

    Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. The fraction of drug absorbed and the maximum absorbable dose (MAD) can be estimated from in vivo clinical pharmacokinetics, mass balance studies or in vivo drug permeability in humans by different calculation methods. Unfortunately, in vivo data are usually unavailable at the early stages of drug discovery and development, and in vitro screening for the permeability, solubility, activity and toxicity of a drug has become a routine measurement in drug discovery and development. These in vitro data could be used to predict drug 'developability' with different calculation methods before selecting candidates for clinical evaluation. The fraction of drug absorbed in human could be predicted by in vivo human permeability or in vitro Caco2 permeability. For example, if drug permeability in Caco2 cells reaches 13.3 to 18.1 x 10(-6) cm/s, its predicted in vivo permeability in humans would reach 2 x 10(-4) cm/s, and its predicted fraction of drug absorbed would be > 90%, which is defined as highly permeable. The MAD could also be predicted with in vitro permeability, or calculated absorption rate constant. In addition, in vitro solubility and permeability data can also be used for the biopharmaceutics classification system (BCS) and, subsequently, to direct formulation optimization strategies. If drug 'developability' becomes an obstacle for drug delivery based on these in vitro data and predictions at the early stages of drug discovery and development, options such as prodrug approaches could be explored to enhance drug 'developability', in addition to different formulation methods. Therefore, in vitro absorption testing is a highly valuable tool in the decision-making process to select candidates for in vivo

  8. Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease.

    PubMed

    Schneider, Lon S

    2014-03-01

    The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving. PMID:24698029

  9. New Developments in the Simulation of Advanced Accelerator Concepts

    SciTech Connect

    Bruhwiler, David L.; Cary, John R.; Cowan, Benjamin M.; Paul, Kevin; Mullowney, Paul J.; Messmer, Peter; Geddes, Cameron G. R.; Esarey, Eric; Cormier-Michel, Estelle; Leemans, Wim; Vay, Jean-Luc

    2009-01-22

    Improved computational methods are essential to the diverse and rapidly developing field of advanced accelerator concepts. We present an overview of some computational algorithms for laser-plasma concepts and high-brightness photocathode electron sources. In particular, we discuss algorithms for reduced laser-plasma models that can be orders of magnitude faster than their higher-fidelity counterparts, as well as important on-going efforts to include relevant additional physics that has been previously neglected. As an example of the former, we present 2D laser wakefield accelerator simulations in an optimal Lorentz frame, demonstrating >10 GeV energy gain of externally injected electrons over a 2 m interaction length, showing good agreement with predictions from scaled simulations and theory, with a speedup factor of {approx}2,000 as compared to standard particle-in-cell.

  10. New Developments in the Simulation of Advanced Accelerator Concepts

    SciTech Connect

    Paul, K.; Cary, J.R.; Cowan, B.; Bruhwiler, D.L.; Geddes, C.G.R.; Mullowney, P.J.; Messmer, P.; Esarey, E.; Cormier-Michel, E.; Leemans, W.P.; Vay, J.-L.

    2008-09-10

    Improved computational methods are essential to the diverse and rapidly developing field of advanced accelerator concepts. We present an overview of some computational algorithms for laser-plasma concepts and high-brightness photocathode electron sources. In particular, we discuss algorithms for reduced laser-plasma models that can be orders of magnitude faster than their higher-fidelity counterparts, as well as important on-going efforts to include relevant additional physics that has been previously neglected. As an example of the former, we present 2D laser wakefield accelerator simulations in an optimal Lorentz frame, demonstrating>10 GeV energy gain of externally injected electrons over a 2 m interaction length, showing good agreement with predictions from scaled simulations and theory, with a speedup factor of ~;;2,000 as compared to standard particle-in-cell.

  11. Research and Development for Ultra-High Gradient Accelerator Structures

    NASA Astrophysics Data System (ADS)

    Tantawi, Sami G.; Dolgashev, Valery; Higashi, Yasuo; Spataro, Bruno

    2010-11-01

    Research on the basic physics of high-gradient, high frequency accelerator structures and the associated RF/microwave technology are essential for the future of discovery science, medicine and biology, energy and environment, and national security. We will review the state-of-the-art for the development of high gradient linear accelerators. We will present the research activities aimed at exploring the basic physics phenomenon of RF breakdown. We present the experimental results of a true systematic study in which the surface processing, geometry, and materials of the structures have been varied, one parameter at a time. The breakdown rate or alternatively, the probability of breakdown/pulse/meter has been recorded for different operating parameters. These statistical data reveal a strong dependence of breakdown probability on surface magnetic field, or alternatively on surface pulsed heating. This is in contrast to the classical view of electric field dependence.

  12. Anticancer Drug Development: The Way Forward.

    PubMed

    Connors

    1996-01-01

    Cancer chemotherapy celebrated its fiftieth anniversary last year. It was in 1945 that wartime research on the nitrogen mustards, which uncovered their potential use in the treatment of leukaemias and other cancers, was first made public. Fifty years later, more than sixty drugs have been registered in the USA for the treatment of cancer, but there are still lessons to be learnt. One problem, paradoxically, is that many anticancer agents produce a response in several different classes of the disease. This means that once a new agent has been shown to be effective in one cancer, much effort is devoted to further investigations of the same drug in various combinations for different disorders. While this approach has led to advances in the treatment of many childhood cancers and some rare diseases, a plethora of studies on metastatic colon cancer, for example, has yielded little benefit. 5-fluorouracil continues to be used in trials, yet there is no evidence for an increase in survival. The lesson to be learnt is that many common cancers are not adequately treated by present-day chemotherapy, and most trials of this sort are a waste of time. Significant increases in survival will only occur if the selectivity of present-day anticancer agents can be increased or new classes of more selective agents can be discovered. There are two fundamental problems in drug development: a lack of suitable laboratory tests and the difficulty of conducting early clinical trials. Firstly, no existing laboratory method can accurately predict which chemical will be effective against a particular class of human cancer. At best, tests can demonstrate a general 'anticancer' property. This is well exemplified by the discovery of cisplatin. The fact that cisplatin caused regression in a number of transplanted rodent tumours created no great excitement amongst chemotherapists. It was only later when it was tested clinically against ovarian cancer that results were sufficiently positive to

  13. The development and maintenance of drug addiction.

    PubMed

    Wise, Roy A; Koob, George F

    2014-01-01

    What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of ‘addiction’ should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents. PMID:24121188

  14. Development of the brine shrimp Artemia is accelerated during spaceflight

    NASA Technical Reports Server (NTRS)

    Spooner, B. S.; Metcalf, J.; DeBell, L.; Paulsen, A.; Noren, W.; Guikema, J. A.

    1994-01-01

    Developmentally arrested brine shrimp cysts have been reactivated during orbital spaceflight on two different Space Shuttle missions (STS-50 and STS-54), and their subsequent development has been compared with that of simultaneously reactivated ground controls. Flight and control brine shrimp do not significantly differ with respect to hatching rates or larval morphology at the scanning and transmission EM levels. A small percentage of the flight larvae had defective nauplier eye development, but the observation was not statistically significant. However, in three different experiments on two different flights, involving a total of 232 larvae that developed in space, a highly significant difference in degree of flight to control development was found. By as early as 2.25 days after reactivation of development, spaceflight brine shrimp were accelerated, by a full instar, over ground control brine shrimp. Although developing more rapidly, flight shrimp grew as long as control shrimp at each developmental instar or stage.

  15. Development of an accelerating-piston implosion-driven launcher

    NASA Astrophysics Data System (ADS)

    Huneault, Justin; Loiseau, Jason; Higgins, Andrew

    2013-06-01

    The ability to soft-launch projectiles at velocities exceeding 10 km/s is of interest to several scientific fields, including orbital debris impact testing and equation of state research. Current soft-launch technologies have reached a performance plateau below this operating range. The energy and power density of high explosives provides a possible avenue to reach this velocity if used to dynamically compress a light driver gas to significantly higher pressures and temperatures compared to light-gas guns. In the implosion-driven launcher (IDL), linear implosion of a pressurized tube drives a strong shock into the gas ahead of the tube pinch, thereby forming an increasingly long column of compressed gas which can be used to propel a projectile. The McGill IDL has demonstrated the ability to launch a 0.1-g projectile to 9.1 km/s. This study focuses on the implementation of a novel launch cycle wherein the explosively driven pinch is accelerated down the length of the tube in order to maintain a relatively constant projectile base pressure early in the launch cycle. The experimental development of an accelerating driver which utilizes an explosive lens to phase the detonation wave is presented. The design and experimental performance of an accelerating-piston IDL is also discussed.

  16. Development of a sealed-accelerator-tube neutron generator

    PubMed

    Verbeke; Leung; Vujic

    2000-10-01

    Sealed-accelerator-tube neutron generators are being developed in Lawrence Berkeley National Laboratory (LBNL) for applications ranging from neutron radiography to boron neutron capture therapy and neutron activation analysis. The new generation of high-output neutron generators is based on the D-T fusion reaction, producing 14.1-MeV neutrons. The main components of the neutron tube--the ion source, the accelerator and the target--are all housed in a sealed metal container without external pumping. Thick-target neutron yield computations are performed in this paper to estimate the neutron yield of titanium and scandium targets. With an average deuteron beam current of 1 A and an energy of 120 keV, a time-averaged neutron production of approximately 10(14) n/s can be estimated for a tritiated target, for both pulsed and cw operations. In mixed deuteron/triton beam operation, a beam current of 2 A at 150 keV is required for the same neutron output. Recent experimental results on ion sources and accelerator columns are presented and discussed. PMID:11003523

  17. Chemical signatures and new drug targets for gametocytocidal drug development

    NASA Astrophysics Data System (ADS)

    Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei

    2014-01-01

    Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

  18. Drugging the undruggables: exploring the ubiquitin system for drug development

    PubMed Central

    Huang, Xiaodong; Dixit, Vishva M

    2016-01-01

    Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system (UPS). Similar to kinases, components of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neurodegeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategies to target the UPS. PMID:27002218

  19. Latest Diagnostic Electronics Development for the PROSCAN Proton Accelerator

    SciTech Connect

    Duperrex, P.A.; Frei, U.; Gamma, G.; Mueller, U.; Rezzonico, L.

    2004-11-10

    New VME-based diagnostic electronics are being developed for PROSCAN, a proton accelerator for medical application presently under construction at PSI. One new development is a VME-based multi-channel logarithmic amplifier for converting current to voltage (LogIV). The LogIV boards are used for measuring current from the multiple wire (harp) profile monitors. The LogIV calibration method, current dependant bandwidth and temperature stability are presented. Another development is a BPM front end, based on the newest digital receiver techniques. Features of this new system are the remote control of the preamplifier stage and the continuous monitoring of each individual signal overall gain. Characteristics of the developed prototype are given.

  20. Development of the accelerator-driven energy production concept

    SciTech Connect

    Venneri, F.; Beard, C.; Bowman, C.

    1996-10-01

    This is the final report of a three-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). Accelerator Driven Transmutation Technology (ADTT) offers a means of generating nuclear energy in a clean, safe way that can be attractive to the general public. However, there are issues associated with the energy story (both at the system level and technical detail) that have to be seriously addressed before the scientific community, the public, and potential industrial sponsors can be compellingly convinced of its cost/benefit.

  1. Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

    PubMed Central

    Ochoa-Cortes, Fernando; Liñán-Rico, Andromeda; Jacobson, Kenneth A.; Christofi, Fievos L.

    2014-01-01

    Treatments for IBD, IBS, FD or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. GI symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation and diarrhea. The focus of this review is on potential for developing purinergic drugs for clinical trials to treat GI symptoms. Purinergic receptors are divided into adenosine P1 (A1,A2A,A2B,A3), ionotropic ATP-gated P2X ion channel (P2X1–7) or metabotropic P2Y1,2,4,6,11–14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory-diarrhea and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal-chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for CD. A3 AR drugs target inflammatory diseases (e.g. CF101; CF102). Dipyridamole, a nucleoside uptake-inhibitor, is in trials for endotoxemia. Drugs for pain in clinical-trials include P2X3/P2X2/3(AF-219) and P2X7(GSK1482160) antagonists and A1(GW493838) or A2A(BVT.115959) agonists. IberogastR is a phytopharmacon targeting purine-mechanisms with efficacy in IBS and FD. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, FD and inflammatory-diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new-generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling. PMID:24859298

  2. Design and development of pulsed electron beam accelerator 'AMBICA - 600'

    NASA Astrophysics Data System (ADS)

    Verma, Rishi; Deb, Pankaj; Shukla, Rohit; Sharma, Surender; Shyam, Anurag

    2012-11-01

    Short duration, high power pulses with fast rise time and good flat-top are essentially required for driving pulsed electron beam diodes. To attain this objective, a dual resonant Tesla transformer based pulsed power accelerator 'AMBICA-600' has been developed. In this newly developed system, a coaxial water line is charged through single turn Tesla transformer that operates in the dual resonant mode. For making the accelerator compact, in the high power pulse forming line, water has been used as dielectric medium because of its high dielectric constant, high dielectric strength and high energy density. The coaxial waterline can be pulsed charged up to 600kV, has impedance of ~5Ω and generates pulse width of ~60ns. The integrated system is capable of producing intense electron beam of 300keV, 60kA when connected to impedance matched vacuum diode. In this paper, system hardware details and experimental results of gigawatt electron beam generation have been presented.

  3. Improving interorganizational data interchange for drug development.

    PubMed

    Canfield, K

    1999-01-01

    This paper presents a reengineered process that uses a markup language to do interorganizational data interchange between the participants in the US drug development process. The two major goals of this paper are to present (1) a detailed enough description of the reengineered version of this process that a practitioner will be able to use it and (2) a case-study of the reengineering of an interorganizational data interchange system that is applicable to other areas in health care. The detailed description is augmented with a companion web-site that shows all programs in a working prototype. The case-study uses an IDEF0 model to show the structure of benefits from markup standards for interorganizational data interchange. PMID:10207657

  4. Neurodegenerative disorders and nanoformulated drug development

    PubMed Central

    Nowacek, Ari; Kosloski, Lisa M; Gendelman, Howard E

    2009-01-01

    Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders. PMID:19572820

  5. Bioavailability and Bioequivalence in Drug Development.

    PubMed

    Chow, Shein-Chung

    2014-01-01

    Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average bioequivalence in drug absorption through the conduct of bioavailability and bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed. PMID:25215170

  6. Development of high purity niobium used in SRF accelerating cavity

    NASA Astrophysics Data System (ADS)

    Chen, Lin; Xie, Wei-Ping; Li, Ming-Yang; He, Ji-Lin; Fan, Hui-Ru; Zhang, Bao-Cheng; He, Fei-Si; Zhao, Kui; Chen, Jia-Er; Liu, Ke-Xin

    2008-12-01

    Niobium is widely used in SRF (Superconducting Radio Frequency) cavities due to its excellent superconductivity and workability. With the continuous development of technology, higher demands of material are raised. One of the key issues is that RRR (Residual Resistance Ratio) of the Nb material should be more than 300, which requires that the Nb ingot have even higher RRR. This article introduces the development and the experimental results of high purity niobium in OTIC in Ningxia (Ningxia Orient Tantalum Industry Co. Ltd.), and the test results of the single cell TESLA (Tera Electron volt energy Superconducting Linear Accelerator) shaped cavity manufactured by Peking University using Nb material from OTIC. Supported by National Basic Research Program of China (2002CB713600)

  7. Highly Productive Application Development with ViennaCL for Accelerators

    NASA Astrophysics Data System (ADS)

    Rupp, K.; Weinbub, J.; Rudolf, F.

    2012-12-01

    The use of graphics processing units (GPUs) for the acceleration of general purpose computations has become very attractive over the last years, and accelerators based on many integrated CPU cores are about to hit the market. However, there are discussions about the benefit of GPU computing when comparing the reduction of execution times with the increased development effort [1]. To counter these concerns, our open-source linear algebra library ViennaCL [2,3] uses modern programming techniques such as generic programming in order to provide a convenient access layer for accelerator and GPU computing. Other GPU-accelerated libraries are primarily tuned for performance, but less tailored to productivity and portability: MAGMA [4] provides dense linear algebra operations via a LAPACK-comparable interface, but no dedicated matrix and vector types. Cusp [5] is closest in functionality to ViennaCL for sparse matrices, but is based on CUDA and thus restricted to devices from NVIDIA. However, no convenience layer for dense linear algebra is provided with Cusp. ViennaCL is written in C++ and uses OpenCL to access the resources of accelerators, GPUs and multi-core CPUs in a unified way. On the one hand, the library provides iterative solvers from the family of Krylov methods, including various preconditioners, for the solution of linear systems typically obtained from the discretization of partial differential equations. On the other hand, dense linear algebra operations are supported, including algorithms such as QR factorization and singular value decomposition. The user application interface of ViennaCL is compatible to uBLAS [6], which is part of the peer-reviewed Boost C++ libraries [7]. This allows to port existing applications based on uBLAS with a minimum of effort to ViennaCL. Conversely, the interface compatibility allows to use the iterative solvers from ViennaCL with uBLAS types directly, thus enabling code reuse beyond CPU-GPU boundaries. Out-of-the-box support

  8. Development of an annular arc accelerator shock tube driver

    NASA Technical Reports Server (NTRS)

    Leibowitz, L. P.

    1973-01-01

    An annular arc accelerator (ANAA) shock tube driver has been developed that deposits the energy of an arc discharge into a flowing gas, which then expands and cools without any delay for the opening of a diaphragm. A simplified one-dimensional flow analysis of the ANAA shock tube has been performed, which indicates that shock velocities greater than 40 km/sec may be obtained using a 300-kJ capacitor bank. The ANAA driver consists of a high-pressure driver, an expansion section, and an electrode section. In operation, the cold gas driver is pressurized until the diaphragm bursts, sending a pressure front down the expansion tube to the arc section. When the accelerated flow arrives at the electrode section, a 100-capacitor, 300-kJ capacitor bank is discharged either by breaking an insulating diaphragm between the electrodes or by the triggering of a series of external switches. Shock velocities of 28 km/sec have been obtained, and modifications are described that are expected to improve performance.

  9. Development of Dielectric-Based High Gradient Accelerating Structures

    SciTech Connect

    Jing, C.; Gai, W.; Konecny, R.; Power, J.; Liu, W.; Gold, S. H.; Kinkead, A. K.; Kanareykin, A.; Kazakov, S.

    2006-11-27

    High gradient accelerating structures using dielectric-lined circular waveguides have been developed for a number of years at Argonne National Laboratory. In this article, we first report the experimental results of high power rf testing on the quartz based Dielectric-Loaded Accelerating (DLA) structure carried out on Feb. 2006 at the Naval Research Laboratory. The motivation for this experiment is to test the multipactor effect on different materials under high power and high vacuum condition. Up to 12 MW pulsed rf went through the tube without breakdown. Multipactor appeared during the experiment but with different features compared to other materials like alumina. Photomultiplier Tube (PMT) measurements were introduced into the experiment for the first time to observe the light emission time and intensity. In the second part of this paper, ways to achieve higher gradient for DLA structures are proposed: 1) smaller ID and longitudinal gap free DLA structures to reduce multipactor and obtain higher gradient; 2) new coaxial type coupler to avoid dielectric gap and improve impedance matching; 3) double layered DLA structure to reduce rf loss and enhance shunt impedance as well.

  10. Orphan drug development across Europe: bottlenecks and opportunities.

    PubMed

    Heemstra, Harald E; de Vrueh, Remco L A; van Weely, Sonja; Büller, Hans A; Leufkens, Hubert G M

    2008-08-01

    With the assignment of the 500th European Union orphan drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European orphan drug development at a national level and unveil a strong relationship between orphan drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into orphan drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of orphan drugs in Europe. PMID:18583178

  11. 78 FR 52933 - Strengthening the Operating Framework and Furthering the Objectives of Coalition for Accelerating...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-27

    ... Objectives of Coalition for Accelerating Standards and Therapies Initiative (U24) AGENCY: Food and Drug... Objectives The CFAST Initiative aims to accelerate clinical research and medical product development...

  12. Analytical Validation of Accelerator Mass Spectrometry for Pharmaceutical Development: the Measurement of Carbon-14 Isotope Ratio.

    SciTech Connect

    Keck, B D; Ognibene, T; Vogel, J S

    2010-02-05

    Accelerator mass spectrometry (AMS) is an isotope based measurement technology that utilizes carbon-14 labeled compounds in the pharmaceutical development process to measure compounds at very low concentrations, empowers microdosing as an investigational tool, and extends the utility of {sup 14}C labeled compounds to dramatically lower levels. It is a form of isotope ratio mass spectrometry that can provide either measurements of total compound equivalents or, when coupled to separation technology such as chromatography, quantitation of specific compounds. The properties of AMS as a measurement technique are investigated here, and the parameters of method validation are shown. AMS, independent of any separation technique to which it may be coupled, is shown to be accurate, linear, precise, and robust. As the sensitivity and universality of AMS is constantly being explored and expanded, this work underpins many areas of pharmaceutical development including drug metabolism as well as absorption, distribution and excretion of pharmaceutical compounds as a fundamental step in drug development. The validation parameters for pharmaceutical analyses were examined for the accelerator mass spectrometry measurement of {sup 14}C/C ratio, independent of chemical separation procedures. The isotope ratio measurement was specific (owing to the {sup 14}C label), stable across samples storage conditions for at least one year, linear over 4 orders of magnitude with an analytical range from one tenth Modern to at least 2000 Modern (instrument specific). Further, accuracy was excellent between 1 and 3 percent while precision expressed as coefficient of variation is between 1 and 6% determined primarily by radiocarbon content and the time spent analyzing a sample. Sensitivity, expressed as LOD and LLOQ was 1 and 10 attomoles of carbon-14 (which can be expressed as compound equivalents) and for a typical small molecule labeled at 10% incorporated with {sup 14}C corresponds to 30 fg

  13. Industry Perspective of Drug Development for Pregnant/Breastfeeding Women.

    PubMed

    Korth-Bradley, J M

    2016-07-01

    As part of drug development, drug companies conduct experiments to gather data about the potential toxicity of medications in pregnant and lactating animals. Increasingly, physiologically based pharmacokinetic models are developed to simulate drug concentrations in pregnant and lactating women. As these women are not usually included in clinical trials, targeted postapproval safety monitoring, registries, or clinical studies may be performed to gather safety and efficacy information about drug use in these special populations. PMID:27082822

  14. The need to accelerate access to new drugs for multidrug-resistant tuberculosis

    PubMed Central

    Furin, Jennifer J; Mitnick, Carole D; Daniels, Colleen; Cox, Vivian; Goemaere, Eric

    2015-01-01

    Abstract Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks – such as the rapid development of resistance to new drugs – need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade. PMID:26170507

  15. Developing an Accelerator Driven System (ADS) based on electron accelerators and heavy water

    NASA Astrophysics Data System (ADS)

    Feizi, H.; Ranjbar, A. H.

    2016-02-01

    An ADS based on electron accelerators has been developed specifically for energy generation and medical applications. Monte Carlo simulations have been performed using FLUKA code to design a hybrid electron target and the core components. The composition, geometry of conversion targets and the coolant system have been optimized for electron beam energies of 20 to 100 MeV . Furthermore, the photon and photoneutron energy spectra, distribution and energy deposition for various incoming electron beam powers have been studied. Light-heavy water of various mixtures have been used as heat removal for the targets, as γ-n converters and as neutron moderators. We have shown that an electron LINAC, as a neutron production driver for ADSs, is capable of producing a neutron output of > 3.5 × 1014 (n/s/mA). Accordingly, the feasibility of an electron-based ADS employing the designed features is promising for energy generation and high intense neutron production which have various applications such as medical therapies.

  16. Development of an Accelerator Mass Spectrometer based on a Cyclotron

    SciTech Connect

    Kim, Dogyun; Bhang, Hyeongchan; Kim, Jongwon

    2011-12-13

    An accelerator mass spectrometer based on a cyclotron has been developed, and a prototype of the injection beam line has been constructed. Mass resolution of the cyclotron is designed to be over 4000. A sawtooth RF buncher in the beam line and a flat-topping RF system for the cyclotron were utilized to enhance beam transmission efficiency, which is a primary factor for improvement compared to previous cyclotron mass spectrometers. The injection beam line comprises an ion source, Einzel lens, RF buncher, 90 deg. dipole magnet and a slit box containing beam diagnostic devices. A carbon beam was measured at the location of the slit box, and beam phase spaces will be measured. The design of a cyclotron magnet was done, and orbit tracking was carried out using cyclotron optics codes. A scheme of radial injection was chosen to place a beam on the equilibrium orbit of the cyclotron. The injection scheme will be optimized after the beam measurements are completed.

  17. Developments of mass spectrometry-based technologies for effective drug development linked with clinical proteomes.

    PubMed

    Nakayama, Noboru; Bando, Yasuhiko; Fukuda, Tetsuya; Kawamura, Takeshi; Nakamura, Haruhiko; Marko-Varga, György; Nishimura, Toshihide

    2016-02-01

    A strong demand in drug discovery and development today is to overcome "Big Gaps" encountered by differences in species and races, to accelerate effective developments in cost and time, and to meet medical needs. Moreover, drugs of various types have emerged which cover middle-size molecules and polymers rather than conventional small molecules. Upon those challenges, mass spectrometry (MS)-based technologies, which will be described in this paper, will play an increasingly important role, among which the liquid chromatography-tandem mass spectrometry (LC/MS/MS) platform will be powerful as rapid and molecule-based analysis more than ever. nanoPore Optical Interferometry (nPOI) newly introduced can detect even weak interactions in protein-protein and protein-compound, and can be connected directly to LC/MS/MS for identification of binding molecular species, which will be quite useful for affinity ranking and high-throughput interaction screening. Imaging MS provides the molecular information and spatial distribution of targeted molecules within a tissue specimen. MS-based clinical proteomics utilizing clinical specimens and empowered by advanced bioinformatics can attain both key protein-protein interaction (PPI) networks with major protein players responsible for functional mechanisms of a disease subtype. An integration of those MS-based technologies will deliver a seamless platform of drug development from molecules identified in human clinical specimens. PMID:26782309

  18. Status and Future Developments in Large Accelerator Control Systems

    SciTech Connect

    Karen S. White

    2006-10-31

    Over the years, accelerator control systems have evolved from small hardwired systems to complex computer controlled systems with many types of graphical user interfaces and electronic data processing. Today's control systems often include multiple software layers, hundreds of distributed processors, and hundreds of thousands of lines of code. While it is clear that the next generation of accelerators will require much bigger control systems, they will also need better systems. Advances in technology will be needed to ensure the network bandwidth and CPU power can provide reasonable update rates and support the requisite timing systems. Beyond the scaling problem, next generation systems face additional challenges due to growing cyber security threats and the likelihood that some degree of remote development and operation will be required. With a large number of components, the need for high reliability increases and commercial solutions can play a key role towards this goal. Future control systems will operate more complex machines and need to present a well integrated, interoperable set of tools with a high degree of automation. Consistency of data presentation and exception handling will contribute to efficient operations. From the development perspective, engineers will need to provide integrated data management in the beginning of the project and build adaptive software components around a central data repository. This will make the system maintainable and ensure consistency throughout the inevitable changes during the machine lifetime. Additionally, such a large project will require professional project management and disciplined use of well-defined engineering processes. Distributed project teams will make the use of standards, formal requirements and design and configuration control vital. Success in building the control system of the future may hinge on how well we integrate commercial components and learn from best practices used in other industries.

  19. Beyond debacle and debate: developing solutions in drug safety.

    PubMed

    Ray, Amrit

    2009-10-01

    In the 5 years since the Vioxx debacle, efforts have been made to enhance drug safety. These include the introduction of legislation that expands the power of drug regulatory agencies, new data transparency standards and increased requirements for funding of post-marketing drug surveillance. Nevertheless, some doubt remains that these changes will be sufficient to address the increasing challenges in the field of drug safety. Here, from the perspective of a drug researcher, I discuss key areas for further development that could deliver long-term solutions to these challenges: enhanced tools for the detection of safety signals, innovative phased drug launches, new risk stratification techniques and improved pharmacovigilance operations. PMID:19763107

  20. Clinical pharmacology: special safety considerations in drug development and pharmacovigilance.

    PubMed

    Atuah, Kwame N; Hughes, Dyfrig; Pirmohamed, Munir

    2004-01-01

    The dose of a drug is a major determinant of its safety, and establishing a safe dose of a novel drug is a prime objective during clinical development. The design of pre-marketing clinical trials precludes the representation of important subpopulations such as children, the elderly and people with co-morbidities. Therefore, postmarketing surveillance (PMS) activities are required to monitor the safety profile of drugs in real clinical practice. Furthermore, individual variations in pharmacogenetic profiles, the immune system, drug metabolic pathways and drug-drug interactions are also important factors in the occurrence of adverse drug reactions. Thus, the safety of a drug is a major clinical consideration before and after it is marketed. A multidisciplinary approach is required to enhance the safety profile of drugs at all stages of development, including PMS activities. Clinical pharmacology encompasses a range of disciplines and forms the backbone of drug safety consideration during clinical drug development. In this review we give an overview of the clinical drug development process and consider its limitations. We present a discussion of several aspects of clinical pharmacology and their application to enhancing drug safety. Pharmacokinetic-pharmacodynamic modelling provides a method of predicting a clinically safe dose; consideration of drug pharmacokinetics in special populations may enhance safe therapeutics in a wider spectrum of patients, while pharmacogenetics provides the possibility of genotype-specific therapeutics. Pharmacovigilance activities are also discussed. Given the complex nature and unpredictability of type B reactions, PMS activities are crucial in managing the risks drugs pose to the general population. The various aspects of clinical pharmacology discussed make a strong case for this field as the backbone of optimising and promoting safe development and use of drugs. PMID:15154826

  1. Development of Antisense Drugs for Dyslipidemia.

    PubMed

    Yamamoto, Tsuyoshi; Wada, Fumito; Harada-Shiba, Mariko

    2016-09-01

    Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies. PMID:27466159

  2. Cryptic prophages as targets for drug development.

    PubMed

    Wang, Xiaoxue; Wood, Thomas K

    2016-07-01

    Bacterial chromosomes may contain up to 20% phage DNA that encodes diverse proteins ranging from those for photosynthesis to those for autoimmunity; hence, phages contribute greatly to the metabolic potential of pathogens. Active prophages carrying genes encoding virulence factors and antibiotic resistance can be excised from the host chromosome to form active phages and are transmissible among different bacterial hosts upon SOS responses. Cryptic prophages are artifacts of mutagenesis in which lysogenic phage are captured in the bacterial chromosome: they may excise but they do not form active phage particles or lyse their captors. Hence, cryptic prophages are relatively permanent reservoirs of genes, many of which benefit pathogens, in ways we are just beginning to discern. Here we explore the role of active prophage- and cryptic prophage-derived proteins in terms of (i) virulence, (ii) antibiotic resistance, and (iii) antibiotic tolerance; antibiotic tolerance occurs as a result of the non-heritable phenotype of dormancy which is a result of activation of toxins of toxin/antitoxin loci that are frequently encoded in cryptic prophages. Therefore, cryptic prophages are promising targets for drug development. PMID:27449596

  3. Ethnobotany and its role in drug development.

    PubMed

    Heinrich, M

    2000-11-01

    The botanical collections of early explorers and the later ethnobotany have played important roles in the development of new drugs for many centuries. In the middle of the last century interest in this approach had declined dramatically, but has risen again during its last decade, and new foci have developed. The systematic evaluation of indigenous pharmacopoeias in order to contribute to improved health care in marginalized regions has been placed on the agenda of international and national organizations and of NGOs. In this paper the results of various projects on Mexican Indian ethnobotany and some of the subsequent pharmacological and phytochemical studies are summarized. Medicinal plants are an important element of indigenous medical systems in Mexico. This study uses the medicinal plants in four indigenous groups of Mexican Indians-Maya, Nahua, Zapotec and Mixe-as an example. The relative importance of a medicinal plant within a culture is documented using a quantitative method and the data are compared intra- and interculturally. While the species used by the indigenous groups vary, the data indicate that there exist well-defined criteria specific for each culture, which lead to the selection of a plant as a medicine. For example, a large number of species are used for gastrointestinal illnesses by two or more of the indigenous groups. At least in this case, the multiple transfers of species and their uses within -Mexico seems to be an important reason for the widespread use of a species. Some of the data we gathered in order to evaluate the indigenous claims are also discussed, focusing on the transcription factor NF-kappaB as a molecular target. This led to the identification of sesquiterpene lactones such as parthenolide as potent and relatively specific inhibitors of this transcription factor. PMID:11054835

  4. Potential of metabolomics in preclinical and clinical drug development.

    PubMed

    Kumar, Baldeep; Prakash, Ajay; Ruhela, Rakesh Kumar; Medhi, Bikash

    2014-12-01

    Metabolomics is an upcoming technology system which involves detailed experimental analysis of metabolic profiles. Due to its diverse applications in preclinical and clinical research, it became an useful tool for the drug discovery and drug development process. This review covers the brief outline about the instrumentation and interpretation of metabolic profiles. The applications of metabolomics have a considerable scope in the pharmaceutical industry, almost at each step from drug discovery to clinical development. These include finding drug target, potential safety and efficacy biomarkers and mechanisms of drug action, the validation of preclinical experimental models against human disease profiles, and the discovery of clinical safety and efficacy biomarkers. As we all know, nowadays the drug discovery and development process is a very expensive, and risky business. Failures at any stage of drug discovery and development process cost millions of dollars to the companies. Some of these failures or the associated risks could be prevented or minimized if there were better ways of drug screening, drug toxicity profiling and monitoring adverse drug reactions. Metabolomics potentially offers an effective route to address all the issues associated with the drug discovery and development. PMID:25443721

  5. [Recent developments of drug eluting stent coatings].

    PubMed

    Chen, Wen-ping; Zhan, Hong-bing

    2011-11-01

    Drug eluting stents (DESs) have revolutionized the interventional cardiology over the past decade since the first DES became commercially available in Europe in 2002. Compared to bare metal stents that are deployed to keep the vessel open by mechanical force, DESs have an additional function of reducing restenosis by the action of the drug on the target site. Coatings on the stent surface which ensure the maximum delivery of therapeutic agents to the target site with minimal systematic toxicity, also play an important role in adjusting the drug release profile. Coating material and technology not only affect the surface biocompatibility and the integrity maintenance during the implanting process, but also decide the way of drug delivering and transmitting from the coating. This paper reviews the basic principles of DES coating design, the categories of DES coatings, the commonly used clinical DES coatings and their efficiency in reducing restenosis, and finally provides the future perspectives for DES coatings. PMID:22260019

  6. Evolution and intelligent design in drug development

    PubMed Central

    Agafonov, Roman V.; Wilson, Christopher; Kern, Dorothee

    2015-01-01

    Sophisticated protein kinase networks, empowering complexity in higher organisms, are also drivers of devastating diseases such as cancer. Accordingly, these enzymes have become major drug targets of the twenty-first century. However, the holy grail of designing specific kinase inhibitors aimed at specific cancers has not been found. Can new approaches in cancer drug design help win the battle with this multi-faced and quickly evolving enemy? In this perspective we discuss new strategies and ideas that were born out of a recent breakthrough in understanding the molecular basis underlying the clinical success of the cancer drug Gleevec. An “old” method, stopped-flow kinetics, combined with old enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs. PMID:26052517

  7. Investigation of toxic metabolites during drug development

    SciTech Connect

    Park, Kevin . E-mail: bkpark@liv.ac.uk; Williams, Dominic P.; Naisbitt, Dean J.; Kitteringham, Neil R.; Pirmohamed, Munir

    2005-09-01

    Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines.

  8. Investigation of toxic metabolites during drug development.

    PubMed

    Park, Kevin; Williams, Dominic P; Naisbitt, Dean J; Kitteringham, Neil R; Pirmohamed, Munir

    2005-09-01

    Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines. PMID:15996699

  9. Accelerating technology development through integrated computation and experimentation

    SciTech Connect

    Shekhawat, Dushyant; Srivastava, Rameshwar

    2013-01-01

    This special section of Energy & Fuels comprises a selection of papers presented at the topical conference “Accelerating Technology Development through Integrated Computation and Experimentation”, sponsored and organized by the United States Department of Energy’s National Energy Technology Laboratory (NETL) as part of the 2012 American Institute of Chemical Engineers (AIChE) Annual Meeting held in Pittsburgh, PA, Oct 28−Nov 2, 2012. That topical conference focused on the latest research and development efforts in five main areas related to fossil energy, with each area focusing on the utilization of both experimental and computational approaches: (1) gas separations (membranes, sorbents, and solvents for CO{sub 2}, H{sub 2}, and O{sub 2} production), (2) CO{sub 2} utilization (enhanced oil recovery, chemical production, mineralization, etc.), (3) carbon sequestration (flow in natural systems), (4) advanced power cycles (oxy-combustion, chemical looping, gasification, etc.), and (5) fuel processing (H{sub 2} production for fuel cells).

  10. Accelerating Adverse Outcome Pathway Development Using Publicly Available Data Sources.

    PubMed

    Oki, Noffisat O; Nelms, Mark D; Bell, Shannon M; Mortensen, Holly M; Edwards, Stephen W

    2016-03-01

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity (HTT) testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledge base; however, this process is currently labor-intensive and time-consuming. Publicly available data sources provide a wealth of information that could be used to define computationally predicted AOPs (cpAOPs), which could serve as a basis for creating expert-derived AOPs in a much more efficient way. Computational tools for mining large datasets provide the means for extracting and organizing the information captured in these public data sources. Using cpAOPs as a starting point for expert-derived AOPs should accelerate AOP development. Coupling this with tools to coordinate and facilitate the expert development efforts will increase the number and quality of AOPs produced, which should play a key role in advancing the adoption of HTT testing, thereby reducing the use of animals in toxicity testing and greatly increasing the number of chemicals that can be tested. PMID:26809562

  11. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study

    PubMed Central

    Wang, Bo; Franklin, Jessica M; Darrow, Jonathan J

    2015-01-01

    Objective To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades. Design Cohort study. Setting FDA approved novel therapeutics between 1987 and 2014. Population Publicly available sources provided each drug’s year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA’s four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review. Main outcome measures Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not. Results The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction). Conclusions In the past two decades, drugs newly approved by the FDA have been associated with an

  12. Attempts to develop radioactive anticancer drugs

    SciTech Connect

    Mitchell, J.S.; Brown, I.; Chir, B.; Carpenter, R.N.

    1983-01-01

    Since 1953, attempts have been made to develop radioactive drugs. Preparations of tritiated menadiol sodium diphosphate (T-MNDP) of high specific activity showed a definite, though limited, but sometimes useful effect in the treatment of certain patients with advanced tumors, especially adenocarcinoma of the colon and of the pancreas and malignant melanoma of the skin. The next step was to use a much more effective isotope. 6-/sup 125/I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) - abbreviated 6-/sup 125/I-iodo-MNDP - has been synthesized, and in laboratory studies appears more promising. /sup 125/I provides radiations which behave predominately like high LET radiation, despite the accompanying X and gamma radiations. The astatine analogue, 6-/sup 211/At-astato-2-methyl-1,4-naphthoquinol bis (disodium phosphate) has also been synthesized. Confirming and greatly extending the earlier findings with T-MNDP, in vitro experiments showed that 6-/sup 125/I-iodo-MNDP is concentrated selectively in the cells of some human malignant tumors by a factor of about 15 to 20 or more in relation to the cells of normal origin that were studied. Macrodosimetric considerations and comparison with clinical treatments with T-MNDP suggest practical dosage. A typical treatment for a patient of body weight 70 kg with localized inoperable carcinoma of the colon could be 8 intravenous injections each of approximately 120mCi of 6-/sup 125/I-iodo-MNDP to a toal of 0.97 Ci in 25 days. Risks of late carcinogenesis and leukemogenesis are calculated to be less than 1%. Clinical indications are discussed briefly. Animal experiments are in progress and further preclinical studies are required.

  13. [Novel insomnia drugs, including drugs currently under development].

    PubMed

    Inada, Ken

    2009-08-01

    Insomnia has mainly been treated with the hypnotic benzodiazepine (BZ). Recent studies have revealed the role and mechanisms of BZ receptors and have led to the development of non-BZ hypnotics. The chemical structures of non-BZ hypnotics differ from that of BZ; these hypnotics selectively bind to the omega 1 receptor of the gamma-aminobutyric acid (GABA)-BZ receptor complex. Because the omega 2 BZ receptors have adverse effects such as muscle relaxant actions, non-BZ hypnotics have lesser adverse effects than BZ. Antipsychotics, antidepressants, and antihistamines are also used for the treatment of insomnia in patients with other medical problems such as schizophrenia and depression. Currently, novel hypnotics are being developed with the manipulation of neurotransmitters and non-GABAergic receptors such as the melatonin and serotonin receptors. PMID:19768946

  14. TB drug development: immunology at the table

    PubMed Central

    Nathan, Carl; Barry, Clifton E.

    2014-01-01

    Summary Our understanding of the host-pathogen relationship in tuberculosis can help guide tuberculosis (TB) drug discovery in at least two ways. First, the recognition that host immunopathology affects lesional TB drug distribution means that pharmacokinetic evaluation of drug candidates needs to move beyond measurements of drug levels in blood, whole lungs or alveolar epithelial lining fluid to include measurements in specific types of lesions. Second, by restricting the replication of M. tuberculosis (Mtb) subpopulations in latent TB infection and in active disease, the host immune response puts Mtb into a state associated with phenotypic tolerance to TB drugs selected for their activity against replicating Mtb. This has spurred a major effort to conduct high throughput screens in vitro for compounds that can kill Mtb when it is replicating slowly if at all. Each condition used in vitro to slow Mtb’s replication and thereby model the phenotypically drug-tolerant state has advantages and disadvantages. Lead candidates emerging from such in vitro studies face daunting challenges in the design of proof-of-concept studies in animal models. Moreover, some non-replicating subpopulations of Mtb fail to resume replication when plated on agar, although their viability is demonstrable by other means. There is as yet no widely replicated assay in which to screen compounds for their ability to kill this ‘viable but non-culturable’ subpopulation. Despite these hurdles, drugs that can kill slowly replicating or non-replicating Mtb may offer our best hope for treatment-shortening combination chemotherapy of TB. PMID:25703568

  15. Recent developments in animal models of drug relapse.

    PubMed

    Marchant, Nathan J; Li, Xuan; Shaham, Yavin

    2013-08-01

    Drug craving and relapse to drug use during abstinence are defining features of addiction. Evidence indicates that drug craving and relapse in humans are often provoked by acute exposure to the self-administered drug, drug-associated cues, or stress. During the last two decades, this clinical scenario has been primarily studied at the preclinical level using the classical reinstatement model. However, a single preclinical model cannot capture the complicated nature of human drug relapse. Therefore, more recently, we and others have developed several other models to study different facets of human drug relapse. In this review, we introduce and discuss recent findings from these other relapse models, including incubation of drug craving, reacquisition and resurgence models, and punishment-based and conflict-based relapse models. PMID:23374536

  16. A drug-induced accelerated senescence (DIAS) is a possibility to study aging in time lapse.

    PubMed

    Alili, Lirija; Diekmann, Johanna; Giesen, Melanie; Holtkötter, Olaf; Brenneisen, Peter

    2014-06-01

    Currently, the oxidative stress (or free radical) theory of aging is the most popular explanation of how aging occurs at the molecular level. Accordingly, a stress-induced senescence-like phenotype of human dermal fibroblasts can be induced in vitro by the exposure of human diploid fibroblasts to subcytotoxic concentrations of hydrogen peroxide. However, several biomarkers of replicative senescence e.g. cell cycle arrest and enlarged morphology are abrogated 14 days after treatment, indicating that reactive oxygen species (ROS) rather acts as a trigger for short-term senescence (1-3 days) than being responsible for the maintenance of the senescence-like phenotype. Further, DNA-damaging factors are discussed resulting in a permanent senescent cell type. To induce long-term premature senescence and to understand the molecular alterations occurring during the aging process, we analyzed mitomycin C (MMC) as an alkylating DNA-damaging agent and ROS producer. Human dermal fibroblasts (HDF), used as model for skin aging, were exposed to non-cytotoxic concentrations of MMC and analyzed for potential markers of cellular aging, for example enlarged morphology, activity of senescence-associated-ß-galactosidase, cell cycle arrest, increased ROS production and MMP1-activity, which are well-documented for HDF in replicative senescence. Our data show that mitomycin C treatment results in a drug-induced accelerated senescence (DIAS) with long-term expression of senescence markers, demonstrating that a combination of different susceptibility factors, here ROS and DNA alkylation, are necessary to induce a permanent senescent cell type. PMID:24833306

  17. Drug loaded composite oxidized pectin and gelatin networks for accelerated wound healing.

    PubMed

    Tummalapalli, Mythili; Berthet, Morgane; Verrier, Bernard; Deopura, B L; Alam, M S; Gupta, Bhuvanesh

    2016-05-30

    Biocomposite interactive wound dressings have been designed and fabricated using oxidized pectin (OP), gelatin and nonwoven cotton fabric. Due to their inherent virtues of antimicrobial activity and cytocompatibility, these composite structures are capable of redirecting the healing cascade and influencing cell attachment and proliferation. A novel in situ reduction process has been followed to synthesize oxidized pectin-gelatin-nanosilver (OP-Gel-NS) flower like nanohydrocolloids. This encapsulation technology controls the diffusion and permeation of nanosilver into the surrounding biological tissues. Ciprofloxacin hydrochloride has also been incorporated into the OP-Gel matrix to produce OP-Gel-Cipro dressings. While OP-Gel-NS dressings exhibited 100% antimicrobial activity at extremely low loadings of 3.75μg/cm(2), OP-Gel-Cipro dressings were highly antimicrobial at 1% drug loading. While NIH3T3 mouse fibroblasts proliferated remarkably well when cultured with OP-Gel and OP-Gel-Cipro dressings, OP-Gel-NS hindered cell growth and Bactigras(®) induced complete lysis. Full thickness excisional wounds were created on C57BL/6J mice and the wound healing potential of the OP-Gel-NS dressings led to accelerated healing within 12days, while OP-Gel-Cipro dressings healed wounds at a rate similar to that of Bactigras(®). Histological examination revealed that OP-Gel-NS and OP-Gel-Cipro treatment led to organized collagen deposition, neovascularization and nuclei migration, unlike Bactigras(®). Therefore, the OP-Gel-NS and OP-Gel-Cipro biocomposite dressings exhibiting good hydrophilicity, sustained antimicrobial nature, promote cell growth and proliferation, and lead to rapid healing, can be considered viable candidates for effective management. PMID:27063849

  18. Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development.

    PubMed

    Bhardwaj, Anshu; Scaria, Vinod; Raghava, Gajendra Pal Singh; Lynn, Andrew Michael; Chandra, Nagasuma; Banerjee, Sulagna; Raghunandanan, Muthukurussi V; Pandey, Vikas; Taneja, Bhupesh; Yadav, Jyoti; Dash, Debasis; Bhattacharya, Jaijit; Misra, Amit; Kumar, Anil; Ramachandran, Srinivasan; Thomas, Zakir; Brahmachari, Samir K

    2011-09-01

    It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. PMID:21782516

  19. The development of children of drug addicts.

    PubMed

    Bauman, P S; Levine, S A

    1986-08-01

    The present study compared 70 methadone-maintained mothers (MM) and their 70 preschool-age children to a matched control group of 70 non-drug-addicted mothers (NDA) and their 70 preschool-age children on mothers' personalities, intelligence levels, and parenting attitudes and behavior; and on children's behavior and intelligence and developmental levels. Findings showed that in comparison to the control group, MM mothers performed less adaptively on measures of intelligence, personality, and parenting behavior. Their scores on the parenting attitude measures reflected authoritarian childrearing beliefs. Children of MM mothers performed more poorly than children of NDA mothers on measures of intelligence and socially adaptive behavior. In a comparison of children of MM mothers who experienced withdrawal from drugs at birth to children of MM mothers who were not born addicted to drugs, results revealed a tendency for withdrawal children to have developmental delays, lower IQ scores, and lower heights and weights. PMID:3771015

  20. A development perspective on adolescent drug abuse.

    PubMed

    Baumrind, D; Moselle, K A

    1985-01-01

    Adolescent drug use is placed in an historical and developmental perspective. Existing evidence concerning causes and consequences of adolescent drug use is inconclusive. In the absence of conclusive empirical evidence and cogent theories, we present a prima facie case against early adolescent drug use by defending six propositions which posit specific cognitive, conative, and affective negative consequences including impairment of attention and memory; developmental lag imposing categorical limitations on the level of maximum functioning available to the user in cognitive, moral and psychosocial domains; amotivational syndrome; consolidation of diffuse or negative identity; and social alienation and estrangement. We call for a program of research which could provide credible evidence to support or rebut these propositions, and thus address the factual claims underlying the sociomoral concerns of social policy planners. PMID:4013874

  1. The Evolution of Drug Development in Schizophrenia

    PubMed Central

    Carpenter, William T; Koenig, James I

    2008-01-01

    Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored. PMID:18046305

  2. Drug Development Value Chain Constructed by Collaboration Between The SOSHO Project and The NPO BIOGRID

    NASA Astrophysics Data System (ADS)

    Inoue, Tsuyoshi; Kado, Yuji; Tokuoka, Keiji; Matsumura, Hiroyoshi; Kai, Yasushi; Mori, Yusuke; Adachi, Hiroaki; Takano, Kazufumi; Murakami, Satoshi; Fukunishi, Yoshifumi; Nakamura, Haruki; Kinoshita, Takayoshi; Nakanishi, Isao; Okuno, Yasushi; Minakata, Seiji; Sakata, Tsuneaki

    2007-03-01

    We recently established a drug development value chain collaborated by The SOSHO project (http://www.sosho.jp) and The BioGrid Project (http://www.biogrid.jp/) to accelerate new drug development. The SOSHO project provides new crystal growth methods including handling of protein crystals, and The BioGrid Project their developing software necessary for the in silico screening of promising drugs and the simulation of biological responses to proteins. We selected the two target enzymes; human hematopoietic prostaglandin D synthase (H-PGDS) and orotidine 5'-monophosphate decarboxylase from human malaria parasite plasmodium falciparum (PfOMPDC). The optimizing of HQL-79, the inhibitor for human H-PGDS and the screening of a lead compound for PfOMPDC by using in silico method are in study.

  3. Application of the EIIP/ISM bioinformatics concept in development of new drugs.

    PubMed

    Veljkovic, V; Veljkovic, N; Esté, J A; Hüther, A; Dietrich, U

    2007-01-01

    The development of a new therapeutic drug is a complex, lengthy and expensive process. On average, only one out of 10,000 - 30,000 originally synthesized compounds will clear all the hurdles on the way to becoming a commercially available drug. The process of early and full preclinical discovery and clinical development for a new drug can take twelve to fifteen years to complete, and cost approximately 800 million dollars. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we reviewed the application of the EIIP/ISM bioinformatics concept for the development of new drugs. This approach, connecting the electron-ion interaction potential of organic molecules and their biological properties, can significantly reduce development time through (i) identification of promising lead compounds that have some activity against a disease by fast virtual screening of the large molecular libraries, (ii) refinement of selected lead compounds in order to increase their biological activity, and (iii) identification of domains of proteins and nucleotide sequences representing potential targets for therapy. Special attention is paid in this review to the application of the EIIP/ISM bioinformatics platform along with other experimental techniques (screening of a phage displayed peptide libraries, testing selected peptides and small molecules for antiviral activity in vitro) in development of HIV entry inhibitors, representing a new generation of the AIDS drugs. PMID:17305545

  4. Polypharmacology in Drug Development: A Minireview of Current Technologies.

    PubMed

    Tan, Zhi; Chaudhai, Rajan; Zhang, Shuxing

    2016-06-20

    Polypharmacology, the process in which a single drug is able to bind to multiple targets specifically and simultaneously, is an emerging paradigm in drug development. The potency of a given drug can be increased through the engagement of multiple targets involved in a certain disease. Polypharmacology may also help identify novel applications of existing drugs through drug repositioning. However, many problems and challenges remain in this field. Rather than covering all aspects of polypharmacology, this Minireview is focused primarily on recently reported techniques, from bioinformatics technologies to cheminformatics approaches as well as text-mining-based methods, all of which have made significant contributions to the research of polypharmacology. PMID:27154144

  5. Optimizing drug development of anti-cancer drugs in children using modelling and simulation

    PubMed Central

    van Hasselt, Johan GC; van Eijkelenburg, Natasha KA; Beijnen, Jos H; Schellens, Jan HM; Huitema, Alwin DR

    2013-01-01

    Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population. PMID:23216601

  6. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability.

    PubMed

    Waterman, Kenneth Craig

    2011-09-01

    An isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a fixed degradant level, is shown to compensate for the complex, non-single order kinetics of solid drug products. A humidity-corrected Arrhenius equation provides reliable estimates for temperature and relative humidity effects on degradation rates. A statistical protocol is employed to determine best fits for chemical stability data, which in turn allows for accurate estimations of shelf life (with appropriate confidence intervals) at any storage condition including inside packaging (based on the moisture vapor transmission rate of the packaging and moisture sorption isotherms of the internal components). These methodologies provide both faster results and far better predictions of chemical stability limited shelf life (expiry) than previously possible. Precise shelf-life estimations are generally determined using a 2-week, product-specific protocol. Once the model for a product is developed, it can play a critical role in providing the product understanding necessary for a quality by design (QbD) filing for product approval and enable rational control strategies to assure product stability. Moreover, this Accelerated Stability Assessment Program (ASAP) enables the coupling of product attributes (e.g., moisture content, packaging options) to allow for flexibility in how control strategies are implemented to provide a balance of cost, speed, and other factors while maintaining adequate stability. PMID:21748541

  7. Accelerated Nuclear Energy Materials Development with Multiple Ion Beams

    SciTech Connect

    Fluss, M J; Bench, G

    2009-08-19

    A fundamental issue in nuclear energy is the changes in material properties as a consequence of time, temperature, and neutron fluence. Usually, candidate materials for nuclear energy applications are tested in nuclear reactors to understand and model the changes that arise from a combination of atomic displacements, helium and hydrogen production, and other nuclear transmutations (e.g. fission and the production of fission products). Experiments may be carried out under neutron irradiation conditions in existing nuclear materials test reactors (at rates of 10 to 20 displacements per atom (DPA) per year or burn-up rates of a few percent per year for fertile fuels), but such an approach takes much too long for many high neutron fluence scenarios (300 DPA for example) expected in reactors of the next generation. Indeed it is reasonable to say that there are no neutron sources available today to accomplish sufficiently rapid accelerated aging let alone also provide the temperature and spectral characteristics of future fast spectrum nuclear energy systems (fusion and fission both). Consequently, materials research and development progress continues to be severely limited by this bottleneck.

  8. Development of Bipolar Pulse Accelerator for Pulsed Ion Beam Implantation to Semiconductor

    NASA Astrophysics Data System (ADS)

    Masugata, Katsumi; Kawahara, Yoshihiro; Mitsui, Chihiro; Kitamura, Iwao; Takahashi, Takakazu; Tanaka, Yasunori; Tanoue, Hisao; Arai, Kazuo

    2002-12-01

    To improve the purity of the ion beams new type of pulsed power ion accelerator named "bipolar pulse accelerator" was proposed. The accelerator consists of two acceleration gaps (an ion source gap and a post acceleration gap) and a drift tube, and a bipolar pulse is applied to the drift tube to accelerate the beam. In the accelerator intended ions are selectively accelerated and the purity of the ion beam is enhanced. As the first step of the development of the accelerator, a Br-type magnetically insulated acceleration gap is developed. The gap has an ion source of coaxial gas puff plasma gun on the grounded anode and a negative pulse is applied to the cathode to accelerate the ion beam. By using the plasma gun, ion source plasma (nitrogen) of current density around 100 A/cm2 is obtained. In the paper, the experimental results of the evaluation of the ion beam and the characteristics of the gap are shown with the principle and the design concept of the proposed accelerator.

  9. Accelerated molecular dynamics methods: introduction and recent developments

    SciTech Connect

    Uberuaga, Blas Pedro; Voter, Arthur F; Perez, Danny; Shim, Y; Amar, J G

    2009-01-01

    reaction pathways may be important, we return instead to a molecular dynamics treatment, in which the trajectory itself finds an appropriate way to escape from each state of the system. Since a direct integration of the trajectory would be limited to nanoseconds, while we are seeking to follow the system for much longer times, we modify the dynamics in some way to cause the first escape to happen much more quickly, thereby accelerating the dynamics. The key is to design the modified dynamics in a way that does as little damage as possible to the probability for escaping along a given pathway - i.e., we try to preserve the relative rate constants for the different possible escape paths out of the state. We can then use this modified dynamics to follow the system from state to state, reaching much longer times than we could reach with direct MD. The dynamics within any one state may no longer be meaningful, but the state-to-state dynamics, in the best case, as we discuss in the paper, can be exact. We have developed three methods in this accelerated molecular dynamics (AMD) class, in each case appealing to TST, either implicitly or explicitly, to design the modified dynamics. Each of these methods has its own advantages, and we and others have applied these methods to a wide range of problems. The purpose of this article is to give the reader a brief introduction to how these methods work, and discuss some of the recent developments that have been made to improve their power and applicability. Note that this brief review does not claim to be exhaustive: various other methods aiming at similar goals have been proposed in the literature. For the sake of brevity, our focus will exclusively be on the methods developed by the group.

  10. Communicating to Influence Drug Development and Regulatory Decisions: A Tutorial.

    PubMed

    Mehrotra, S; Gobburu, J

    2016-04-01

    Pharmacometricians require three skills to be influential: technical, business (e.g., drug development), and soft skills (e.g., communication). Effective communication is required to translate technical and often complicated quantitative findings to interdisciplinary team members in order to influence drug development or regulatory decisions. In this tutorial, we highlight important aspects related to communicating pharmacometric analysis to influence decisions. PMID:27299706

  11. Rethinking the paradigm for the development of inhaled drugs.

    PubMed

    Pritchard, John N

    2015-12-30

    Nebulized treatment is an important delivery option for the young, elderly, and those with severe chronic respiratory disease, but there is a lack of new nebulized drug products being produced for these patients, leading to the potential for under-treatment. This communication describes a new drug development paradigm as a timely solution to this issue. Often, drug development is initiated with nebulizers in the early stages, to provide cheaper and faster drug development, and then switched to inhaler devices in later clinical trials to address the majority of patients. However, the waste of resource on parallel development of the inhaler can be large due to the high early attrition rate of new drug development. The new paradigm uses the nebulizer to continue drug development through to market, and initiates inhaler development after completion of the riskier early phase studies. New drug safety and efficacy can be assessed faster and more efficiently by using a nebulized formulation rather than developing an inhaler. The results of calculations of expected net present value showed that the new paradigm produced higher expected net present values than the conventional model over a range of economic scenarios. This new paradigm could therefore provide improved returns on investments, as well as more modern drugs in nebulized form for those patients unable to use inhalers. PMID:26475968

  12. Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

    PubMed Central

    Blakeley, Jaishri; Portnow, Jana

    2014-01-01

    Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID:20969450

  13. Implementation of mechanism of action biology-driven early drug development for children with cancer.

    PubMed

    Pearson, Andrew D J; Herold, Ralf; Rousseau, Raphaël; Copland, Chris; Bradley-Garelik, Brigid; Binner, Debbie; Capdeville, Renaud; Caron, Hubert; Carleer, Jacqueline; Chesler, Louis; Geoerger, Birgit; Kearns, Pamela; Marshall, Lynley V; Pfister, Stefan M; Schleiermacher, Gudrun; Skolnik, Jeffrey; Spadoni, Cesare; Sterba, Jaroslav; van den Berg, Hendrick; Uttenreuther-Fischer, Martina; Witt, Olaf; Norga, Koen; Vassal, Gilles

    2016-07-01

    An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric

  14. Recent advances in the design and development of soft drugs.

    PubMed

    Buchwald, P; Bodor, N

    2014-06-01

    This paper summarizes recent developments in the field of soft drug development as collected and reviewed for the 9th Retrometabolism-Based Drug Design and Targeting Conference. Soft drugs are still often confused with prodrugs because they both require metabolic transformations; however, they are conceptual opposites: whereas, prodrugs are pharmacologically inactive and are converted by a predictable mechanism to the active drug, soft drugs are active therapeutic agents as such and are designed to undergo a predictable and controllable metabolic deactivation after exerting their desired therapeutic effect. Several rationally designed soft drug examples including clinically approved ones (e.g., clevidipine, esmolol, landiolol, loteprednol etabonate, and remifentanil) as well as others that have reached clinical investigations within different therapeutic areas (e.g., budiodarone, naronapride, remimazolam, tecarfarine) are briefly summarized. Anesthesiology, which requires a high degree of pharmacologic control during the surgical procedure to maintain the anesthetic state together with a quick return to responsiveness at the end of this procedure, is a particularly well-suited area for soft drug development. Several new initiatives (e.g., MOC-etomidate, AZD3043) are focused in this area; they are also briefly reviewed. Finally, just as there are many 'accidental' prodrugs, there are 'accidental' soft drugs too: i.e., therapeutics that were not intentionally designed to be soft drugs, but turned out to be essentially soft drugs. Some examples, such as articaine or methylphenidate, are briefly reviewed. PMID:24974571

  15. Designed amphiphilic peptide forms stable nanoweb, slowly releases encapsulated hydrophobic drug, and accelerates animal hemostasis

    PubMed Central

    Ruan, Liping; Zhang, Hangyu; Luo, Hanlin; Liu, Jingping; Tang, Fushan; Shi, Ying-Kang; Zhao, Xiaojun

    2009-01-01

    How do you design a peptide building block to make 2-dimentional nanowebs and 3-dimensional fibrous mats? This question has not been addressed with peptide self-assembling nanomaterials. This article describes a designed 9-residue peptide, N-Pro-Ser-Phe-Cys-Phe-Lys-Phe-Glu-Pro-C, which creates a strong fishnet-like nanostructure depending on the peptide concentrations and mechanical disruptions. This peptide is intramolecularly amphiphilic because of a single pair of ionic residues, Lys and Glu, at one end and nonionic residues, Phe, Cys, and Phe, at the other end. Circular dichroism and Fourier transform infrared spectroscopy analysis demonstrated that this peptide adopts stable β-turn and β-sheet structures and self-assembles into hierarchically arranged supramolecular aggregates in a concentration-dependent fashion, demonstrated by atomic force microscopy and electron microscopy. At high concentrations, the peptide dominantly self-assembled into globular aggregates that were extensively connected with each other to form “beads-on-a-thread” type nanofibers. These long nanofibers were extensively branched and overlapped to form a self-healing peptide hydrogel consisting of >99% water. This peptide can encapsulate the hydrophobic model drug pyrene and slowly release pyrene from coated microcrystals to liposomes. It can effectively stop animal bleeding within 30 s. We proposed a plausible model to interpret the intramolecular amphiphilic self-assembly process and suggest its importance for the future development of new biomaterials for drug delivery and regenerative medicine. PMID:19289834

  16. Recent developments in anti-herpesvirus drugs.

    PubMed

    Field, Hugh J; Vere Hodge, R Anthony

    2013-01-01

    Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the

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

    PubMed

    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

    2016-09-01

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale 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 multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models. PMID:26885640

  18. Accelerated killing of cancer cells using a multifunctional single-walled carbon nanotube-based system for targeted drug delivery in combination with photothermal therapy

    PubMed Central

    Jeyamohan, Prashanti; Hasumura, Takashi; Nagaoka, Yutaka; Yoshida, Yasuhiko; Maekawa, Toru; Kumar, D Sakthi

    2013-01-01

    The photothermal effect of single-walled carbon nanotubes (SWCNTs) in combination with the anticancer drug doxorubicin (DOX) for targeting and accelerated destruction of breast cancer cells is demonstrated in this paper. A targeted drug-delivery system was developed for selective killing of breast cancer cells with polyethylene glycol biofunctionalized and DOX-loaded SWCNTs conjugated with folic acid. In our work, in vitro drug-release studies showed that the drug (DOX) binds at physiological pH (pH 7.4) and is released only at a lower pH, ie, lysosomal pH (pH 4.0), which is the characteristic pH of the tumor environment. A sustained release of DOX from the SWCNTs was observed for a period of 3 days. SWCNTs have strong optical absorbance in the near-infrared (NIR) region. In this special spectral window, biological systems are highly transparent. Our study reports that under laser irradiation at 800 nm, SWCNTs exhibited strong light–heat transfer characteristics. These optical properties of SWCNTs open the way for selective photothermal ablation in cancer therapy. It was also observed that internalization and uptake of folate-conjugated NTs into cancer cells was achieved by a receptor-mediated endocytosis mechanism. Results of the in vitro experiments show that laser was effective in destroying the cancer cells, while sparing the normal cells. When the above laser effect was combined with DOX-conjugated SWCNTs, we found enhanced and accelerated killing of breast cancer cells. Thus, this nanodrug-delivery system, consisting of laser, drug, and SWCNTs, looks to be a promising selective modality with high treatment efficacy and low side effects for cancer therapy. PMID:23926428

  19. Accelerator developments since the ZGS by ZGS people

    SciTech Connect

    Cho, Y.

    1994-12-31

    The ZGS was a facility, as well as an organization, where people got together to pursue a common goal of doing exciting science of the day. In this note, the authors describe notable events related to accelerators and accelerator people since the closing of the ZGS program some 15 years ago. Many of the same ZGS people have been carrying out the state-of-the art accelerator work around the Laboratory with the same dedication that characterized their work in the earlier days. First the authors describe how the activities were re-organized after the closing of the ZGS, the migration of people, and the organizational evolution since that time. Doing this shows the similarity between the birth of the ZGS and the birth of the Advanced Photon Source (APS). Then, some of the accelerator work by the former ZGS people are described. These include: (1) Intense Pulsed Neutron Source (IPNS), (2) GeV Electron Microtron (GEM), (3) Wake Field Accelerator Test Facility, (4) Advanced Photon Source, and (5) IPNS Upgrade.

  20. Liposomes and nanotechnology in drug development: focus on ocular targets

    PubMed Central

    Honda, Miki; Asai, Tomohiro; Oku, Naoto; Araki, Yoshihiko; Tanaka, Minoru; Ebihara, Nobuyuki

    2013-01-01

    Poor drug delivery to lesions in patients’ eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood–retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases. PMID:23439842

  1. Liposomes and nanotechnology in drug development: focus on ocular targets.

    PubMed

    Honda, Miki; Asai, Tomohiro; Oku, Naoto; Araki, Yoshihiko; Tanaka, Minoru; Ebihara, Nobuyuki

    2013-01-01

    Poor drug delivery to lesions in patients' eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood-retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases. PMID:23439842

  2. Defining "innovativeness" in drug development: a systematic review.

    PubMed

    Kesselheim, A S; Wang, B; Avorn, J

    2013-09-01

    Some observers of drug development argue that the pace of pharmaceutical innovation is declining, but others deny that contention. This controversy may be due to different methods of defining and assessing innovation. We conducted a systematic review of the literature to develop a taxonomy of methods for measuring innovation in drug development. The 42 studies fell into four main categories: counts of new drugs approved, assessments of therapeutic value, economic outcomes, and patents issued. The definition determined whether a study found a positive or negative trend in innovative drug development. Of 21 studies that relied on counts, 9 (43%) concluded that the trend for drug discovery was favorable, 11 (52%) concluded that the trend was not favorable, and 1 reached no conclusion. By contrast, of 21 studies that used other measures of innovation, 0 concluded that the trend was favorable, 8 (47%) concluded that the trend was not favorable, and 13 reached no conclusion (P = 0.03). PMID:23722626

  3. Prediction of resistance development against drug combinations by collateral responses to component drugs

    PubMed Central

    Munck, Christian; Gumpert, Heidi K.; Nilsson Wallin, Annika I.; Wang, Harris H.; Sommer, Morten O. A.

    2015-01-01

    Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution. PMID:25391482

  4. Prediction of resistance development against drug combinations by collateral responses to component drugs.

    PubMed

    Munck, Christian; Gumpert, Heidi K; Wallin, Annika I Nilsson; Wang, Harris H; Sommer, Morten O A

    2014-11-12

    Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution. PMID:25391482

  5. Residual acceleration data on IML-1: Development of a data reduction and dissemination plan

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.; Alexander, J. Iwan D.; Wolf, Randy

    1991-01-01

    A residual acceleration data analysis plan is developed that will allow principal investigators of low-gravity experiments to efficiently process their experimental results in conjunction with accelerometer data. The basic approach consisted of the following program of research: (1) identification of sensitive experiments and sensitivity ranges by order of magnitude estimates, numerical modelling, and investigator input; (2) research and development towards reduction, supplementation, and dissemination of residual acceleration data; and (3) implementation of the plan on existing acceleration data bases.

  6. Single cell analytic tools for drug discovery and development

    PubMed Central

    Heath, James R.; Ribas, Antoni; Mischel, Paul S.

    2016-01-01

    The genetic, functional, or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development.1-3 In cancers, heterogeneity may be essential for tumor stability,4 but its precise role in tumor biology is poorly resolved. This challenges the design of accurate disease models for use in drug development, and can confound the interpretation of biomarker levels, and of patient responses to specific therapies. The complex nature of heterogeneous tissues has motivated the development of tools for single cell genomic, transcriptomic, and multiplex proteomic analysis. We review these tools, assess their advantages and limitations, and explore their potential applications in drug discovery and development. PMID:26669673

  7. Exploring the ocean for new drug developments: Marine pharmacology

    PubMed Central

    Malve, Harshad

    2016-01-01

    Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses. PMID:27134458

  8. Exploring the ocean for new drug developments: Marine pharmacology.

    PubMed

    Malve, Harshad

    2016-01-01

    Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses. PMID:27134458

  9. Niobium resonator development for high-brightness ion beam acceleration

    SciTech Connect

    Delayen, J.R.; Bohn, C.L.; Roche, C.T.

    1990-01-01

    Two niobium resonant cavities for high-brightness ion beam acceleration have been constructed and tested. The first was based on a coaxial quarter-wave geometry and was optimized for phase velocity {beta}{sub o} = 0.15. This cavity, which resonates at 400 MHz in the fundamental mode, operated at an average (wall-to-wall) accelerating gradient of 12.9 MV/m under continuous-wave (cw) fields. At this gradient, a cavity Q of 1.4 {times} 10{sup 8} was measured. The second was based on a coaxial half-wave geometry and was optimized for {beta}{sub o} = 0.12. This cavity, which resonates at 355 MHz in the fundamental mode, operated at an average accelerating gradient of 18.0 MV/m under cw fields. This is the highest average accelerating gradient achieved to date in low-velocity structures designed for cw operation. At this gradient, a cavity Q of 1.2 {times} 10{sup 8} was measured.

  10. Developing and Maintaining Accelerated Degree Programs within Traditional Institutions.

    ERIC Educational Resources Information Center

    Husson, William J.; Kennedy, Tom

    2003-01-01

    Successful accelerated degree programs should be learner focused, market sensitive, accessible, and high quality. They should offer a variety of options and excellent customer service. Key elements include institutional purpose, decision-making process, curricular design, adjunct faculty, marketing, and promotional materials. (SK)

  11. Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels.

    PubMed

    Carmona-Moran, Carlos A; Zavgorodnya, Oleksandra; Penman, Andrew D; Kharlampieva, Eugenia; Bridges, S Louis; Hergenrother, Robert W; Singh, Jasvinder A; Wick, Timothy M

    2016-07-25

    Enhancing skin permeation is important for development of new transdermal drug delivery formulations. This is particularly relevant for non-steroidal anti-inflammatory drugs (NSAIDs). To address this, semisolid gel and solid hydrogel film formulations containing gellan gum as a gelling agent were developed and the effects of penetration enhancers (dimethyl sulfoxide, isopropyl alcohol and propylene glycol) on transport of the NSAID diclofenac sodium was quantified. A transwell diffusion system was used to accelerate formulation development. After 4h, diclofenac flux from a superior formulation of the semisolid gel or the solid hydrogel film was 130±11μg/cm(2)h and 108±7μg/cm(2)h, respectively, and significantly greater than that measured for a currently available diclofenac sodium topical gel (30±4μg/cm(2)h, p<0.05) or solution formulation (44±6μg/cm(2)h, p<0.05) under identical conditions. Over 24h diclofenac transport from the solid hydrogel film was greater than that measured for any new or commercial diclofenac formulation. Entrapment of temperature-responsive nanogels within the solid hydrogel film provides temperature-activated prolonged release of diclofenac. Diclofenac transport was minimal at 22°C, when diclofenac is entrapped within temperature-responsive nanogels incorporated into the solid hydrogel film, but increased 6-fold when the temperature was increased to skin surface temperature of 32°C. These results demonstrate the feasibility of the semisolid gel and solid hydrogel film formulations that can include thermo-responsive nanogels for development of transdermal drug formulations with adjustable drug transport kinetics. PMID:27260133

  12. Drug development for controlling Ebola epidemic - a race against time.

    PubMed

    Gao, Jianjun; Yin, Lin

    2014-10-01

    The Ebola outbreak in West Africa this year is causing global panic. The high mortality of this disease is largely due to lack of effective preventive vaccines or therapeutic drugs. Realizing the gravity and urgency in controlling the epidemic, governments and drug companies across the world have taken many strong measures to speed up the process of drug development. Several representative candidate drugs that demonstrate potent anti-Ebola activity in preclinical studies have been pushed forward to higher research stages to obtain an earlier official license. It is expected that proven preventive or therapeutic regimens could be established in the near future. PMID:25382559

  13. E-beam accelerator cavity development for the ground-based free electron laser

    NASA Astrophysics Data System (ADS)

    Bultman, N. K.; Spalek, G.

    Los Alamos National Laboratory is designing and developing four prototype accelerator cavities for high power testing on the Modular Component Technology Development (MCTD) test stand at Boeing. These cavities provide the basis for the e-beam accelerator hardware that will be used in the Ground Based Free Electron Laser (GBFEL) to be sited at the White Sands Missile Range (WSMR) in New Mexico.

  14. On the Boundaries of the Acceleration of the Development of Intelligence.

    ERIC Educational Resources Information Center

    Kingma, Johannes; Tomic, Welko

    This paper examines the possibility of accelerating the development of intelligence when applying stringent Piagetian standards to evaluate the effects of short- and long-term intervention or instruction programs. The paper reviews previous Genevan and American research that shows that development can be accelerated by means of only a few…

  15. The paradigm shift to an "open" model in drug development.

    PubMed

    Au, Regina

    2014-12-01

    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. PMID:27294020

  16. Cardiovascular safety monitoring during oncology drug development and therapy.

    PubMed

    Turner, J Rick; Panicker, Gopi Krishna; Karnad, Dilip R; Cabell, Christopher H; Lieberman, Ronald; Kothari, Snehal

    2014-01-01

    Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers. PMID:24451296

  17. Systems drug discovery: a quantitative, objective approach for safer drug development.

    PubMed

    Bickle, Marc

    2012-09-01

    We are currently witnessing a dramatic change in the pharmaceutical industry as many companies are downscaling their efforts to discover new drug candidates and are instead turning toward collaboration with academic partners. This trend has been dubbed open innovation. The reason for this change of policy stems from the realization that, in spite of massive investments in their drug development programs in the past 30 years, the number of new drugs reaching the market has remained stable over the same period. We review past and present drug discovery strategies and present a novel more holistic approach that we term Systems Drug Discovery. This approach aims at quantifying the physiological state of organ slice cultures using high content imaging and metabolomics. The characterization in a quantitative manner of healthy, diseased, and drug-treated tissues will allow defining a multiparametric space, within which tissues are healthy. This in turn will allow an objective assessment of the impact of candidate drugs on cells. This quantitative approach should help guide the development of new drugs reducing failure rates in clinical phase. PMID:22827715

  18. Tumor lymphangiogenesis and new drug development.

    PubMed

    Dieterich, Lothar C; Detmar, Michael

    2016-04-01

    Traditionally, tumor-associated lymphatic vessels have been regarded as passive by-standers, serving simply as a drainage system for interstitial fluid generated within the tumor. However, with growing evidence that tumors actively induce lymphangiogenesis, and that the number of lymphatic vessels closely correlates with metastasis and clinical outcome in various types of cancer, this picture has changed dramatically in recent years. Tumor-associated lymphatic vessels have now emerged as a valid therapeutic target to control metastatic disease, and the first specific anti-lymphangiogenic drugs have recently entered clinical testing. Furthermore, we are just beginning to understand the whole functional spectrum of tumor-associated lymphatic vessels, which not only concerns transport of fluid and metastatic cells, but also includes the regulation of cancer stemness and specific inhibition of immune responses, opening new venues for therapeutic applications. Therefore, we predict that specific targeting of lymphatic vessels and their function will become an important tool for future cancer treatment. PMID:26705849

  19. Novel drug development for neuromuscular blockade.

    PubMed

    Prabhakar, Amit; Kaye, Alan D; Wyche, Melville Q; Salinas, Orlando J; Mancuso, Kenneth; Urman, Richard D

    2016-01-01

    Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review. With regard to nondepolarizer neuromuscular blocker agents, the enantiomers Gantacurium and CW002, which are olefinic isoquinolinium diester fumarates, have shown potential for clinical application. Advantages include ultra rapid reversal of neuromuscular blockade via cysteine adduction and minimal systemic hemodynamic effects with administration. PMID:27625489

  20. Novel drug development for neuromuscular blockade

    PubMed Central

    Prabhakar, Amit; Kaye, Alan D; Wyche, Melville Q; Salinas, Orlando J; Mancuso, Kenneth; Urman, Richard D

    2016-01-01

    Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review. With regard to nondepolarizer neuromuscular blocker agents, the enantiomers Gantacurium and CW002, which are olefinic isoquinolinium diester fumarates, have shown potential for clinical application. Advantages include ultra rapid reversal of neuromuscular blockade via cysteine adduction and minimal systemic hemodynamic effects with administration. PMID:27625489

  1. Alternative strategies in drug development: clinical pharmacological aspects.

    PubMed

    Kuhlmann, J

    1999-12-01

    Due to the continuous increase in time and cost of drug development and the considerable amount of resources required by the traditional approach, companies can no longer afford to continue to late phase 3 with drugs which are unlikely to be therapeutically effective. The future challenge must be for the pharmaceutical industry to slash its research and development costs by achieving a significant cut in the attrition rate for drugs entering preclinical and clinical development, and to reduce the development time and to increase the probability of success in later clinical trials by streamlining the development processes. In the 100 years to 1995, the pharmaceutical industry worked on about 500 targets with a limited number of compounds, whereas now, using new technologies like genomics, high throughput screening and combinatorial chemistry, drug companies will see an explosion in the number of targets and leads it can explore. Therefore, a tough selection process for picking candidate compounds out of research and a quick kill process for the candidate, which does not measure up in advanced trials, is mandatory to avoid wasting time, energy and money. To improve the transition from research to development it is necessary to validate new targets, define success criteria for research, integrate bioinformation at every stage in drug discovery, define prerequisites for development, identify the "losers" and select the "winners" early and concentrate efforts on them, and to automate the research and development (R&D) process to optimize resource requirements versus time lines and to ensure effective flow of information from drug discovery to late phase of development. In drug development a deeper understanding of a drugs' action is necessary from animal models and phase I, IIa studies prior to taking the drug further in development. Instead of moving from discovery thorough development phases in sequential steps, drug development should be streamlined combining

  2. Combination therapy: the propitious rationale for drug development.

    PubMed

    Phougat, Neetu; Khatri, Savita; Singh, Anu; Dangi, Mrridula; Kumar, Manish; Dabur, Rajesh; Chhillar, Anil Kumar

    2014-01-01

    Therapeutic options for many infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. There had been no miracle drug for the patients infected by resistant microbial pathogens. Most of the very few new drugs under development have problems with their toxicity, or pharmacokinetics and pharmacodynamics. We are already decades behind in the discovery, characterization and development of new antimicrobials. In that scenario, we could not imagine surviving without newer and effective antimicrobial agents. Bacteria have been the champions of evolution and are still evolving continuously, where they pose serious challenges for humans. Along with the crisis of evolving resistance, the condition is made worst by the meager drug pipeline for new antimicrobials. Despite ongoing efforts only 2 new antibiotics (Telavancin in 2009 and Ceftaroline fosamil in 2010) have been approved since 2009 pipeline status report of Infectious Disease Society of America (IDSA). Recent approval of new combination based antiviral drugs such as Stribild (combination of four drugs for HIV treatment) and Menhibrix (combination vaccine to prevent meningococcal disease and Haemophilus influenzae type b in children) proves that combination therapy is still the most promising approach to combat the ever evolving pathogens. Combination therapy involves the drug repurposing and regrouping of the existing antimicrobial agents to provide a synergistic approach for management of infectious diseases. This review article is an effort to highlight the challenges in new drug development and potential of combination drug therapy to deal with them. PMID:24138510

  3. Drug Repurposing for the Development of Novel Analgesics.

    PubMed

    Sisignano, Marco; Parnham, Michael J; Geisslinger, Gerd

    2016-03-01

    Drug development consumes huge amounts of time and money and the search for novel analgesics, which are urgently required, is particularly difficult, having resulted in many setbacks in the past. Drug repurposing - the identification of new uses for existing drugs - is an alternative approach, which bypasses most of the time- and cost-consuming components of drug development. Recent, unexpected findings suggest a role for several existing drugs, such as minocycline, ceftriaxone, sivelestat, and pioglitazone, as novel analgesics in chronic and neuropathic pain states. Here, we discuss these findings as well as their proposed antihyperalgesic mechanisms and outline the merits of pathway-based repurposing screens, in combination with bioinformatics and novel cellular reprogramming techniques, for the identification of novel analgesics. PMID:26706620

  4. High Temperature μSR Experiments for Accelerator Developments

    NASA Astrophysics Data System (ADS)

    Ohmori, Chihiro; Koda, Akihiro; Miyake, Yasuhiro; Nishiyama, Kusuo; Shimomura, Koichiro; Schnase, Alexander; Ezura, Eiji; Hara, Keigo; Hasegawa, Katsushi; Nomura, Masahiro; Shimada, Taihei; Takata, Koji; Tamura, Fumihiko; Toda, Makoto; Yamamoto, Masanobu; Yoshii, Masahito

    High temperature μSR is a powerful technique to study magnetic materials. In J-PARC accelerator synchrotrons, the Rapid Cycling Synchrotron (RCS) and Main Ring (MR), a unique magnetic alloy-loaded cavity is used for the beam acceleration and much higher field gradient has been achieved. Such high field gradient cavities made a compact RCS possible by reducing the length for beam acceleration. Now, further upgrades of the J-PARC, RF cavities with higher RF voltage and less power loss in the magnetic core are needed for the MR. For the improvements of the magnetic property of magnetic alloy core, the high temperature μSR (muon Spin Rotation/Relaxation) was used to investigate the crystallization process of the material. Based on the measurement results, the test production of the large ring cores of a magnetic alloy, FT3L, was tried. The FT3L is the magnetic alloy which has two times better performance than the present one, FT3M. For the FT3L production, the magnetic annealing is needed to control the easy-magnetized axis of the crystalline. After the success of the test production, a mass production was started in the industry to replace all existing cavities in the MR. The first 5-cell FT3L cavity is assembled for the bench test before the installation in the accelerator tunnel. By the new cavities, the total RF voltage of J-PARC MR will be doubled to increase the beam power for neutrino experiment. In future, the cavities will be also used for the RCS to increase the beam power beyond 1 MW.

  5. Compulsory drug treatment in Canada: historical origins and recent developments.

    PubMed

    Fischer, Benedikt; Roberts, Julian V; Kirst, Maritt

    2002-04-01

    In Canada, illicit drug use and addiction have traditionally been considered as a criminal justice problem and have been addressed from a legal perspective. Over the past century, a medical approach to drug addiction has slowly crept into the criminal justice processing of drug offenders. This has happened through the combination of principles of punishment with principles of addiction treatment in the sentencing of drug offenders to create a distinct application of 'compulsory drug treatment' in Canada. However, this evolution has occurred sporadically over time, with punishment and coercion as predominantly the main approach to dealing with this population. This evolution has recently culminated in Canada with the development of two criminal justice approaches to dealing with the substance use problems of drug offenders that incorporate concepts of punishment and treatment more equally than ever before - conditional sentencing and drug courts. This paper outlines the historical evolution of concepts of 'compulsory treatment', discusses such examples of contemporary 'compulsory treatment' as conditional sentencing and drug courts, and analyses the implications, concerns and challenges associated with these tools currently used in the sentencing of drug offenders in the Canadian context. PMID:11979008

  6. Development and characterization of an orodispersible film containing drug nanoparticles.

    PubMed

    Shen, Bao-de; Shen, Cheng-ying; Yuan, Xu-dong; Bai, Jin-xia; Lv, Qing-yuan; Xu, He; Dai, Ling; Yu, Chao; Han, Jin; Yuan, Hai-long

    2013-11-01

    In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC0-24h, Cmax and decrease in Tmax, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs. PMID:24103635

  7. TRI-SERVICE SITE CHARACTERIZATION AND ANALYSIS PENETROMETER SYSTEM (SCAPS) ACCELERATED SENSOR DEVELOPMENT PROJECT

    EPA Science Inventory

    In 1994, the Strategic Environmental Research and Development Program (SERDP) funded a Tri-Service effort to accelerate the development and fielding of environmental sensing technologies to extend the capabilities of the Site Characterization and Analysis Penetrometer System (SCA...

  8. Current Status of Celiac Disease Drug Development.

    PubMed

    Wungjiranirun, Manida; Kelly, Ciaran P; Leffler, Daniel A

    2016-06-01

    Celiac disease (CeD) is one of the most common immune-mediated diseases. Symptoms and disease activity are incompletely controlled by the gluten-free diet, which is currently the only available therapy. Although no therapies are yet approved, there is a growing field of candidates and an improving understanding of the regulatory pathway. In this review, we briefly discuss the epidemiology, pathophysiology, and current treatment paradigm for CeD. We also review the major classes of therapies being considered for CeD and discuss extensively what is known and can be surmised regarding the regulatory pathway for approval of a CeD therapeutic. The coming years will see an increasing number and diversity of potential therapies entering clinical trials and hopefully the first approved agents targeting this significant unmet medical need. Although biomarkers including histology and serology will always be important in therapeutic clinical trials, they currently lack the necessary evidence linking them to improved patient outcomes required for use as primary outcomes for drug approval. For this reason, patient-reported outcomes will likely be primary end points in Phase III CeD trials for the foreseeable future. PMID:27021196

  9. Development of a 20-MeV Dielectric-Loaded Accelerator Test Facility

    SciTech Connect

    Gold, S.H.; Kinkead, A.K.; Gai, W.; Power, J.G.; Konecny, R.; Jing, C.G.; Tantawi, S.G.; Nantista, C.D.; Hu, Y.; Chen, H.; Tang, C.; Lin, Y.; Bruce, R.W.; Bruce, R.L.; Fliflet, A.W.; Lewis, D.; /Naval Research Lab, Wash., D.C. /LET Corp., Washington /Argonne /SLAC /Tsinghua U., Beijing

    2005-06-22

    This paper describes a joint project by the Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), to develop a dielectric-loaded accelerator (DLA) test facility powered by a high-power 11.424-GHz magnicon amplifier. The magnicon can presently produce 25 MW of output power in a 250-ns pulse at 10 Hz, and efforts are in progress to increase this to 50 MW. The facility will include a 5 MeV electron inector being developed by the Accelerator Laboratory of Tsinghua University in Beijing, China. The DLA test structures are being developed by ANL, and some have undergone testing at NRL at gradients up to {approx} 8 MV/m. SLAC is developing a means to combine the two magnicon output arms, and to drive an injector and accelerator with separate control of the power ratio and relative phase. RWBruce Associates, Inc., working with NRl, is developing a means to join short ceramic sections into a continuous accelerator tube by ceramic brazing using an intense millimeter-wave beam. The installation and testing of the first dielectric-loaded test accelerator, including injector, DLA structure, and spectrometer, should take place within the next year. The facility will be used for testing DLA structures using a variety of materials and configurations, and also for testing other X-band accelerator concepts. The initial goal is to produce a compact 20 MeV dielectric-loaded test accelerator.

  10. Quasi-Drugs Developed in Japan for the Prevention or Treatment of Hyperpigmentary Disorders

    PubMed Central

    Ando, Hideya; Matsui, Mary S.; Ichihashi, Masamitsu

    2010-01-01

    Excess production of melanin or its abnormal distribution, or both, can cause irregular hyperpigmentation of the skin, leading to melasma and age spots. To date, various quasi-drugs that prevent or improve hyperpigmentary disorders have been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan. Many of these inhibit the activity of tyrosinase, an enzyme required for melanin synthesis, for example, by competitive or non-competitive inhibition of its catalytic activity, by inhibiting its maturation, or by accelerating its degradation. In this review, we categorize the quasi-drugs developed in Japan to prevent or treat hyperpigmentary disorders, or both, and discuss perspectives for future development. PMID:20640168

  11. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

    PubMed

    Chen, Shan; Grover, Monica; Sibai, Tarek; Black, Jennifer; Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

    2015-05-01

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. PMID:25779879

  12. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

    PubMed Central

    Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

    2015-01-01

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. PMID:25779879

  13. A Comprehensive Review of Novel Drug-Disease Models in Diabetes Drug Development.

    PubMed

    Gaitonde, Puneet; Garhyan, Parag; Link, Catharina; Chien, Jenny Y; Trame, Mirjam N; Schmidt, Stephan

    2016-07-01

    Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which affects millions of people worldwide. The disease is characterized by chronically elevated blood glucose concentrations (hyperglycaemia), which result in comorbidities and multi-organ dysfunction. This is due to a gradual loss of glycaemic control as a result of increasing insulin resistance, as well as decreasing β-cell function. The objective of T2DM drug interventions is, therefore, to reduce fasting and postprandial blood glucose concentrations to normal, healthy levels without hypoglycaemia. Several classes of novel antihyperglycaemic drugs with various mechanisms of action have been developed over the past decades or are currently under clinical development. The development of these drugs is routinely supported by the application of pharmacokinetic/pharmacodynamic modelling and simulation approaches. They integrate information on the drug's pharmacokinetics, clinically relevant biomarker information and disease progression into a single, unifying approach, which can be used to inform clinical study design, dose selection and drug labelling. The objective of this review is to provide a comprehensive overview of the quantitative approaches that have been reported since the 2008 review by Landersdorfer and Jusko in an increasing order of complexity, starting with glucose homeostasis models. Each of the presented approaches is discussed with respect to its strengths and limitations, and respective knowledge gaps are highlighted as potential opportunities for future drug-disease model development in the area of T2DM. PMID:26798033

  14. Accelerating the development of improved analgesic treatments: the ACTION public-private partnership.

    PubMed

    Dworkin, Robert H; Turk, Dennis C

    2011-07-01

    There has been considerable progress identifying pathophysiologic mechanisms of neuropathic pain, but analgesic medications with improved efficacy, safety, and tolerability still represent an unmet public health need. Numerous treatments examined in recent randomized clinical trials (RCTs) have failed to show efficacy for neuropathic pain, including treatments that had previously demonstrated efficacy. This suggests that at least some negative results reflect limited assay sensitivity of RCTs to distinguish efficacious treatments from placebo. Patient characteristics, clinical trial research designs and methods, outcome measures, approaches to data analysis, and statistical power may all play a role in accounting for difficulties in demonstrating the benefits of efficacious analgesic treatments vs placebo. The identification of specific clinical trial characteristics associated with assay sensitivity in existing data has the potential to provide an evidence-based approach to the design of analgesic clinical trials. The US Food and Drug Administration recently launched the Analgesic Clinical Trial Innovations, Opportunities, and Networks (ACTION) public-private partnership, which is designed to facilitate the discovery and development of analgesics with improved efficacy, safety, and tolerability for acute and chronic pain conditions. ACTION will establish a collaborative effort to prioritize research objectives, develop a standardized analgesic database platform, and conduct methodologically focused studies to increase the assay sensitivity and efficiency of analgesic clinical trials. The results of these activities have the potential to inform and accelerate the development of improved pain management interventions of all types, not just pharmacologic treatments. PMID:21752182

  15. Drug-Induced Torsade de Pointes and Implications for Drug Development

    PubMed Central

    Fenichel, Robert R.; Malik, Marek; Antzelevitch, Charles; Sanguinetti, Michael; Roden, Dan M.; Priori, Silvia G.; Ruskin, Jeremy N.; Lipicky, Raymond J.; Cantilena, Lou

    2006-01-01

    Torsade de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently-developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks, and explains the failures of older approaches through the surface electrocardiogram. The article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarisation changes, on their preclinical and clinical evaluation, and on the risk-benefit interpretation of drug-induced torsade de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsade within drug development program. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion-channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and at interpretation of human electrocardiograms obtained in clinical studies. Final section of the text discusses drug-induced torsade within the larger evaluation of drug-related risks and benefits. PMID:15090000

  16. Development of the Accelerator Mass Spectrometry technology at the Comenius University in Bratislava

    NASA Astrophysics Data System (ADS)

    Povinec, Pavel P.; Masarik, Jozef; Ješkovský, Miroslav; Kaizer, Jakub; Šivo, Alexander; Breier, Robert; Pánik, Ján; Staníček, Jaroslav; Richtáriková, Marta; Zahoran, Miroslav; Zeman, Jakub

    2015-10-01

    An Accelerator Mass Spectrometry (AMS) laboratory has been established at the Centre for Nuclear and Accelerator Technologies (CENTA) at the Comenius University in Bratislava comprising of a MC-SNICS ion source, 3 MV Pelletron tandem accelerator, and an analyzer of accelerated ions. The preparation of targets for 14C and 129I AMS measurements is described in detail. The development of AMS techniques for potassium, uranium and thorium analysis in radiopure materials required for ultra-low background underground experiments is briefly mentioned.

  17. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  18. Involvement of Drug Transporters in Organ Toxicity: The Fundamental Basis of Drug Discovery and Development.

    PubMed

    Cheng, Yaofeng; El-Kattan, Ayman; Zhang, Yan; Ray, Adrian S; Lai, Yurong

    2016-04-18

    Membrane transporters play a pivotal role in many organs to maintain their normal physiological functions and contribute significantly to drug absorption, distribution, and elimination. Knowledge gained from gene modified animal models or human genetic disorders has demonstrated that interruption of the transporter activity can lead to debilitating diseases or organ toxicities. Herein we describe transporter associated diseases and organ toxicities resulting from transporter gene deficiency or functional inhibition in the liver, kidney, gastrointestinal tract (GIT), and central nervous system (CNS). While proposing additional transporters as targets for drug-induced organ toxicity, strategies and future perspectives are discussed for transporter risk assessment in drug discovery and development. PMID:26889774

  19. Development of an Optimised Application Protocol For Sonophoretic Transdermal Delivery of a Model Hydrophilic Drug

    PubMed Central

    Sarheed, Omar; Abdul Rasool, Bazigha K

    2011-01-01

    It has now been known for over a decade that low frequency ultrasound can be used to effectively enhance transdermal drug penetration - an approach termed sonophoresis. Mechanistically, acoustic cavitation results in the creation of defects in the stratum corneum that allow accelerated absorption of topically applied molecules. The aim of this study was to develop an optimised sonophoresis protocol for studying transdermal drug delivery in vitro. To this end, caffeine was selected as a model hydrophilic drug while porcine skin was used as a model barrier. Following acoustic validation, 20kHz ultrasound was applied for different durations (range: 5 s to 10 min) using three different modes (10%, 33% or 100% duty cycles) and two distinct sonication procedures (either before or concurrent with drug deposition). Each ultrasonic protocol was assessed in terms of its heating and caffeine flux-enhancing effects. It was found that the best regimen was a concurrent 5 min, pulsed (10% duty cycle) beam of SATA intensity 0.37 W/cm2. A key insight was that in the case of pulsed beams of 10% duty cycle, sonication concurrent with drug deposition was superior to sonication prior to drug deposition and potential mechanisms for this are discussed. PMID:21629673

  20. New avenues for anti-epileptic drug discovery and development.

    PubMed

    Löscher, Wolfgang; Klitgaard, Henrik; Twyman, Roy E; Schmidt, Dieter

    2013-10-01

    Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs. PMID:24052047

  1. Waterborne psychoactive drugs impair the initial development of Zebrafish.

    PubMed

    Kalichak, Fabiana; Idalencio, Renan; Rosa, João Gabriel S; de Oliveira, Thiago A; Koakoski, Gessi; Gusso, Darlan; de Abreu, Murilo S; Giacomini, Ana Cristina V; Barcellos, Heloísa H A; Fagundes, Michele; Piato, Angelo L; Barcellos, Leonardo J G

    2016-01-01

    The contamination of rivers and other natural water bodies, including underground waters, is a current reality. Human occupation and some economic activities generate a wide range of contaminated effluents that reach these water resources, including psychotropic drug residues. Here we show that fluoxetine, diazepam and risperidone affected the initial development of zebrafish. All drugs increased mortality rate and heart frequency and decreased larvae length. In addition, risperidone and fluoxetine decreased egg hatching. The overall results points to a strong potential of these drugs to cause a negative impact on zebrafish initial development and, since the larvae viability was reduced, promote adverse effects at the population level. We hypothesized that eggs and larvae absorbed the drugs that exert its effects in the central nervous system. These effects on early development may have significant environmental implications. PMID:26667671

  2. Hurdles in anticancer drug development from a regulatory perspective.

    PubMed

    Jonsson, Bertil; Bergh, Jonas

    2012-04-01

    Between January 2001 and January 2012, 48 new medicinal products for cancer treatment were licensed within the EU, and 77 new indications were granted for products already licensed. In some cases, a major improvement to existing therapies was achieved, for example, trastuzumab in breast cancer. In other cases, new fields for effective drug therapy opened up, such as in chronic myeloid leukemia, and renal-cell carcinoma. In most cases, however, the benefit-risk balance was considered to be only borderline favorable. Based on our assessment of advice procedures for marketing authorization, 'need for speed' seems to be the guiding principle in anticancer drug development. Although, for drugs that make a difference, early licensure is of obvious importance to patients, this is less evident in the case of borderline drugs. Without proper incentives and with hurdles inside and outside companies, a change in drug development cannot be expected; drugs improving benefit-risk modestly over available therapies will be brought forward towards licensure. In this Perspectives article, we discuss some hurdles to biomarker-driven drug development and provide some suggestions to overcome them. PMID:22349015

  3. Development of antiparasitic drugs in the 21st century.

    PubMed

    Geary, Timothy G; Thompson, David P

    2003-07-25

    Prospects for discovering new antiparasitic drugs for veterinary medicine in the coming century will be determined by economic, social and scientific factors. Consolidation in the pharmaceutical industry in general, and the animal health industry in particular, changes the business conditions in which drug discovery for veterinary medicine occurs. Social pressures on traditional animal agriculture and companion animal ownership have shifted the interest of animal companies primarily to pet medicine. Antiparasitic drug discovery is more than ever targeted to the most lucrative market segments, but the excellence of available drugs, and the apparent lack of resistance in important parasites, reduces industrial motivation to invest in parasitology. Veterinary parasitologists in academia will still have the chance to interact with their industrial counterparts in the traditional ways of supporting drug discovery and development. Nonetheless, there are many new opportunities to expand the research horizons of veterinary parasitology to strengthen the case for retaining a significant presence in the animal health industry. PMID:12878421

  4. Targeting the mycobacterial envelope for tuberculosis drug development

    PubMed Central

    Favrot, Lorenza; Ronning, Donald R

    2013-01-01

    The bacterium that causes tuberculosis, Mycobacterium tuberculosis, possesses a rather unique outer membrane composed largely of lipids that possess long-chain and branched fatty acids, called mycolic acids. These lipids form a permeability barrier that prevents entry of many environmental solutes, thereby making these bacteria acid-fast and able to survive extremely hostile surroundings. Antitubercular drugs must penetrate this layer to reach their target. This review highlights drug development efforts that have added to the slowly growing tuberculosis drug pipeline, identified new enzyme activities to target with drugs and increased the understanding of important biosynthetic pathways for mycobacterial outer membrane and cell wall core assembly. In addition, a portion of this review looks at discovery efforts aimed at weakening this barrier to decrease mycobacterial virulence, decrease fitness in the host or enhance the efficacy of the current drug repertoire by disrupting the permeability barrier. PMID:23106277

  5. Residual acceleration data on IML-1: Development of a data reduction and dissemination plan

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.; Alexander, J. Iwan D.

    1993-01-01

    The research performed consisted of three stages: (1) identification of sensitive IML-1 experiments and sensitivity ranges by order of magnitude estimates, numerical modeling, and investigator input; (2) research and development towards reduction, supplementation, and dissemination of residual acceleration data; and (3) implementation of the plan on existing acceleration databases.

  6. Jefferson Lab Accelerator Operations Training and Development Program

    SciTech Connect

    Michael A. Epps

    2008-01-23

    The mission of the Jefferson Lab Operations Group is to provide safe and efficient delivery of high quality electron beam for Jefferson Laboratory's nuclear and accelerator physics programs. The Operations staff must be able to setup, transport, maintain, and troubleshoot beam to all three experimental halls in a safe, efficient, and expeditious manner. Due to the nature of shift work, high employee turnover is always as issue. This creates a unique situation where highly trained staff members must quickly be produced and maintained in order to meet the needs of the Laboratory. Some methods used to address this problem will be presented here.

  7. Drug discovery and development for neglected diseases: the DNDi model.

    PubMed

    Chatelain, Eric; Ioset, Jean-Robert

    2011-01-01

    New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness), leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public-private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi's own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven. PMID:21552487

  8. Clinical drugs that interact with St. John's wort and implication in drug development.

    PubMed

    Di, Yuan Ming; Li, Chun Guang; Xue, Charlie Changli; Zhou, Shu-Feng

    2008-01-01

    St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and

  9. New Financial and Research Models for Pediatric Orphan Drug Development - Focus on the NCATS TRND Program

    PubMed Central

    Shen, John; Grewal, Gurmit; Pilon, Andre M.; McKew, John C.

    2014-01-01

    While there are approximately 7,000 identified human diseases considered as "rare" based on population prevalence or incidence, the cumulative impact runs into the millions of patients globally. Although the genetic underpinnings of more than 2,000 rare diseases have been elucidated, there remains a paucity of therapeutic options, frequently due to lack of commercial interest. Development programs suffer high attrition within the so-called "Valley of Death," in which the risks of scientific failure are still too high to justify the increasing development costs. This problem is common to any drug development campaign, but it is particularly exacerbated in the rare diseases, many of which arise in childhood. To stimulate development of therapeutics for these otherwise underserved patient populations, a number of regulatory incentives and research initiatives have been established. Extended patent protections, expedited regulatory reviews for qualified drug sponsors, and clinical trial grant support aim to foster interest in completing development programs. To stimulate researchers to embark on rare disease drug development campaigns, earlier-stage preclinical research resources have been created, as well, such as the Therapeutics for Rare and Neglected Diseases (TRND) program at the U.S. National Institutes of Health (NIH). TRND is a unique NIH program created to support drug development through formation of public-private partnerships. These partnerships leverage the robust biopharmaceutical industry experience of the TRND staff scientists and the deep disease area expertise of the collaborating partners. Each project adopted into the TRND portfolio aims to satisfy two broad goals: developing a novel therapy for a rare or otherwise neglected disease, and exploring ways to accelerate the drug development process overall so that lessons learned can be disseminated to the wider community undertaking translational research. This article discusses common obstacles and

  10. Development of new anti-tuberculosis drug candidates.

    PubMed

    Shi, Ruiru; Sugawara, Isamu

    2010-06-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, is a tenacious and remarkably successful pathogen that has latently infected one third of the world's population, according to the World Health Organization (WHO) statistics. It is anticipated that 10% of these infected individuals will develop active tuberculosis at some point in their lifetime. The long-term use of the current drug regimen, the emergence of drug-resistant strains, and HIV co-infection have resulted in a resurgence of research efforts to address the urgent need for new anti-tuberculosis drugs. A number of potential candidate drugs with novel modes of action have entered clinical trials in recent years, and these are likely to be effective against anti-tuberculosis drug-resistant strains. They include neuroquinolone derivatives, a modified ethambutol, nitro-imidazole groups and so on. This mini-review summarizes the latest information about eight new anti-tuberculosis drug candidates and describes their activities, pharmacokinetics, mechanisms of action, and mechanisms of drug-resistance induced by these drug candidates. PMID:20467231

  11. The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

    PubMed Central

    2011-01-01

    Background Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases. Methods To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments. Results We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment. Conclusion Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases. PMID:21733145

  12. Importance of molecular computer modeling in anticancer drug development.

    PubMed

    Geromichalos, George D

    2007-09-01

    Increasing insight into the genetics and molecular biology of cancer has resulted in the identification of an increasing number of potential molecular targets for anticancer drug discovery and development. These targets can be approached through exploitation of emerging structural biology, "rational" drug design, screening of chemical libraries, or a combination of these methods. The result is the rapid discovery of new anticancer drugs. The processes used by academic and industrial scientists to discover new drugs has recently experienced a true renaissance with many new and exciting techniques being developed in the past 5-10 years. In this review, we will attempt to outline these latest protocols that chemists and biomedical scientists are currently employing to rapidly bring new drugs to the clinic. Structure-based drug design is perhaps the most elegant approach for discovering compounds exhibiting high specificity and efficacy. Nowadays, a number of recent successful drugs have in part or in whole emerged from a structure-based research approach. Many advances including crystallography and informatics are behind these successes. Of great importance is also the impact these advances in structure-based drug design are likely to have on the economics of drug discovery. As the structures of more and more proteins and nucleic acids become available, molecular docking is increasingly considered for lead discovery. Recent studies consider the hit-rate enhancement of docking screens and the accuracy of docking structure predictions. As more structures are determined experimentally, docking against homology-modeled targets also becomes possible for more proteins. With more docking studies being undertaken, the "drug-likeness" and specificity of docking hits is also being examined. In this article we discuss the application of molecular modeling, molecular docking and virtual molecular high-throughput, targeted drug screening to anticancer drug discovery. Currently

  13. A case for developing antiviral drugs against polio.

    PubMed

    Collett, Marc S; Neyts, Johan; Modlin, John F

    2008-09-01

    Polio eradication is within sight. In bringing the world close to this ultimate goal, the Global Polio Eradication Initiative (GPEI) has relied exclusively on the live, attenuated oral poliovirus vaccine (OPV). However, as eradication nears, continued OPV use becomes less tenable due to the incidence of vaccine associated paralytic poliomyelitis (VAPP) in vaccine recipients and disease caused by circulating vaccine-derived polioviruses (cVDPVs) in contacts. Once wild poliovirus transmission has been interrupted globally, OPV use will stop. This will leave the inactivated poliovirus vaccine (IPV) as the only weapon to defend a polio-free world. Outbreaks caused by cVDPVs are expected post-OPV cessation, and accidental or deliberate releases of virus could also occur. There are serious doubts regarding the ability of IPV alone to control outbreaks. Here, we argue that antiviral drugs against poliovirus be added to the arsenal. Anti-poliovirus drugs could be used to treat the infected and protect the exposed, acting rapidly on their own to contain an outbreak and used as a complement to IPV. While there are no polio antiviral drugs today, the technological feasibility of developing such drugs and their probability of clinical success have been established by over three decades of drug development targeting the related rhinoviruses and non-polio enteroviruses (NPEVs). Because of this history, there are known compounds with anti-poliovirus activity in vitro that represent excellent starting points for polio drug development. Stakeholders must come to understand the potential public health benefits of polio drugs, the feasibility of their development, and the relatively modest costs involved. Given the timelines for eradication and those for drug development, the time for action is now. PMID:18513807

  14. Development of a low-energy beam transport system at KBSI heavy-ion accelerator

    NASA Astrophysics Data System (ADS)

    Bahng, Jungbae; Lee, Byoung-Seob; Sato, Yoichi; Ok, Jung-Woo; Park, Jin Yong; Yoon, Jang-Hee; Choi, Seyong; Won, Mi-Sook; Kim, Eun-San

    2015-01-01

    The Korea Basic Science Institute has developed a heavy ion accelerator for fast neutron radiography [1]. To meet the requirements for fast neutron generation, we have developed an accelerator system that consists of an electron cyclotron resonance ion source (ECR-IS), low-energy beam transport (LEBT) system, radio-frequency quadrupole (RFQ), medium-energy beam transport system, and drift tube linac. In this paper, we present the development of the LEBT system as a part of the heavy ion accelerator system, which operates from the ECR-IS to the RFQ entrance.

  15. [Role of Academia in Regulatory Science for Global Drug Development].

    PubMed

    Tsukamoto, Katsura; Takenaka, Toichi

    2016-01-01

    As diseases know no national boundaries, drug development must be designed at a global level. Drugs are highly regulated to maximize the benefits to public health, which is assessed on a regional basis. The complexity and diversity of stakeholders increase dramatically once multiple international regions are involved. Each stakeholder in drug development depends on customized criteria to make decisions for its own benefit. Thus, a huge gap exists among drug discovery researchers, developers, clinicians, patients, and regulatory bodies. With reasonable scientific evidence gathered and analyzed, mutual agreement can be reached. We believe that this important role of regulatory science and academic involvement will create harmony. By practicing diverse, innovative regulatory scientific research, academia has the potential to become the core of communication among various stakeholder groups. Furthermore, another important responsibility of academia, i.e., knowledge, provides additional aspects to the field of drug development. Those who understand regulatory science can contribute to the efficient achievement of innovative, effective, safe drugs. Thus, research and education are essential roles of academia to allow a better understanding of the balance between benefits and risks. Communication and knowledge will promote the prompt delivery of better medical products to patients in need. PMID:27040336

  16. Regulatory considerations in oncologic biosimilar drug development

    PubMed Central

    Macdonald, Judith C; Hartman, Helen; Jacobs, Ira A

    2015-01-01

    Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice. PMID:25961747

  17. Modeling accelerated and decelerated drug release in terms of fractional release rate.

    PubMed

    Weiss, Michael

    2015-02-20

    The model of a proportional change in fractional dissolution rate was used to quantify influences on the vitro dissolution process. After fitting the original dissolution profile with an empirical model (inverse Gaussian distribution), acceleration and deceleration effects due to dissolution conditions or formulation parameters could be described by one parameter only. Acceleration of dissolution due to elevated temperature and deceleration by increasing the content of glyceryl monostearate in theophylline tablets are presented as examples. Likewise, this approach was applied to in vitro-in vivo correlation (IVIVC). It is shown that the model is appropriate when the plot of the in vivo versus in vivo times is nonlinear and can be described by a power function. The results demonstrate the utility of the model in dissolution testing and IVIVC assessment. PMID:25486334

  18. Challenges in the clinical development of new antiepileptic drugs.

    PubMed

    Franco, Valentina; French, Jacqueline A; Perucca, Emilio

    2016-01-01

    Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. PMID:26611249

  19. Tuberculosis--advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers.

    PubMed

    Wallis, Robert S; Maeurer, Markus; Mwaba, Peter; Chakaya, Jeremiah; Rustomjee, Roxana; Migliori, Giovanni Battista; Marais, Ben; Schito, Marco; Churchyard, Gavin; Swaminathan, Soumya; Hoelscher, Michael; Zumla, Alimuddin

    2016-04-01

    Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480,000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to

  20. Histone deacetylases: Targets for antifungal drug development

    PubMed Central

    Kmetzsch, Livia

    2015-01-01

    The interaction of pathogens and its hosts causes a drastic change in the transcriptional landscape in both cells. Among the several mechanisms of gene regulation, transcriptional initiation is probably the main point. In such scenario, the access of transcriptional machinery to promoter is highly regulated by post-translational modification of histones, such as acetylation, phosphorylation and others. Inhibition of histone deacetylases is able to reduce fungal pathogens fitness during infection and, therefore, is currently being considered for the development of new antifungal therapy strategies. PMID:26151486

  1. Development of accelerator mass spectrometer based on a compact cyclotron

    NASA Astrophysics Data System (ADS)

    Kim, J.-W.; Kim, D.-G.

    2011-07-01

    A small cyclotron has been designed for accelerator mass spectrometry, and the injection beam line is constructed as part of prototyping. Mass resolution of the cyclotron is estimated to be around 4000. The design of the cyclotron was performed with orbit-tracking computations using 3D magnetic and electric fields, and beam optics of the injection line was calculated using the codes such as IGUN and TRANSPORT. The radial injection scheme is chosen to place a beam on equilibrium orbit of the cyclotron. The injection line includes an ion source, Einzel lens, rf buncher, 90° dipole magnet, and quadrupole triplet magnet. A carbon beam was extracted from the front part of the injection line. An rf cavity system for the cyclotron was built and tested. A multi channel plates (MCP) detector to measure low-current ion beams was also tested. Design considerations are given to analyzing a few different radioisotopes in form of positive ions as well as negative ions.

  2. Development of a dual layered dielectric-loaded accelerating structure.

    SciTech Connect

    Gai, W.; Liu, W.; Jing, C.; Kanareykin, A.; Antipov, S.; Nenasheva, E.; Schoessow, P.; High Energy Physics; Euclid Techlabs, LLC; Illinois Inst. of Tech.; KEK

    2008-09-01

    Due to the high magnetic field-induced surface currents on its conducting sleeve, a conventional single layer Dielectric-Loaded Accelerating (DLA) structure exhibits a relatively high RF loss. One possible way to solve this problem is to use multilayered DLA structures. In these devices, the RF power attenuation is reduced by making use of the Bragg Fiber concept: the EM fields are well confined by multiple reflections from multiple dielectric layers. This paper presents the design of an X-band dual layer DLA structure as well as the results of bench tests of the device. We will also present results on the design, numerical modeling, and fabrication of structures for coupling RF into multilayer DLAs such as a novel TM{sub 03} mode launcher and a TM{sub 01}-TM{sub 03} mode converter using dielectric-loaded corrugated waveguide.

  3. Development of biosimilars in an era of oncologic drug shortages.

    PubMed

    Li, Edward; Subramanian, Janakiraman; Anderson, Scott; Thomas, Dolca; McKinley, Jason; Jacobs, Ira A

    2015-01-01

    Acute and chronic shortages of various pharmaceuticals and particularly of sterile injectable products are being reported on a global scale, prompting evaluation of more effective strategies to manage current shortages and development of new, high-quality pharmaceutical products to mitigate the risk of potential future shortages. Oncology drugs such as liposomal doxorubicin and 5-fluorouracil represent examples of first-choice drugs critically affected by shortages. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, which may have compromised patient safety and clinical outcomes, and increased health care costs, due to delays or changes in treatment regimens. Clinical trials evaluating novel agents in combination with standard-of-care drugs are also being affected by drug shortages. Clinical and ethical considerations on treatment objectives, drug indication, and availability of alternative options may help in prioritizing cancer patients involved in active drug shortages. The United States Food and Drug Administration and the European Medicines Agency have identified manufacturing problems, delays in supply, and lack of available active ingredients as the most frequent causes of recent or ongoing drug shortages, and have released specific guidance to monitor, manage, and reduce the risk of shortages. The upcoming loss of exclusivity for a number of anticancer biologics, together with the introduction of an abbreviated approval pathway for biosimilars, raises the question of whether these products will be vulnerable to shortages. Future supply by reliable manufacturers of well characterized biosimilar monoclonal antibodies, developed in compliance with regulatory and manufacturing guidelines and with substantial investments, may contribute to prevent future biologics shortages and ensure access to effective and safe treatment options for patients with cancer. Preclinical and clinical characterization

  4. Development of biosimilars in an era of oncologic drug shortages

    PubMed Central

    Li, Edward; Subramanian, Janakiraman; Anderson, Scott; Thomas, Dolca; McKinley, Jason; Jacobs, Ira A

    2015-01-01

    Acute and chronic shortages of various pharmaceuticals and particularly of sterile injectable products are being reported on a global scale, prompting evaluation of more effective strategies to manage current shortages and development of new, high-quality pharmaceutical products to mitigate the risk of potential future shortages. Oncology drugs such as liposomal doxorubicin and 5-fluorouracil represent examples of first-choice drugs critically affected by shortages. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, which may have compromised patient safety and clinical outcomes, and increased health care costs, due to delays or changes in treatment regimens. Clinical trials evaluating novel agents in combination with standard-of-care drugs are also being affected by drug shortages. Clinical and ethical considerations on treatment objectives, drug indication, and availability of alternative options may help in prioritizing cancer patients involved in active drug shortages. The United States Food and Drug Administration and the European Medicines Agency have identified manufacturing problems, delays in supply, and lack of available active ingredients as the most frequent causes of recent or ongoing drug shortages, and have released specific guidance to monitor, manage, and reduce the risk of shortages. The upcoming loss of exclusivity for a number of anticancer biologics, together with the introduction of an abbreviated approval pathway for biosimilars, raises the question of whether these products will be vulnerable to shortages. Future supply by reliable manufacturers of well characterized biosimilar monoclonal antibodies, developed in compliance with regulatory and manufacturing guidelines and with substantial investments, may contribute to prevent future biologics shortages and ensure access to effective and safe treatment options for patients with cancer. Preclinical and clinical characterization

  5. Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development

    PubMed Central

    Guengerich, F. Peter

    2016-01-01

    Toxicity has been estimated to be responsible for the attrition of ~ 1/3 of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in the clinical trials or post-marketing. The causes of drug toxicity can be organized in several ways and include mechanism-based (on-target) toxicity, immune hypersensitivity, off-target toxicity, and bioactivation/covalent modification. In addition, idiosyncratic responses are rare but one of the most problematic issues; several hypotheses for these have been advanced. Although covalent binding of drugs to proteins was described almost 40 years ago, the significance to toxicity has been difficult to establish; recent literature in this field is considered. The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using “omics” approaches. PMID:20978361

  6. Mechanisms of drug toxicity and relevance to pharmaceutical development.

    PubMed

    Guengerich, F Peter

    2011-01-01

    Toxicity has been estimated to be responsible for the attrition of approximately one-third of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in clinical trials or post-marketing. The causes of drug toxicity can be classified in several ways and include mechanism-based (on-target) toxicity, immune hypersensitivity, off-target toxicity, and bioactivation/covalent modification. In addition, idiosyncratic responses are rare but can be one of the most problematic issues; several hypotheses for these have been advanced. Although covalent binding of drugs to proteins was described almost 40 years ago, the significance to toxicity has been difficult to establish; recent literature in this field is considered. The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using "omics" approaches. PMID:20978361

  7. Myeloperoxidase: a target for new drug development?

    PubMed Central

    Malle, E; Furtmüller, P G; Sattler, W; Obinger, C

    2007-01-01

    Myeloperoxidase (MPO), a member of the haem peroxidase-cyclooxygenase superfamily, is abundantly expressed in neutrophils and to a lesser extent in monocytes and certain type of macrophages. MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO-derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low- and high-spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO. The various approaches to inhibit enzyme activity of MPO and to ameliorate adverse effects of MPO-derived oxidants will be discussed. Emphasis will be put on mechanism-based inhibitors and high-throughput screening of compounds as well as the discussion of physiologically useful HOCl scavengers. PMID:17592500

  8. Myeloperoxidase: a target for new drug development?

    PubMed

    Malle, E; Furtmüller, P G; Sattler, W; Obinger, C

    2007-11-01

    Myeloperoxidase (MPO), a member of the haem peroxidase-cyclooxygenase superfamily, is abundantly expressed in neutrophils and to a lesser extent in monocytes and certain type of macrophages. MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO-derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low- and high-spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO. The various approaches to inhibit enzyme activity of MPO and to ameliorate adverse effects of MPO-derived oxidants will be discussed. Emphasis will be put on mechanism-based inhibitors and high-throughput screening of compounds as well as the discussion of physiologically useful HOCl scavengers. PMID:17592500

  9. Mechanistic systems modeling to guide drug discovery and development

    PubMed Central

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

    2013-01-01

    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. PMID:22999913

  10. Impact of biomarker development on drug safety assessment

    SciTech Connect

    Marrer, Estelle; Dieterle, Frank

    2010-03-01

    Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

  11. Impact of biomarker development on drug safety assessment.

    PubMed

    Marrer, Estelle; Dieterle, Frank

    2010-03-01

    Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and "door opening" safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the "know how" acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example. PMID:20036272

  12. Development of a 20 MeV Dielectric-Loaded Test Accelerator

    SciTech Connect

    Gold, S.H.; Kinkead, A.K.; Gai, W.; Power, J.G.; Konecny, R.; Jing, C.; Long, J.; Tantawi, S.G.; Nantista, C.D.; Fliflet, A.W.; Lombardi, M.; Lewis, D.; Bruce, R.W.; /Unlisted

    2007-04-13

    This paper presents a progress report on a joint project by the Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), to develop a dielectric-loaded test accelerator in the magnicon facility at NRL. The accelerator will be powered by an experimental 11.424-GHz magnicon amplifier that presently produces 25 MW of output power in a {approx}250-ns pulse at up to 10 Hz. The accelerator will include a 5-MeV electron injector originally developed at the Tsinghua University in Beijing, China, and can incorporate DLA structures up to 0.5 m in length. The DLA structures are being developed by ANL, and shorter test structures fabricated from a variety of dielectric materials have undergone testing at NRL at gradients up to {approx}8 MV/m. SLAC has developed components to distribute the power from the two magnicon output arms to the injector and to the DLA accelerating structure with separate control of the power ratio and relative phase. RWBruce Associates, Inc., working with NRL, has investigated means to join short ceramic sections into a continuous accelerator tube by a brazing process using an intense 83-GHz beam. The installation and testing of the first dielectric-loaded test accelerator, including injector, DLA test structure, and spectrometer, should take place within the next year.

  13. Development of a 20 MeV Dielectric-Loaded Test Accelerator

    SciTech Connect

    Gold, Steven H.; Fliflet, Arne W.; Lombardi, Marcie; Kinkead, Allen K.; Gai, Wei; Power, John G.; Konecny, Richard; Long, Jidong; Jing, Chunguang; Tantawi, Sami G.; Nantista, Christopher D.; Bruce, Ralph W.; Lewis, David III

    2006-11-27

    This paper presents a progress report on a joint project by the Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), to develop a dielectric-loaded test accelerator in the magnicon facility at NRL. The accelerator will be powered by an experimental 11.424-GHz magnicon amplifier that presently produces 25 MW of output power in a {approx}250-ns pulse at up to 10 Hz. The accelerator will include a 5-MeV electron injector originally developed at the Tsinghua University in Beijing, China, and can incorporate DLA structures up to 0.5 m in length. The DLA structures are being developed by ANL, and shorter test structures fabricated from a variety of dielectric materials have undergone testing at NRL at gradients up to {approx}8 MV/m. SLAC has developed components to distribute the power from the two magnicon output arms to the injector and to the DLA accelerating structure with separate control of the power ratio and relative phase. RWBruce Associates, Inc., working with NRL, has investigated means to join short ceramic sections into a continuous accelerator tube by a brazing process using an intense 83-GHz beam. The installation and testing of the first dielectric-loaded test accelerator, including injector, DLA test structure, and spectrometer, should take place within the next year.

  14. FETAL DEXAMETHASONE EXPOSURE ACCELERATES DEVELOPMENT OF RENAL FUNCTION: RELATIONSHIP TO DOSE, CELL DIFFERENTIATION AND GROWTH INHIBITION

    EPA Science Inventory

    Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. evertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. he current study examine...

  15. NASA - 77M prototype hall thruster built under the High Voltage Hall accelerator development project

    NASA Technical Reports Server (NTRS)

    2005-01-01

    NASA - 77M prototype hall thruster built under the High Voltage Hall accelerator development project funded by the Science Mission Directorate ; potential use is propulsion for deep space science missions

  16. Development of High Power Vacuum Tubes for Accelerators and Plasma Heating

    NASA Astrophysics Data System (ADS)

    Srivastava, Vishnu

    2012-11-01

    High pulsed power magnetrons and klystrons for medical and industrial accelerators, and high CW power klystrons and gyrotrons for plasma heating in tokamak, are being developed at CEERI. S-band 2.0MW pulsed tunable magnetrons of centre frequency 2856MHz and 2998 MHz were developed, and S-band 2.6MW pulsed tunable magnetron is being developed for medical LINAC, and 3MW pulsed tunable magnetron is being developed for industrial accelerator. S-band (2856MHz), 5MW pulsed klystron was developed for particle accelerator, and S-band 6MW pulsed klystron is under development for 10MeV industrial accelerator. 350MHz, 100kW (CW) klystron is being developed for proton accelerator, and C-band 250kW (CW) klystron is being developed for plasma heating. 42GHz, 200kW (CW/Long pulse) gyrotron is under development for plasma heating. Plasma filled tubes are also being developed for switching. 25kV/1kA and 40kV/3kA thyratrons were developed for high voltage high current switching in pulse modulators for magnetrons and klystrons. 25kV/3kA Pseudospark switch of current rise time of 1kA/|a-sec and pulse repetition rate of 500Hz is being developed. Plasma assisted high power microwave device is also being investigated.

  17. Drug Design, Development, and Delivery: An Interdisciplinary Course on Pharmaceuticals

    ERIC Educational Resources Information Center

    Prausnitz, Mark R.; Bommarius, Andreas S.

    2011-01-01

    We developed a new interdisciplinary course on pharmaceuticals to address needs of undergraduate and graduate students in chemical engineering and other departments. This course introduces drug design, development, and delivery in an integrated fashion that provides scientific depth in context with broader impacts in business, policy, and ethics.…

  18. EuCARD2: enhanced accelerator research and development in Europe

    NASA Astrophysics Data System (ADS)

    Romaniuk, Ryszard S.

    2013-10-01

    Accelerator science and technology is one of a key enablers of the developments in the particle physic, photon physics and also applications in medicine and industry. EuCARD2 is an European research project which will be realized during 2013-2017 inside the EC FP7 framework. The project concerns the development and coordination of European Accelerator Research and Development. The project is particularly important, to a number of domestic laboratories, due to some plans to build large accelerator infrastructure in Poland. Large accelerator infrastructure of fundamental and applied research character stimulates around it the development and industrial applications as well as biomedical of advanced accelerators, material research and engineering, cryo-technology, mechatronics, robotics, and in particular electronics - like networked measurement and control systems, sensors, computer systems, automation and control systems. The paper presents a digest of the European project EuCARD2 which is Enhanced European Coordination for Accelerator Research and Development. The paper presents a digest of the research results and assumptions in the domain of accelerator science and technology in Europe, shown during the final fourth annual meeting of the EuCARD - European Coordination of Accelerator R&D, and the kick-off meeting of the EuCARD2. There are debated a few basic groups of accelerator systems components like: measurement - control networks of large geometrical extent, multichannel systems for large amounts of metrological data acquisition, precision photonic networks of reference time, frequency and phase distribution, high field magnets, superconducting cavities, novel beam collimators, etc. The paper bases on the following materials: Internet and Intranet documents combined with EuCARD2, Description of Work FP7 EuCARD-2 DoW-312453, 2013-02-13, and discussions and preparatory materials worked on by Eucard-2 initiators.

  19. Development of novel small molecules for imaging and drug release

    NASA Astrophysics Data System (ADS)

    Cao, Yanting

    Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the

  20. The basics of preclinical drug development for neurodegenerative disease indications.

    PubMed

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  1. The basics of preclinical drug development for neurodegenerative disease indications

    PubMed Central

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  2. Controversies in Glaucoma: Current Medical Treatment and Drug Development.

    PubMed

    Bucolo, Claudio; Platania, Chiara Bianca Maria; Reibaldi, Michele; Bonfiglio, Vincenza; Longo, Antonio; Salomone, Salvatore; Drago, Filippo

    2015-01-01

    Elevated eye pressure is the main risk factor for glaucoma; intraocular pressure rises when the ratio between aqueous humor formation (inflow) and its outflow is unbalanced. Currently, the main goal of medical treatment is the reduction of intraocular pressure. Five main classes of topical drugs are available; they include betablockers, carbonic anhydrase inhibitors, prostaglandin derivatives, sympathomimetics and miotics. Beta-blockers and carbonic anhydrase inhibitors slow the formation of aqueous humor and may be considered as "inflow" drugs; the other three classes reduce the resistance to the drainage of aqueous humor and may be considered as "outflow" drugs. Despite the variety of drugs accessible in the market, there is a real need for ophthalmologists to have more potent medications for this disease. This review focuses on medical treatment of glaucoma with particular attention to novel molecules in pre-clinical or clinical development. PMID:26350532

  3. Adsorption of drugs on nanodiamond: toward development of a drug delivery platform.

    PubMed

    Mochalin, Vadym N; Pentecost, Amanda; Li, Xue-Mei; Neitzel, Ioannis; Nelson, Matthew; Wei, Chongyang; He, Tao; Guo, Fang; Gogotsi, Yury

    2013-10-01

    Nanodiamond particles produced by detonation synthesis and having ∼5 nm diameter possess unique properties, including low cell toxicity, biocompatibility, stable structure, and highly tailorable surface chemistry, which render them an attractive material for developing drug delivery systems. Although the potential for nanodiamonds in delivery and sustained release of anticancer drugs has been recently demonstrated, very little is known about the details of adsorption/desorption equilibria of these and other drugs on/from nanodiamonds with different purity, surface chemistry, and agglomeration state. Since adsorption is the basic mechanism most commonly used for the loading of drugs onto nanodiamond, the fundamental studies into the details of adsorption and desorption on nanodiamond are critically important for the rational design of the nanodiamond drug delivery systems capable of targeted delivery and triggered release, while minimizing potential leaks of dangerous drugs. In this paper we report on a physical-chemical study of the adsorption of doxorubicin and polymyxin B on nanodiamonds, analyzing the role of purification and surface chemistry of the adsorbent. PMID:23941665

  4. Animal experimentation: a rational approach towards drug development.

    PubMed

    Kumar, V; Singh, P N; Mishra, B

    2000-06-01

    Man's observation of animals as objects of study undoubtedly began in prehistoric times. The first recorded attempt involving the use of live animals for research was by Ersistratis in Alexandria in 300 B.C. Animal investigation has clearly made possible the enormous advances in drug development in this century. A cursory review of any modern text book of pharmacology or medicine will attest the many drugs currently available to benefit mankind in the struggle to eradicate and control diseases. The main purpose of this article is to describe some of the experimental work on animals which contributed to the discovery and development of drugs benefiting human beings and other animal species. Since animal experimentation has occupied a focal position in all the research leading to useful drugs, one will appreciate that it will be necessary to limit the discussion to certain aspects of this broad and interesting topic. With this in mind, an attempt is made to relate briefly the nature of animal investigations which were instrumental in the development of major classes of drugs. Some attention has also been focused on legislation's on animal experimentation of some developed countries with emphasis on India and to views on animal experimentation. We hope this article will stimulate the minds of the scientists for a rational debate on the future of animal experimentation. PMID:11116523

  5. The significance of chirality in drug design and development.

    PubMed

    Brooks, W H; Guida, W C; Daniel, K G

    2011-01-01

    Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance. PMID:21291399

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

    PubMed

    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. PMID:25853828

  7. Cardiovascular drug development: is it dead or just hibernating?

    PubMed

    Fordyce, Christopher B; Roe, Matthew T; Ahmad, Tariq; Libby, Peter; Borer, Jeffrey S; Hiatt, William R; Bristow, Michael R; Packer, Milton; Wasserman, Scott M; Braunstein, Ned; Pitt, Bertram; DeMets, David L; Cooper-Arnold, Katharine; Armstrong, Paul W; Berkowitz, Scott D; Scott, Rob; Prats, Jayne; Galis, Zorina S; Stockbridge, Norman; Peterson, Eric D; Califf, Robert M

    2015-04-21

    Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified. PMID:25881939

  8. ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

    PubMed Central

    Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

    2009-01-01

    The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

  9. Development of a Compact Dielectric-Loaded Test Accelerator at 11.4 GHz

    SciTech Connect

    Gold, S. H.; Fliflet, A. W.; Kinkead, A. K.; Gai, W.; Power, J. G.; Konecny, R.; Jing, C.

    2009-01-22

    This paper presents a progress report on the development of a dielectric-loaded test accelerator in the Magnicon Facility at the Naval Research Laboratory (NRL). The accelerator will be powered by an 11.4-GHz magnicon amplifier that provides up to 25 MW of output power in a {approx}250-ns pulse at up to 10 Hz. The accelerator includes a 5-MeV electron injector originally developed at the Tsinghua University in Beijing, China, and can incorporate dielectric-loaded accelerating (DLA) structures of up to 0.5 m in length. The DLA structures are being developed by Argonne National Laboratory and Euclid Techlabs, and shorter test structures fabricated from a variety of dielectric materials have undergone rf testing at NRL at accelerating gradients up to 15 MV/m. The first stage of the accelerator, including the 5-MeV injector, has recently begun operation, and initial operation of the complete dielectric-loaded test accelerator, including injector, DLA test structure, and spectrometer, should take place within the next year.

  10. Scorpion Peptides: Potential Use for New Drug Development

    PubMed Central

    Hmed, BenNasr; Serria, Hammami Turky; Mounir, Zeghal Khaled

    2013-01-01

    Several peptides contained in scorpion fluids showed diverse array of biological activities with high specificities to their targeted sites. Many investigations outlined their potent effects against microbes and showed their potential to modulate various biological mechanisms that are involved in immune, nervous, cardiovascular, and neoplastic diseases. Because of their important structural and functional diversity, it is projected that scorpion-derived peptides could be used to develop new specific drugs. This review summarizes relevant findings improving their use as valuable tools for new drugs development. PMID:23843786

  11. Assessment of cognitive safety in clinical drug development

    PubMed Central

    Roiser, Jonathan P.; Nathan, Pradeep J.; Mander, Adrian P.; Adusei, Gabriel; Zavitz, Kenton H.; Blackwell, Andrew D.

    2016-01-01

    Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks. PMID:26610416

  12. Drugs, Biogenic Amine Targets and the Developing Brain

    PubMed Central

    Frederick, Aliya L.; Stanwood, Gregg D.

    2009-01-01

    Defects in the development of the brain have profound impacts on mature brain functions and underlie psychopathology. Classical neurotransmitters and neuromodulators, such as dopamine, serotonin, norepinephrine, acetycholine, glutamate and GABA, have pleiotropic effects during brain development. In other words, these molecules produce multiple, diverse effects to serve as regulators of distinct cellular functions at different times in neurodevelopment. These systems are impacted upon by a variety of illicit drugs of abuse, neurotherapeutics, and environmental contaminants. In this review, we describe the impact of drugs and chemicals on brain formation and function in animal models and in human populations, highlighting sensitive periods and effects that may not emerge until later in life. PMID:19372683

  13. Cancer drug development in China: recent advances and future challenges.

    PubMed

    Wu, Yi-Long; Zhang, Helena; Yang, Yumei

    2015-06-01

    Over the past 10 years, the Chinese Government, academic organizations, and biopharmaceutical companies have tried to transition the nation from a consumer of generic drugs into a developer of innovative therapies. Here, we present a timeline of recent innovative cancer drug development, with a particular focus on four case studies that have reshaped perceptions of what can be done in China. We present metrics comparing China with other countries alongside analysis of what national authorities are doing to close the gap in areas where China still lags behind the West. PMID:25463037

  14. Low hanging fruit in infectious disease drug development.

    PubMed

    Kraus, Carl N

    2008-10-01

    Cost estimates for developing new molecular entities (NME) are reaching non-sustainable levels and coupled with increasing regulatory requirements and oversight have led many pharmaceutical sponsors to divest their anti-microbial development portfolios [Projan SJ: Why is big Pharma getting out of anti-bacterial drug discovery?Curr Opin Microbiol 2003, 6:427-430] [Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE, Jr: Trends in antimicrobial drug development: implications for the future.Clin Infect Dis 2004, 38:1279-1286]. Operational issues such as study planning and execution are significant contributors to the overall cost of drug development that can benefit from the leveraging of pre-randomization data in an evidence-based approach to protocol development, site selection and patient recruitment. For non-NME products there is even greater benefit from available data resources since these data may permit smaller and shorter study programs. There are now many available open source intelligence (OSINT) resources that are being integrated into drug development programs, permitting an evidence-based or 'operational epidemiology' approach to study planning and execution. PMID:18822387

  15. Diabetes mellitus: Exploring the challenges in the drug development process.

    PubMed

    Vaz, Julius A; Patnaik, Ashis

    2012-07-01

    Diabetes mellitus has reached epidemic proportions and continues to be a major burden on society globally. The International Diabetes Federation (IDF) estimated the global burden of diabetes to be 366 million in 2011 and predicted that by 2030 this will have risen to 552 million. In spite of newer and effective treatment options, newer delivery and diagnostic devices, stricter glycaemic targets, better treatment guidelines and increased awareness of the disease, baseline glycosylated hemoglobin remains relatively high in subjects diagnosed and treated with type 2 diabetes. The search continues for an ideal anti diabetic drug that will not only normalize blood glucose but also provide beta cell rest and possibly restoration of beta cell function. The development of anti diabetic drugs is riddled with fundamental challenges. The concept of beta cell rest and restoration is yet to be completely understood and proven on a long term. The ideal therapeutic approach to treating type 2 diabetes is not yet determined. Our understanding of drug safety in early clinical development is primarily limited to "Type A" reactions. Until marketing authorization most drugs are approved based on the principle of confirming non-inferiority with an existing gold standard or determining superiority to a placebo. The need to obtain robust pharmaco-economic data prior to marketing authorization in order to determine appropriate pricing of a new drug remains a major challenge. The present review outlines some of the challenges in drug development of anti-diabetic drugs citing examples of pulmonary insulin, insulin analogues, thiazolidinediones and the GLP1 analogues. PMID:23125962

  16. Liposomes and nanotechnology in drug development: focus on neurological targets

    PubMed Central

    Ramos-Cabrer, Pedro; Campos, Francisco

    2013-01-01

    Neurological diseases represent a medical, social, and economic problem of paramount importance in developed countries. Although their etiology is generally known, developing therapeutic interventions for the central nervous system is challenging due to the impermeability of the blood–brain barrier. Thus, the fight against neurological diseases usually struggles “at the gates” of the brain. Flooding the bloodstream with drugs, where only a minor fraction reaches its target therapeutic site, is an inefficient, expensive, and dangerous procedure, because of the risk of side effects at nontargeted sites. Currently, advances in the field of nanotechnology have enabled development of a generation of multifunctional molecular platforms that are capable of transporting drugs across the blood–brain barrier, targeting specific cell types or functional states within the brain, releasing drugs in a controlled manner, and enabling visualization of processes in vivo using conventional imaging systems. The marriage between drug delivery and molecular imaging disciplines has resulted in a relatively new discipline, known as theranostics, which represents the basis of the concept of personalized medicine. In this study, we review the concepts of the blood–brain barrier and the strategies used to traverse/bypass it, the role of nanotechnology in theranostics, the wide range of nanoparticles (with emphasis on liposomes) that can be used as stealth drug carriers, imaging probes and targeting devices for the treatment of neurological diseases, and the targets and targeting strategies envisaged in the treatment of different types of brain pathology. PMID:23486739

  17. Barriers to Alzheimer disease drug discovery and development in academia.

    PubMed

    Van Eldik, Linda J; Koppal, Tanuja; Watterson, D Martin

    2002-01-01

    The drug discovery and the drug development processes represent a continuum of recursive activities that range from initial drug target identification to final Food and Drug Administration approval and marketing of a new therapeutic. Drug discovery, as its name implies, is more exploratory and less focused in many cases, whereas drug development has a clinically defined endpoint and a specific disease goal. Academia has historically made major contributions to this process at the early discovery phases. However, current trends in the organization of the pharmaceutical industry suggest an expanded role for academia in the near future. Megamergers among major pharmaceutical corporations indicate their movement toward a focus on end-stage clinical trials, manufacturing, and marketing. There has been a parallel increase in outsourcing of intermediate steps to specialty small pharmaceutical, biotechnology, and contract service companies. The new paradigm suggests that academia will play an increasingly important role at the proof-of-principle stage of basic and clinical drug discovery research, in training the future skilled work force, and in close partnerships with small pharmaceutical and biotechnology companies. However, academic drug discovery research faces a set of barriers to progress, the relative importance of which varies with the home institution and the details of the research area. These barriers fall into four general categories: (1) the historical administrative structure and environment of academia; (2) the structure and emphasis of peer review panels that control research funding by government and private agencies; (3) the organization and operation of the academic infrastructure; and (4) the structure and availability of specialized resources and information management. Selected examples of barriers to drug discovery and drug development research and training in academia are presented, as are some specific recommendations designed to minimize or

  18. Group living accelerates bed bug (Hemiptera: Cimicidae) development.

    PubMed

    Saenz, Virna L; Santangelo, Richard G; Vargo, Edward L; Schal, Coby

    2014-01-01

    For many insect species, group living provides physiological and behavioral benefits, including faster development. Bed bugs (Cimex lectularius L.) live in aggregations composed of eggs, nymphs, and adults of various ages. Our aim was to determine whether bed bug nymphs reared in groups develop faster than solitary nymphs. We reared first instars either in isolation or in groups from hatching to adult emergence and recorded their development time. In addition, we investigated the effects of group housing on same-age nymphs versus nymphs reared with adults. Nymphal development was 2.2 d faster in grouped nymphs than in solitary-housed nymphs, representing 7.3% faster overall development. However, this grouping effect did not appear to be influenced by group composition. Thus, similar to other gregarious insect species, nymph development in bed bugs is faster in aggregations than in isolation. PMID:24605482

  19. Developments in laser wakefield accelerators: From single-stage to two-stage

    NASA Astrophysics Data System (ADS)

    Li, Wen-Tao; Wang, Wen-Tao; Liu, Jian-Sheng; Wang, Cheng; Zhang, Zhi-Jun; Qi, Rong; Yu, Chang-Hai; Li, Ru-Xin; Xu, Zhi-Zhan

    2015-01-01

    Laser wakefield accelerators (LWFAs) are compact accelerators which can produce femtosecond high-energy electron beams on a much smaller scale than the conventional radiofrequency accelerators. It is attributed to their high acceleration gradient which is about 3 orders of magnitude larger than the traditional ones. The past decade has witnessed the major breakthroughs and progress in developing the laser wakfield accelerators. To achieve the LWFAs suitable for applications, more and more attention has been paid to optimize the LWFAs for high-quality electron beams. A single-staged LWFA does not favor generating controllable electron beams beyond 1 GeV since electron injection and acceleration are coupled and cannot be independently controlled. Staged LWFAs provide a promising route to overcome this disadvantage by decoupling injection from acceleration and thus the electron-beam quality as well as the stability can be greatly improved. This paper provides an overview of the physical conceptions of the LWFA, as well as the major breakthroughs and progress in developing LWFAs from single-stage to two-stage LWFAs. Project supported by the National Natural Science Foundation of China (Grant Nos. 11127901, 11425418, and 61221064), the National Basic Research Program of China (Grant No. 2011CB808100), and the Science and Technology Talent Project of Shanghai City, China (Grant Nos. 12XD1405200 and 12ZR1451700).

  20. Perestroika in pharma: evolution or revolution in drug development?

    PubMed

    FitzGerald, Garret A

    2010-01-01

    New-drug approvals have remained roughly constant since 1950, while the cost of drug development has soared. It seems likely that a more modular approach to drug discovery and development will evolve, deriving some features from the not-for-profit sector. For this to occur, we must address the deficit in human capital with expertise in both translational medicine and therapeutics and also in regulatory science; utilize regulatory reform to incentivize innovation and the expansion of the precompetitive space; and develop an informatics infrastructure that permits the global, secure, and compliant sharing of heterogeneous data across academic and industry sectors. These developments, likely prompted by the perception of crisis rather than opportunity, will require linked initiatives among academia, the pharmaceutical industry, the US National Institutes of Health, and the US Food and Drug Administration, along with a more adventurous role for venture capital. A failure to respond threatens the United States' lead in biomedical science and in the development and regulation of novel therapeutics. PMID:20687177

  1. Accelerating NASA GN&C Flight Software Development

    NASA Technical Reports Server (NTRS)

    Tamblyn, Scott; Henry, Joel; Rapp, John

    2010-01-01

    When the guidance, navigation, and control (GN&C) system for the Orion crew vehicle undergoes Critical Design Review (CDR), more than 90% of the flight software will already be developed - a first for NASA on a project of this scope and complexity. This achievement is due in large part to a new development approach using Model-Based Design.

  2. Accelerating the paradigm shift toward inclusion of pregnant women in drug research: Ethical and regulatory considerations.

    PubMed

    White, Amina

    2015-11-01

    Although there has been long-standing reluctance to include pregnant women as clinical trial participants, increasing recognition of profound gaps in research on the safety and efficacy of drugs often prescribed to pregnant women calls into question the practice of routinely excluding them. This article presents compelling reasons for including pregnant women in clinical research, highlights certain regulatory barriers to the inclusion of pregnant women, and proposes that professional societies with expertise in obstetrics and maternal-fetal medicine can be instrumental in hastening the paradigm shift from the systematic exclusion of pregnant women in research to a one of responsible and fair inclusion. PMID:26385413

  3. Latest Development in Superconducting RF Structures for beta=1 Particle Acceleration

    SciTech Connect

    Peter Kneisel

    2006-06-26

    Superconducting RF technology is since nearly a decade routinely applied to different kinds of accelerating devices: linear accelerators, storage rings, synchrotron light sources and FEL's. With the technology recommendation for the International Linear Collider (ILC) a year ago, new emphasis has been placed on improving the performance of accelerating cavities both in Q-value and in accelerating gradients with the goal to achieve performance levels close to the fundamental limits given by the material parameters of the choice material, niobium. This paper will summarize the challenges to SRF technology and will review the latest developments in superconducting structure design. Additionally, it will give an overview of the newest results and will report on the developments in alternative materials and technologies.

  4. Quantitative EEG Brain Mapping In Psychotropic Drug Development, Drug Treatment Selection, and Monitoring.

    PubMed

    Itil, Turan M.; Itil, Kurt Z.

    1995-05-01

    Quantification of standard electroencephalogram (EEG) by digital computers [computer-analyzed EEG (CEEG)] has transformed the subjective analog EEG into an objective scientific method. Until a few years ago, CEEG was only used to assist in the development of psychotropic drugs by means of the quantitative pharmaco EEG. Thanks to the computer revolution and the accompanying reductions in cost of quantification, CEEG can now also be applied in psychiatric practice. CEEG can assist the physician in confirming clinical diagnoses, selecting psychotropic drugs for treatment, and drug treatment monitoring. Advancements in communications technology allow physicians and researchers to reduce the costs of acquiring a high-technology CEEG brain mapping system by utilizing the more economical telephonic services. PMID:11850678

  5. Validation of Analytical Methods for Biomarkers Employed in Drug Development

    PubMed Central

    Chau, Cindy H.; Rixe, Olivier; McLeod, Howard; Figg, William D.

    2008-01-01

    The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and in particular assay validation becomes essential with the need to establish standardized guidelines for analytical methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics, but is contingent upon the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development. PMID:18829475

  6. Renal Safety Pharmacology in Drug Discovery and Development.

    PubMed

    Benjamin, Amanda; Nogueira da Costa, Andre; Delaunois, Annie; Rosseels, Marie-Luce; Valentin, Jean-Pierre

    2015-01-01

    The kidney is a complex excretory organ playing a crucial role in various physiological processes such as fluid and electrolyte balance, control of blood pressure, removal of waste products, and drug disposition. Drug-induced kidney injury (DIKI) remains a significant cause of candidate drug attrition during drug development. However, the incidence of renal toxicities in preclinical studies is low, and the mechanisms by which drugs induce kidney injury are still poorly understood. Although some in vitro investigational tools have been developed, the in vivo assessment of renal function remains the most widely used methodology to identify DIKI. Stand-alone safety pharmacology studies usually include assessment of glomerular and hemodynamic function, coupled with urine and plasma analyses. However, as renal function is not part of the ICH S7A core battery, such studies are not routinely conducted by pharmaceutical companies. The most common approach consists in integrating renal/urinary measurements in repeat-dose toxicity studies. In addition to the standard analyses and histopathological examination of kidneys, novel promising urinary biomarkers have emerged over the last decade, offering greater sensitivity and specificity than traditional renal parameters. Seven of these biomarkers have been qualified by regulatory agencies for use in rat toxicity studies. PMID:26091646

  7. Role of flavin-containing monooxygenase in drug development.

    PubMed

    Cashman, John R

    2008-12-01

    This review summarizes some recent observations and information related to the role of the flavin-containing monooxygenase (FMO) in preclinical drug development. Flavin-containing monooxygenase is a complimentary enzyme system to the cytochrome P450 (CYP) family of enzymes and oxygenates several soft, highly polarizable nucleophilic heteroatom-containing chemicals and drugs. The products of FMO-mediated metabolism are generally benign and highly polar, readily excreted materials. There may be some advantages in designing drugs that are metabolized in part by FMO and not exclusively by CYP. In this review, I describe the practical aspects for the participation of FMO in drug and chemical metabolism including: i) the study of FMO using in vitro preparations; ii) some observations about metabolism of drugs and chemicals by FMO in vivo; and iii) the consequences of studying FMO-related metabolism in various small animal models. Some of the preclinical research and development areas related to FMO are not fully mature areas and there are certain gaps in our knowledge. However, I include discussion of these areas to stimulate further work and invite further discussion. PMID:19040327

  8. EMERGING MICROTECHNOLOGIES FOR THE DEVELOPMENT OF ORAL DRUG DELIVERY DEVICES

    PubMed Central

    Chirra, Hariharasudhan D.; Desai, Tejal A.

    2012-01-01

    The development of oral drug delivery platforms for administering therapeutics in a safe and effective manner across the gastrointestinal epithelium is of much importance. A variety of delivery systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, orally administered drugs suffer from poor localization and therapeutic efficacy due to various physiological conditions such as low pH, and high shear intestinal fluid flow. Novel platforms combining controlled release, improved adhesion, tissue penetration, and selective intestinal targeting may overcome these issues and potentially diminish the toxicity and high frequency of administration associated with conventional oral delivery. Microfabrication along with appropriate surface chemistry, provide a means to fabricate these platforms en masse with flexibility in tailoring the shape, size, reservoir volume, and surface characteristics of microdevices. Moreover, the same technology can be used to include integrated circuit technology and sensors for designing sophisticated autonomous drug delivery devices that promise to significantly improve point of care diagnostic and therapeutic medical applications. This review sheds light on some of the fabrication techniques and addresses a few of the microfabricated devices that can be effectively used for controlled oral drug delivery applications. PMID:22981755

  9. Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases.

    PubMed

    Williams, Kevin; Bilsland, Elizabeth; Sparkes, Andrew; Aubrey, Wayne; Young, Michael; Soldatova, Larisa N; De Grave, Kurt; Ramon, Jan; de Clare, Michaela; Sirawaraporn, Worachart; Oliver, Stephen G; King, Ross D

    2015-03-01

    There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist 'Eve' designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax. PMID:25652463

  10. [International Partnership for Therapeutic Drug Development of NTDs by DNDi].

    PubMed

    Yamada, Haruki; Hirabayashi, Fumiko; Brünger, Chris

    2016-01-01

    The Drugs for Neglected Diseases initiative (DNDi), with headquarters in Geneva, is a non-profit drug research and development (R&D) organization and Product Development Partnership (PDP) which was established in 2003 by 7 founding organizations such as Médecins Sans Frontières (MSF), the Pasteur Institute, The Specific Programme for Research and Training in Tropical Diseases (WHO-TDR), etc. DNDi has worked mainly on the development of new treatments for neglected tropical diseases (NTDs), which is difficult to achieve under market economy conditions. DNDi has promoted overall drug discovery research including the screening of drug candidates, hit to lead, lead optimization, pre-clinical and clinical studies in the area of infectious diseases with a focus on malaria, sleeping sickness (human African trypanosomiasis; HAT), Chagas disease, leishmaniasis, filarial diseases and pediatric formulations for HIV treatment. DNDi's achievements include the development of novel therapies based on patient needs through innovative partnerships with over 130 organizations in industry, government, academia, and public institutions around the world. To date, DNDi has registered 6 novel treatments adapted to the needs of patients in poor countries, and has another 12 novel entities in development. DNDi Japan is a Japanese non-profit organization (NPO) based on the global principles of DNDi and, as the only PDP in Japan, is supporting NTD drug discovery projects in collaboration with Japanese pharmaceutical companies, academic institutions and government agencies by utilizing Japan's excellent R&D capabilities to develop new treatments for NTDs in order to contribute to global health. PMID:26831796

  11. Interactive perspective: drug development and FDA approval, 1938-2013.

    PubMed

    2015-02-01

    Interactive Perspective: Drug Development and FDA Approval, 1938-2013 (June 26, 2014;370:e39). The order of authors was incorrect; Dr. Darrow should have been listed first, and Dr. Kesselheim second. The article is correct at NEJM.org. PMID:25651270

  12. Energetics of pathogenic bacteria and opportunities for drug development.

    PubMed

    Cook, Gregory M; Greening, Chris; Hards, Kiel; Berney, Michael

    2014-01-01

    The emergence and spread of drug-resistant pathogens and our inability to develop new antimicrobials to overcome resistance has inspired scientists to consider new targets for drug development. Cellular bioenergetics is an area showing promise for the development of new antimicrobials, particularly in the discovery of new anti-tuberculosis drugs where several new compounds have entered clinical trials. In this review, we have examined the bioenergetics of various bacterial pathogens, highlighting the versatility of electron donor and acceptor utilisation and the modularity of electron transport chain components in bacteria. In addition to re-examining classical concepts, we explore new literature that reveals the intricacies of pathogen energetics, for example, how Salmonella enterica and Campylobacter jejuni exploit host and microbiota to derive powerful electron donors and sinks; the strategies Mycobacterium tuberculosis and Pseudomonas aeruginosa use to persist in lung tissues; and the importance of sodium energetics and electron bifurcation in the chemiosmotic anaerobe Fusobacterium nucleatum. A combination of physiological, biochemical, and pharmacological data suggests that, in addition to the clinically-approved target F1Fo-ATP synthase, NADH dehydrogenase type II, succinate dehydrogenase, hydrogenase, cytochrome bd oxidase, and menaquinone biosynthesis pathways are particularly promising next-generation drug targets. The realisation of cellular energetics as a rich target space for the development of new antimicrobials will be dependent upon gaining increased understanding of the energetic processes utilised by pathogens in host environments and the ability to design bacterial-specific inhibitors of these processes. PMID:25476763

  13. Sustainable Energy in Remote Indonesian Grids. Accelerating Project Development

    SciTech Connect

    Hirsch, Brian; Burman, Kari; Davidson, Carolyn; Elchinger, Michael; Hardison, R.; Karsiwulan, D.; Castermans, B.

    2015-06-30

    Sustainable Energy for Remote Indonesian Grids (SERIG) is a U.S. Department of Energy (DOE) funded initiative to support Indonesia’s efforts to develop clean energy and increase access to electricity in remote locations throughout the country. With DOE support, the SERIG implementation team consists of the National Renewable Energy Laboratory (NREL) and Winrock International’s Jakarta, Indonesia office. Through technical assistance that includes techno-economic feasibility evaluation for selected projects, government-to-government coordination, infrastructure assessment, stakeholder outreach, and policy analysis, SERIG seeks to provide opportunities for individual project development and a collective framework for national replication office.

  14. [Trade-offs in oral drug product development].

    PubMed

    Kondo, Hiromu; Sako, Kazuhiro

    2015-01-01

    Drug products are developed to meet multiple targets, thereby increasing their value. Pharmaceutical scientists encounter several trade-offs during the development of novel oral formulations. These trade-offs are generated by their desire to supply the highest possible quality products under the prevailing conditions of limited time and cost, and feasible options. When there are two incompatible factors, it is sometimes difficult to dismiss one element. This is because a quality target product profile (QTPP) is critical for each product being developed, and all elements should basically be satisfied with the criteria. Therefore, technological innovation becomes important to overcome the trade-offs. This article introduces examples of such innovations which have been successful in doing this, as well as some encountered in the oral formulation development and in the selection of proper dosage forms. Based on these examples, points to be considered in order to produce the drug product are thoroughly discussed. PMID:25747218

  15. Fast Track Teaching: Beginning the Experiment in Accelerated Leadership Development

    ERIC Educational Resources Information Center

    Churches, Richard; Hutchinson, Geraldine; Jones, Jeff

    2009-01-01

    This article provides an overview of the development of the Fast Track teaching programme and personalised nature of the training and support that has been delivered. Fast Track teacher promotion rates are compared to national statistics demonstrating significant progression for certain groups, particularly women. (Contains 3 tables and 3 figures.)

  16. [Post-authorization research, registries, and drug development].

    PubMed

    Patarnello, Francesca; Recchia, Giuseppe

    2013-06-01

    In the last decade regulators, payers and health care providers tried to react to three major problems in drug development and drug use in clinical practice: the pharmaceutical R&D productivity crisis, the immaturity of benefit-risk profile for several newly approved drugs and the overall impact on economic sustainability of reimbursing new high cost drugs in their systems. The potentiality of create a continuum between the evidence requirements relevant for registration, for reimbursement and for post authorization research is clear. All different parties involved, like regulators, HTA agencies, scientific communities and manufacturers, are working to improve the knowledge profile of new drugs in order to anticipate the patient access to innovation, limiting or preventing the clinical and economical risks deriving from an incomplete safety and effectiveness profile. The Italian example of "New Drugs AIFA Registries", with or without the application of risk sharing schemes (cost sharing, pay for performance, etc.), introduced a new process and increased the sensitivity on this topic. However this might probably represents only a partial answer to the problem of how to set up the governance of coverage with evidence, drug utilization monitoring, comparative effectiveness research, outcome research programs and may be how to link them to access, pricing and reimbursement. The step change in post authorization research could be to "integrate" different sources and stakeholders in a wider and continuous approach, in a well designed and inclusive "second generation" HTA approach, where all resources (competencies, data, funding) will concur to increase the evidence profile and reduce the risks, and where any "evidence generation approach" is really compliant with the standard and rules of best research practices. PMID:23801233

  17. Development of novel drug delivery systems using phage display technology for clinical application of protein drugs.

    PubMed

    Nagano, Kazuya; Tsutsumi, Yasuo

    2016-01-01

    Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony-stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects. Additionally, bioactive proteins have poor therapeutic effects owing to degradation by proteases and rapid excretion from the circulatory system. Therefore, it is essential to establish a series of novel drug delivery systems (DDS) to overcome these problems. Here, we review original technologies in DDS. First, we introduce antibody proteomics technology for effective selection of proteins useful as therapeutic seeds or targets and identification of various kinds of proteins, such as cancer-specific proteins, cancer metastasis-related proteins, and a cisplatin resistance-related protein. Especially Ephrin receptor A10 is expressed in breast tumor tissues but not in normal tissues and is a promising drug target potentially useful for breast cancer treatment. Moreover, we have developed a system for rapidly creating functional mutant proteins to optimize the seeds for therapeutic applications and used this system to generate various kinds of functional cytokine muteins. Among them, R1antTNF is a TNFR1-selective antagonistic mutant of TNF and is the first mutein converted from agonist to antagonist. We also review a novel polymer-conjugation system to improve the in vivo stability of bioactive proteins. Site-specific PEGylated R1antTNF is uniform at the molecular level, and its bioactivity is similar to that of unmodified R1antTNF. In the future, we hope that many innovative protein drugs will be

  18. Latest drug developments in the field of cardiovascular disease

    PubMed Central

    Stern, Craig S; Lebowitz, Jason

    2010-01-01

    Cardiovascular disease has been responsible for more deaths annually than any other disease category since 1900, except for the influenza epidemic in 1916. Yet, the drug pipeline has been largely bereft of new entrants. In 2008, one new cardiovascular medication was marketed in the United States. In 2009, there were two new cardiovascular medications. In comparison, there were seven new drugs for oncology in 2009. The present review explores new agents within the context of models currently in the drug pipeline. Of course, there is no guarantee that any of these agents will be marketed. A discussion of the models is illustrative of the types of approaches being used to develop new cardiovascular agents. PMID:22477616

  19. In Vitro Cell Models for Ophthalmic Drug Development Applications

    PubMed Central

    Shafaie, Sara; Hutter, Victoria; Cook, Michael T.; Brown, Marc B.; Chau, David Y.S.

    2016-01-01

    Abstract Tissue engineering is a rapidly expanding field that aims to establish feasible techniques to fabricate biologically equivalent replacements for diseased and damaged tissues/organs. Emerging from this prospect is the development of in vitro representations of organs for drug toxicity assessment. Due to the ever-increasing interest in ocular drug delivery as a route for administration as well as the rise of new ophthalmic therapeutics, there is a demand for physiologically accurate in vitro models of the eye to assess drug delivery and safety of new ocular medicines. This review summarizes current existing ocular models and highlights the important factors and limitations that need to be considered during their use. PMID:27158563

  20. Conference report: hot topics in antibody-drug conjugate development.

    PubMed

    Thudium, Karen; Bilic, Sanela

    2013-12-01

    American Association of Pharmaceutical Scientists National Biotechnology Conference Sheraton San Diego Hotel and Marina, San Diego, CA, USA, 19-23 May 2013 The National Biotechnology Conference, is a premier meeting for biotechnology professionals covering a broad range of hot topics in the biotechnology industry. Attracting participants from academia, industry and regulatory, this meeting features sessions that aim to address emerging subjects of interest and allows for open exchange between scientists. The 2013 conference featured leading researchers in the fields of antibody-drug conjugates (ADCs) and immunogenicity. Herein, we present a summary of the ADC hot topics, including bioanalytical and PK considerations, quantitative evaluation of the impact of immunogenicity and ADME to understand ADC drug-drug interactions, and clinical considerations for ADC development. This article aims to summarize the recommendations that were made by the speakers during various sessions throughout the conference. PMID:24320125

  1. Expression genomics and drug development: towards predictive pharmacology.

    PubMed

    Liu, Edison T

    2005-02-01

    Expression genomics can be defined as the study of the dynamic transciptome and its regulatory elements. Technologies are available that can assess transcripts on a genome-wide scale over time and across many samples. This comprehensive and dynamic database is being used to decipher signalling pathways and to identify new biomarkers and targets. Biomarkers emerging from these studies have prognostic potential and can be used to predict therapeutic outcome. The multiplex nature of this approach not only telescopes the time to discovery, but also allows for detection of complex interactions. Taken together, these capabilities, if carefully used, can speed drug development, enhance the identification of potent drug combinations and identify patient populations that will benefit from these new drugs. PMID:15814022

  2. Anti-influenza drugs: the development of sialidase inhibitors.

    PubMed

    von Itzstein, Mark; Thomson, Robin

    2009-01-01

    Viruses, particularly those that are harmful to humans, are the 'silent terrorists' of the twenty-first century. Well over four million humans die per annum as a result of viral infections alone. The scourge of influenza virus has plagued mankind throughout the ages. The fact that new viral strains emerge on a regular basis, particularly out of Asia, establishes a continual socio-economic threat to mankind. The arrival of the highly pathogenic avian influenza H5N1 heightened the threat of a potential human pandemic to the point where many countries have put in place 'preparedness plans' to defend against such an outcome. The discovery of the first designer influenza virus sialidase inhibitor and anti-influenza drug Relenza, and subsequently Tamiflu, has now inspired a number of continuing efforts towards the discovery of next generation anti-influenza drugs. Such drugs may act as 'first-line-of-defence' against the spread of influenza infection and buy time for necessary vaccine development particularly in a human pandemic setting. Furthermore, the fact that influenza virus can develop resistance to therapeutics makes these continuing efforts extremely important. An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. PMID:19048199

  3. Developing doctoral scientists for drug discovery: pluridimensional education required.

    PubMed

    Janero, David R

    2013-02-01

    Research universities continue to produce new scientists capable of generating knowledge with the potential to inform disease etiology and treatment. Mounting interest of doctoral-level experimental science students in therapeutics-related research careers is discordant with the widespread lack of direct drug-discovery and development experience, let alone commercialization success, among university faculty and administrators. Likewise, the archetypical publication- and grant-fueled, principal investigator (PI)-focused academic system ("PI-stan") risks commoditization of science students pursuing their doctorates as a labor source, rendering them ill-prepared for career options related to therapeutics innovation by marginalizing their development of "beyond-the-bench" professional skills foundational to modern drug-discovery campaigns and career fluency. To militate against professionalization deficits in doctoral drug-discovery researchers, the author--a scientist-administrator-consultant with decades of discovery research and development (R&D), business, and educator experience in commercial and university settings--posits a critical need for pluridimensionality in graduate education and mentorship that extends well beyond thesis-related scientific domains/laboratory techniques to instill transferable operational-intelligence, project/people-management, and communication competencies. Specific initiatives are advocated to help enhance the doctoral science student's market competitiveness, adaptability, and navigation of the significant research, commercial, and occupational challenges associated with contemporary preclinical drug-discovery R&D. PMID:23231364

  4. Development of polarized ion source for the JINR accelerator complex

    NASA Astrophysics Data System (ADS)

    Fimushkin, V. V.; Kovalenko, A. D.; Kutuzova, L. V.; Prokofichev, Yu V.; Shutov, B.; Belov, A. S.; Zubets, V. N.; Turbabin, A. V.

    2016-02-01

    Status of the JINR polarized ion source development is described. The source is under tests at the test-bench of LHEP, JINR. A charge-exchange plasma ionizer has been tested initially without a storage cell in the ionization region. An unpolarized deuterium ion beam with peak current of 160 mA, 23 keV energy, pulse duration of 100 μs and repetition rate of 1 Hz has been extracted from the ionizer. With a free polarized atomic hydrogen beam injected into the ionizer a polarized proton beam with peak current of 1.4 mA has been obtained. The nearest plans for the source development include tests of the ionizer with the storage cell and tuning of the high frequency transition units installed in their operating position with a Breit-Rabi polarimeter.

  5. Computational Tools for Accelerating Carbon Capture Process Development

    SciTech Connect

    Miller, David

    2013-01-01

    The goals of the work reported are: to develop new computational tools and models to enable industry to more rapidly develop and deploy new advanced energy technologies; to demonstrate the capabilities of the CCSI Toolset on non-proprietary case studies; and to deploy the CCSI Toolset to industry. Challenges of simulating carbon capture (and other) processes include: dealing with multiple scales (particle, device, and whole process scales); integration across scales; verification, validation, and uncertainty; and decision support. The tools cover: risk analysis and decision making; validated, high-fidelity CFD; high-resolution filtered sub-models; process design and optimization tools; advanced process control and dynamics; process models; basic data sub-models; and cross-cutting integration tools.

  6. Current developments in drug testing in oral fluid.

    PubMed

    Pil, Kristof; Verstraete, Alain

    2008-04-01

    In the last few years, significant developments have occurred on the key issues involved in oral fluid drug testing. New pharmacokinetic studies have been conducted, optimal cutoffs have been proposed, and new studies have examined the correlation between oral fluid drug concentrations and impairment. Recent studies (eg, the discovery of the presence of THC-COOH in oral fluid) can contribute to solve the issue of false-positive results caused by passive exposure to marijuana. Reliable point-of-care drug testing is still problematic, especially for cannabinoids and benzodiazepines. To date, there is no device that allows both reliable and practical point-of-care testing. The importance of liquid chromatography- tandem mass spectrometry in confirmation analysis has increased over the last several years. It can be expected that this trend will continue because the low sample volumes make simultaneous detection of different drug classes with limited sample preparation necessary. Literature on proficiency testing to ensure reliability and comparability of results is limited. Oral fluid has become an important sample type in driving under the influence research, and the first legal random drug testing program in oral fluid since 2004 has been organized in Victoria. It can be expected that the role of oral fluid as an alternative matrix will keep increasing in the future. PMID:18367980

  7. Project development teams: a novel mechanism for accelerating translational research.

    PubMed

    Sajdyk, Tammy J; Sors, Thomas G; Hunt, Joe D; Murray, Mary E; Deford, Melanie E; Shekhar, Anantha; Denne, Scott C

    2015-01-01

    The trend in conducting successful biomedical research is shifting from individual academic labs to coordinated collaborative research teams. Teams of experienced investigators with a wide variety of expertise are now critical for developing and maintaining a successful, productive research program. However, assembling a team whose members have the right expertise requires a great deal of time and many resources. To assist investigators seeking such resources, the Indiana Clinical and Translational Sciences Institute (Indiana CTSI) created the Project Development Teams (PDTs) program to support translational research on and across the Indiana University-Purdue University Indianapolis, Indiana University, Purdue University, and University of Notre Dame campuses. PDTs are multidisciplinary committees of seasoned researchers who assist investigators, at any stage of research, in transforming ideas/hypotheses into well-designed translational research projects. The teams help investigators capitalize on Indiana CTSI resources by providing investigators with, as needed, mentoring and career development; protocol development; pilot funding; institutional review board, regulatory, and/or nursing support; intellectual property support; access to institutional technology; and assistance with biostatistics, bioethics, recruiting participants, data mining, engaging community health, and collaborating with other investigators.Indiana CTSI leaders have analyzed metrics, collected since the inception of the PDT program in 2008 from both investigators and team members, and found evidence strongly suggesting that the highly responsive teams have become an important one-stop venue for facilitating productive interactions between basic and clinical scientists across four campuses, have aided in advancing the careers of junior faculty, and have helped investigators successfully obtain external funds. PMID:25319172

  8. Photoneutron target development for the RPI linear accelerator

    NASA Astrophysics Data System (ADS)

    Overberg, M. E.; Moretti, B. E.; Slovacek, R. E.; Block, R. C.

    1999-12-01

    Two new photoneutron targets have been developed for neutron time-of-flight experiments, the axial water-moderated target (AWMT) and the bare bounce target (BBT). These targets operate without any lead shielding nearby and both have superior neutron resolution compared to the older bounce target. The BBT has been selected over the AWMT for general time-of-flight measurements because it exhibited lower neutron background in the keV energy region.

  9. Accelerated field facility development for hot sour gas

    SciTech Connect

    Kuntz, L.K.

    1983-10-01

    This paper presents the chronological plan by which a grass roots sweetening facility was constructed in a minimum amount of time. The facility design was based on production with 9% carbon dioxide and 40 ppm hydrogen sulfide. Flowing wellhead temperatures were predicted to be approximately 300/sup 0/F with flowing wellhead pressures to 11,500 psi. The production facility, with a current total nominal capacity of 100 MMcf/D, was installed as five separate parallel sweetening units. The units were put on-stream in phases in order to maintain a sweetening capacity schedule compatible with wells being put on production. The first units were available for service in three months. All five units were complete in nine months, and a permanent facility installation was commissioned three months later. The process design, equipment procurement, and installation phases of the project were pursued concurrently. Three different sweetening systems were operated during the facility development. A conventional DEA (diethanolamine) system was used because of its simple operation. Conversions were made to a proprietary MDEA (methyldiethanolamine) system in order to increase capacity. A proprietary activated MDEA was tested and operated in order to determine sweetening system selection for future facility capacity and for other applications. Included is a discussion of the project development procedure and key considerations that led to minimal development time. General comparisons are made concerning the performance of several sweetening systems.

  10. Using pattern enumeration to accelerate process development and ramp yield

    NASA Astrophysics Data System (ADS)

    Zhuang, Linda; Pang, Jenny; Xu, Jessy; Tsai, Mengfeng; Wang, Amy; Zhang, Yifan; Sweis, Jason; Lai, Ya-Chieh; Ding, Hua

    2016-03-01

    During a new technology node process setup phase, foundries do not initially have enough product chip designs to conduct exhaustive process development. Different operational teams use manually designed simple test keys to set up their process flows and recipes. When the very first version of the design rule manual (DRM) is ready, foundries enter the process development phase where new experiment design data is manually created based on these design rules. However, these IP/test keys contain very uniform or simple design structures. This kind of design normally does not contain critical design structures or process unfriendly design patterns that pass design rule checks but are found to be less manufacturable. It is desired to have a method to generate exhaustive test patterns allowed by design rules at development stage to verify the gap of design rule and process. This paper presents a novel method of how to generate test key patterns which contain known problematic patterns as well as any constructs which designers could possibly draw based on current design rules. The enumerated test key patterns will contain the most critical design structures which are allowed by any particular design rule. A layout profiling method is used to do design chip analysis in order to find potential weak points on new incoming products so fab can take preemptive action to avoid yield loss. It can be achieved by comparing different products and leveraging the knowledge learned from previous manufactured chips to find possible yield detractors.

  11. Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation

    SciTech Connect

    Lawton, C.A.; Fish, B.L.; Moulder, J.E. )

    1994-03-01

    Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy. 34 refs., 4 figs., 2 tabs.

  12. Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening.

    PubMed

    Shao, Xiaojian; Gao, Dan; Chen, Yongli; Jin, Feng; Hu, Guangnan; Jiang, Yuyang; Liu, Hongxia

    2016-08-31

    Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (μSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 μL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs. PMID:27506359

  13. Advanced low-beta cavity development for proton and ion accelerators

    NASA Astrophysics Data System (ADS)

    Conway, Z. A.; Kelly, M. P.; Ostroumov, P. N.

    2015-05-01

    Recent developments in designing and processing low-beta superconducting cavities at Argonne National Laboratory are very encouraging for future applications requiring compact proton and ion accelerators. One of the major benefits of these accelerating structures is achieving real-estate accelerating gradients greater than 3 MV/m very efficiently either continuously or for long-duty cycle operation (>1%). The technology has been implemented in low-beta accelerator cryomodules for the Argonne ATLAS heavy-ion linac where the cryomodules are required to have real-estate gradients of more than 3 MV/m. In offline testing low-beta cavities with even higher gradients have already been achieved. This paper will review this work where we have achieved surface fields greater than 166 mT magnetic and 117 MV/m electric in a 72 MHz quarter-wave resonator optimized for β = 0.077 ions.

  14. Development of a 10 MW, 91 GHz gyroklystron for accelerator applications

    NASA Astrophysics Data System (ADS)

    Ives, R. Lawrence; Lawson, Wes; Neilson, Jeff M.; Read, Michael

    2001-05-01

    A 10 MW, 91 GHz gyroklystron is under development for W-Band accelerator applications. The device will generate 1.5 microsecond pulses at 120 Hz and will be provided to Stanford Linear Accelerator Center for testing of W-Band accelerator components and subsystems. A magnetron injection gun operating at 500 kV will provide a 55 amp beam for interaction in a 5 cavity circuit. The output will be in a hybrid TE01/TE02 mode that can be converted to a more suitable mode at the accelerator. The device is expected to operate with efficiency close to 40% with a gain of 55 dB. A depressed collector will be implemented to allow improvement in the total efficiency to more than 50%.

  15. Development of repetitive railgun pellet accelerator and steady-state pellet supply system

    SciTech Connect

    Oda, Y.; Onozuka, M.; Azuma, K.; Kasai, S.; Hasegawa, K.

    1995-12-31

    A railgun system for repetitive high-speed pellet acceleration and steady-state pellet supply system has been developed and investigated. Using a 2m-long railgun system, the hydrogen pellet was accelerated to 2.6km/sec by the supplied energy of 1.7kJ. It is expected that the hydrogen pellet can be accelerated to 3km/sec using the present pneumatic pellet accelerator and a 2m-long augment railgun. Screw-driven hydrogen-isotope filament extruding system has been fabricated and will be tested to examine its applicability to the steady-state extrusion of the solid hydrogen-isotope filament.

  16. Compact Dielectric Wall Accelerator Development For Intensity Modulated Proton Therapy And Homeland Security Applications

    SciTech Connect

    Chen, Y -; Caporaso, G J; Guethlein, G; Sampayan, S; Akana, G; Anaya, R; Blackfield, D; Cook, E; Falabella, S; Gower, E; Harris, J; Hawkins, S; Hickman, B; Holmes, C; Horner, A; Nelson, S; Paul, A; Pearson, D; Poole, B; Richardson, R; Sanders, D; Stanley, J; Sullivan, J; Wang, L; Watson, J; Weir, J

    2009-06-17

    Compact dielectric wall (DWA) accelerator technology is being developed at the Lawrence Livermore National Laboratory. The DWA accelerator uses fast switched high voltage transmission lines to generate pulsed electric fields on the inside of a high gradient insulating (HGI) acceleration tube. Its high electric field gradients are achieved by the use of alternating insulators and conductors and short pulse times. The DWA concept can be applied to accelerate charge particle beams with any charge to mass ratio and energy. Based on the DWA system, a novel compact proton therapy accelerator is being developed. This proton therapy system will produce individual pulses that can be varied in intensity, energy and spot width. The system will be capable of being sited in a conventional linac vault and provide intensity modulated rotational therapy. The status of the developmental new technologies that make the compact system possible will be reviewed. These include, high gradient vacuum insulators, solid dielectric materials, SiC photoconductive switches and compact proton sources. Applications of the DWA accelerator to problems in homeland security will also be discussed.

  17. Pre-Implementation and Performance Plan for the Latino Development and Technology Accelerator Center

    SciTech Connect

    Quiroga, Marcelo

    2007-03-30

    This report discusses the Latino Development and Technology Accelerator Center (Center) and its innovative economic development program. The chapters describe the organization and the operations of a two-pillar model for training and business acceleration and how the program focuses on the economic development of a disadvantaged Chicago, Illinois, Hispanic community located in Humboldt Park. The Humboldt Park community is located 3 miles west of Chicago's affluent downtown. Humboldt Park residents have income levels below the poverty line and unemployment rates twice the national average.

  18. A snapshot of biologic drug development: Challenges and opportunities.

    PubMed

    Andrews, L; Ralston, S; Blomme, E; Barnhart, K

    2015-12-01

    Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products. PMID:26614816

  19. Accelerating materials discovery through the development of polymer databases

    NASA Astrophysics Data System (ADS)

    Audus, Debra

    In our line of business we create chemical solutions for a wide range of applications, such as home and personal care, printing and packaging, automotive and structural coatings, and structural plastics and foams applications. In this environment, stable and highly automated workflows suitable to handle complex systems are a must. By satisfying these prerequisites, efficiency for the development of new materials can be significantly improved by combining modeling and experimental approaches. This is in fact in line with recent Materials Genome Initiative efforts sponsored by the US administration. From our experience, we know, that valuable contributions to product development are possible today by combining existing modeling techniques in an intelligent fashion, provided modeling and experiment work closely together. In my presentation I intend to review approaches to build and parameterize soft matter systems. As an example of our standard workflow, I will show a few applications, which include the design of a stabilizer molecule for dispersing polymer particles and the simulation of polystyrene dispersions.

  20. Cardiac models in drug discovery and development: a review.

    PubMed

    Amanfu, Robert K; Saucerman, Jeffrey J

    2011-01-01

    Cardiovascular diseases are among the leading causes of death in the developed world. Developing novel therapies for diseases like heart failure is crucial, but this is hampered by the high attrition rate in drug development. The withdrawal of drugs at the final hurdle of approval is mostly because of their unpredictable effects on normal cardiac rhythm. The advent of cardiac computational modeling in the last 5 decades has aided the understanding of heart function significantly. Recently, these models increasingly have been applied toward designing and understanding therapies for cardiac disease. This article will discuss how cellular models of electrophysiology, cell signaling, and metabolism have been used to investigate pharmacologic therapies for cardiac diseases including arrhythmia, ischemia, and heart failure. PMID:22196160

  1. Implications of pharmacogenomics for drug development and clinical practice.

    PubMed

    Ginsburg, Geoffrey S; Konstance, Richard P; Allsbrook, Jennifer S; Schulman, Kevin A

    2005-11-14

    Pharmacogenomics is likely to be among the first clinical applications of the Human Genome Project and is certain to have an enormous impact on the clinical practice of medicine. Herein, we discuss the potential implications of pharmacogenomics on the drug development process, including drug safety, productivity, market segmentation, market expansion, differentiation, and personalized health care. We also review 3 challenges facing the translation of pharmacogenomics into clinical practice: dependence on information technology, limited health care financing, and the scientific uncertainty surrounding validation of specific applications of the technology. To our knowledge, there is currently no formal agenda to promote and cultivate innovation, to develop progressive information technology, or to obtain the financing that would be required to advance the use of pharmacogenomic technologies in patient care. Although the potential of these technologies is driving change in the development of clinical sciences, it remains to be seen which health care systems level needs will be addressed. PMID:16287761

  2. Lipophilicity in Drug Development: Too Much or Not Enough?

    PubMed

    Bergström, Christel A S; Yazdanian, Mehran

    2016-09-01

    A round table discussion was held during the AAPS Annual Meeting on October 27, 2015, with the somewhat provocative topic of whether we need more or less lipophilic compounds in drug development. The session was attended by more than 250 participants, and the feedback was very positive as this round table became a forum for the exchange of ideas from scientists within the academia and industry. Most importantly, the discussion highlighted the difference in approaches to compound selection and development strategies in various companies and organizations. As moderators of this session, we are writing this report to highlight the points and counterpoints made at the session and to bring the importance of the dialogue and debate to the forefront of discussions on how to select the best drug development candidates to enable efficient delivery and, hence, treatment of diseases. PMID:27393481

  3. 77 FR 58848 - Prescription Drug User Fee Act V Patient-Focused Drug Development; Consultation Meetings; Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-24

    ...The Food and Drug Administration (FDA) is issuing this notice to request that patient stakeholders notify FDA of their intention to participate in periodic consultation meetings on process issues related to FDA's patient-focused drug development initiative. This initiative is being conducted to fulfill FDA performance commitments made as part of the fifth authorization of the Prescription Drug......

  4. Core competencies for pharmaceutical physicians and drug development scientists

    PubMed Central

    Silva, Honorio; Stonier, Peter; Buhler, Fritz; Deslypere, Jean-Paul; Criscuolo, Domenico; Nell, Gerfried; Massud, Joao; Geary, Stewart; Schenk, Johanna; Kerpel-Fronius, Sandor; Koski, Greg; Clemens, Norbert; Klingmann, Ingrid; Kesselring, Gustavo; van Olden, Rudolf; Dubois, Dominique

    2013-01-01

    Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide. PMID:23986704

  5. Regulatory affairs issues and legal ontologies in drug development.

    PubMed

    Munteanu, Cristian Robert; Dorado, Julian; Matei-Ilfoveanu, Ion; Nita, Silvia Ana

    2013-01-01

    It usually can take more than ten years from the time a new drug is discovered, until can be launched on the market. Regulatory requirements are part of the process of drug discovery and drug development. It acts at every developmental stage. Regulatory affairs works to establish an effective and uniform balance between voluntary and regulatory compliance and agency responsiveness to consumer needs. It evaluates and coordinates all proposed legal actions to ascertain compliance with regulatory policy. The ontology presented for regulatory affairs and drug research and development gives us the possibility to correlate information from different levels and to discover new relationships between the legal aspects. In addition, the transparency of the information is affected by the inability of existing integration strategies to organize and apply the available knowledge to the range of real scientific and business issue in critical safety and regulatory applications. Therefore, the semantic technologies based on ontologies make the knowledge reusable by several applications across business, from discovery to corporate affairs. PMID:23277001

  6. Tuberculosis: the drug development pipeline at a glance.

    PubMed

    Villemagne, Baptiste; Crauste, Céline; Flipo, Marion; Baulard, Alain R; Déprez, Benoit; Willand, Nicolas

    2012-05-01

    Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis. PMID:22421275

  7. How Multi-Organ Microdevices Can Help Foster Drug Development

    PubMed Central

    Esch, Mandy B.; Smith, Alec; Prot, Jean-Matthieu; Sancho, Carlotta Oleaga; Hickman, James; Shuler, Michael L.

    2014-01-01

    Multi-organ microdevices can mimic tissue-tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue-tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices presents an opportunity to improve the drug development process. The goals are to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices’ capabilities can present unique opportunities for the study of drug action. We also discuss the challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion. PMID:24412641

  8. Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases

    PubMed Central

    Olliaro, Piero; Seiler, Jürg; Kuesel, Annette; Horton, John; Clark, Jeffrey N.; Don, Robert; Keiser, Jennifer

    2011-01-01

    Background Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives. Methodology We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared. Principal Findings The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files. Conclusions/Significance Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made. PMID:21695247

  9. Development of accelerator radiation protection at the SSC

    SciTech Connect

    Toohig, T.

    1993-11-01

    The design of the Superconducting Super Collider evolved over a series of studies from 1984 to 1989. Considerations of concentration of radiation sources and provisions for operational control and monitoring of radiation were determining elements in the design concepts for the facility. The development of the designs involved an extension of the range of applicability of energy deposition and radiation shielding codes beyond the 3 TeV level of the proposed UNK collider to 20 TeV for single beam effects and to 40 TeV in the collision regions. This extrapolation was complicated by the newly discovered, very energetic muons from short-lived states associated with heavy quark states. The design guideline for radiation protection was specified to be 10 mRem/yr, 10% of the Federal limit. In order to limit the amount of land required for the facility, which would extend over some 250 mi. sq., the configuration of the land to be acquired was tailored to the requirements for radiation containment below the levels of the guideline.

  10. Accelerating development of a predictive science of climate.

    SciTech Connect

    Drake, John B; Jones, Phil

    2007-01-01

    Climate change and studies of its implications are front page news. Could the heat waves of July 2006 in Europe and the US be caused by global warming? Are increased incidences of strong tropical storms and hurricanes like Katrina to be expected? Will coastal cities be flooded due to sea level rise? The National Climatic Data Center (NCDC) which archives all weather data for the nation reports that global surface temperatures have increased at a rate near 0.6 C over the last century but that the trend is three times larger since 1976 [Easterling, 2006]. Will this rate continue or will climate change be even more abrupt? Stepping back from the flurry of questions, scientists must take a systematic approach and develop a predictive framework. With responsibility for advising on energy and technology strategies, the Department of Energy Office of Biological and Environmental Research has chosen to bolster the science of climate in order to get the story straight on the factors that cause climate change and the role of carbon loading from fossil fuel use.

  11. Synapsin IIa accelerates functional development of neuromuscular synapses.

    PubMed Central

    Schaeffer, E; Alder, J; Greengard, P; Poo, M M

    1994-01-01

    We have investigated the possible involvement of the synaptic vesicle protein synapsin IIa in synapse development. Synapsin IIa was introduced into Xenopus embryonic spinal neurons by early blastomere injection, and nerve-muscle cultures were prepared. Synaptic currents were measured by comparing synapses in which the presynaptic neuron either contained [syn IIa (+)] or lacked (control) exogenous synapsin IIa. Syn IIa (+) synapses had a 3.6-fold increase in the frequency and a 2.1-fold increase in the amplitude of spontaneous synaptic currents, compared to controls, after 2 days in culture. Synapsin IIa also increased the amplitude of evoked synaptic currents by 2.3-fold in 2-day cultures. The evoked synaptic current amplitudes of syn IIa (+) synapses had a lower coefficient of variation indicating a more stable evoked response. These enhanced synaptic activities were independent of the presence or absence of the protein in the postsynaptic muscle cell. The findings indicate a role for synapsin IIa in synapse maturation. Images PMID:8171006

  12. Noninvasive Laser Probing of Ultrashort Single Electron Bunches for Accelerator And Light Source Development

    SciTech Connect

    Bolton, P.R.; /SLAC

    2007-06-11

    Companion development of ultrafast electron beam diagnostics capable of noninvasively resolving single bunch detail is essential for the development of high energy, high brightness accelerator facilities and associated beam-based light source applications. Existing conventional accelerators can exhibit timing-jitter down to the 100 femtosecond level which exceeds their single bunch duration capability. At the other extreme, in relatively jitterless environments, laser-plasma wakefield accelerators (LWFA) can generate single electron bunches of duration estimated to be of order 10 femtoseconds making this setting a valuable testbed for development of broadband electron bunch diagnostics. Characteristics of electro-optic schemes and laser-induced reflectance are discussed with emphasis on temporal resolution.

  13. Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

    PubMed Central

    Shapiro, Rebecca S.; Robbins, Nicole; Cowen, Leah E.

    2011-01-01

    Summary: Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease. PMID:21646428

  14. Impact analysis of ICH S9 on non-clinical development of anticancer drugs.

    PubMed

    Bonelli, Milton; Di Giuseppe, Francesca; Beken, Sonja

    2015-10-01

    Cancer presents a major healthcare challenge worldwide, with several millions new cases a year, and represents a therapeutic area with a high need for new drugs. To respond to this, the parties of the International Conference for Harmonization agreed in 2007 to develop a guideline on nonclinical requirements for oncology therapeutics' development (ICH S9), which came into effect in early 2010. This guideline includes recommendations to facilitate and accelerate the development and marketing of cancer therapeutic agents for serious and life threatening malignancies and aims to address this need through a refinement and a reduction in the use of experimental animals, following the 3Rs principles. To assess the impact of ICH S9 on drug development and reduction of animal use, we performed an analysis of Marketing Authorization Applications at the European Medicines Agency relevant to the period in which the development of the guideline was approaching the final steps and its early implementation period. From the analysis performed, a consistent trend towards a decrease in the average number of non-clinical studies performed (-40.7%) and number of animals used per development program (-58.1%) for new chemical entities has been detected, highlighting increasing compliance by companies to the recommendations of ICH S9. PMID:26232707

  15. Collaborative workbench for cyberinfrastructure to accelerate science algorithm development

    NASA Astrophysics Data System (ADS)

    Ramachandran, R.; Maskey, M.; Kuo, K.; Lynnes, C.

    2013-12-01

    There are significant untapped resources for information and knowledge creation within the Earth Science community in the form of data, algorithms, services, analysis workflows or scripts, and the related knowledge about these resources. Despite the huge growth in social networking and collaboration platforms, these resources often reside on an investigator's workstation or laboratory and are rarely shared. A major reason for this is that there are very few scientific collaboration platforms, and those that exist typically require the use of a new set of analysis tools and paradigms to leverage the shared infrastructure. As a result, adoption of these collaborative platforms for science research is inhibited by the high cost to an individual scientist of switching from his or her own familiar environment and set of tools to a new environment and tool set. This presentation will describe an ongoing project developing an Earth Science Collaborative Workbench (CWB). The CWB approach will eliminate this barrier by augmenting a scientist's current research environment and tool set to allow him or her to easily share diverse data and algorithms. The CWB will leverage evolving technologies such as commodity computing and social networking to design an architecture for scalable collaboration that will support the emerging vision of an Earth Science Collaboratory. The CWB is being implemented on the robust and open source Eclipse framework and will be compatible with widely used scientific analysis tools such as IDL. The myScience Catalog built into CWB will capture and track metadata and provenance about data and algorithms for the researchers in a non-intrusive manner with minimal overhead. Seamless interfaces to multiple Cloud services will support sharing algorithms, data, and analysis results, as well as access to storage and computer resources. A Community Catalog will track the use of shared science artifacts and manage collaborations among researchers.

  16. Residual acceleration data on IML-1: Development of a data reduction and dissemination plan

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.; Alexander, J. Iwan D.; Wolf, Randy

    1992-01-01

    The main thrust of our work in the third year of contract NAG8-759 was the development and analysis of various data processing techniques that may be applicable to residual acceleration data. Our goal is the development of a data processing guide that low gravity principal investigators can use to assess their need for accelerometer data and then formulate an acceleration data analysis strategy. The work focused on the flight of the first International Microgravity Laboratory (IML-1) mission. We are also developing a data base management system to handle large quantities of residual acceleration data. This type of system should be an integral tool in the detailed analysis of accelerometer data. The system will manage a large graphics data base in the support of supervised and unsupervised pattern recognition. The goal of the pattern recognition phase is to identify specific classes of accelerations so that these classes can be easily recognized in any data base. The data base management system is being tested on the Spacelab 3 (SL3) residual acceleration data.

  17. A physiome interoperability roadmap for personalized drug development.

    PubMed

    Thomas, Simon; Wolstencroft, Katherine; de Bono, Bernard; Hunter, Peter J

    2016-04-01

    The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as '-omics'), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development. PMID:27051513

  18. Exosomes in development, metastasis and drug resistance of breast cancer

    PubMed Central

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-01-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID:26052865

  19. Exosomes in development, metastasis and drug resistance of breast cancer.

    PubMed

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-08-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID:26052865

  20. Gene Expression Profiling and its Practice in Drug Development

    PubMed Central

    Chengalvala, Murty V; Chennathukuzhi, Vargheese M; Johnston, Daniel S; Stevis, Panayiotis E; Kopf, Gregory S

    2007-01-01

    The availability of sequenced genomes of human and many experimental animals necessitated the development of new technologies and powerful computational tools that are capable of exploiting these genomic data and ask intriguing questions about complex nature of biological processes. This gave impetus for developing whole genome approaches that can produce functional information of genes in the form of expression profiles and unscramble the relationships between variation in gene expression and the resulting physiological outcome. These profiles represent genetic fingerprints or catalogue of genes that characterize the cell or tissue being studied and provide a basis from which to begin an investigation of the underlying biology. Among the most powerful and versatile tools are high-density DNA microarrays to analyze the expression patterns of large numbers of genes across different tissues or within the same tissue under a variety of experimental conditions or even between species. The wide spread use of microarray technologies is generating large sets of data that is stimulating the development of better analytical tools so that functions can be predicted for novel genes. In this review, the authors discuss how these profiles are being used at various stages of the drug discovery process and help in the identification of new drug targets, predict the function of novel genes, and understand individual variability in response to drugs PMID:18645595

  1. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development

    PubMed Central

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships. Database URL: http://drumpid.bioapps.biozentrum.uni-wuerzburg.de PMID:27055828

  2. The MIT Accelerator Laboratory for Diagnostic Development for OMEGA, Z and the NIF

    NASA Astrophysics Data System (ADS)

    Petrasso, R.; Gatu Johnson, M.; Armstrong, E.; Orozco, D.; Rinderknecht, H. G.; Rojas Herrera, J.; Rosenberg, M.; Sio, H.; Zylstra, A.; Frenje, J.; Li, C. K.; Seguin, F. H.; Hahn, K.; Jones, B.; Ruiz, C. L.; Sangster, T. C.

    2014-10-01

    The MIT Linear Electrostatic Ion Accelerator generates D-D and D-3He fusion products, which are used for development of nuclear diagnostics for OMEGA, Z, and the NIF. Fusion reaction rates around 106 s-1 are routinely achieved with this accelerator, and fluence and energy of the fusion products are accurately characterized. Diagnostics developed and calibrated at this facility include CR-39 based charged-particle spectrometers, neutron detectors, and the particle Time-Of-Flight (pTOF) CVD-diamond-based bang time detector. The accelerator is also a vital tool in the education of graduate and undergraduate students at MIT. This work was supported in part by SNL, DOE, LLE and LLNL.

  3. Development of and flight results from the Space Acceleration Measurement System (SAMS)

    NASA Technical Reports Server (NTRS)

    Delombard, Richard; Finley, Brian D.; Baugher, Charles R.

    1992-01-01

    Described here is the development of and the flight results from the Space Acceleration Measurement System (SAMS) flight units used in the Orbiter middeck, Spacelab module, and the Orbitercargo bay. The SAMS units are general purpose microgravity accelerometers designed to support a variety of science experiments with microgravity acceleration measurements. A total of six flight units have been fabricated; four for use in the Orbiter middeck and Spacelab module, and two for use in the Orbiter cargo bay. The design of the units is briefly described. The initial two flights of SAMS units on STS-40 (June 1991) and STS-43 (August 1991) resulted in 371 megabytes and 2.6 gigabytes of data respectively. Analytical techniques developed to examine this quantity of acceleration data are described and sample plots of analyzed data are illustrated. Future missions for the SAMS units are listed.

  4. Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice.

    PubMed

    Ramakrishnan, Parameswaran; Yui, Mary A; Tomalka, Jeffrey A; Majumdar, Devdoot; Parameswaran, Reshmi; Baltimore, David

    2016-08-01

    The nuclear factor-κB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel-deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel-deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4(+) and CD8(+) T cells from c-Rel-deficient NOD mice showed significantly decreased T-cell receptor-induced IL-2, IFN-γ, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel-competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel-deficient NOD mice. The results suggest that c-Rel-dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel-dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell-dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity. PMID:27217485

  5. Tyrosine Kinase Inhibition: An Approach to Drug Development

    NASA Astrophysics Data System (ADS)

    Levitzki, Alexander; Gazit, Aviv

    1995-03-01

    Protein tyrosine kinases (PTKs) regulate cell proliferation, cell differentiation, and signaling processes in the cells of the immune system. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases can lead to inflammatory responses and to diseases such as cancer, atherosclerosis, and psoriasis. Thus, inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate may provide a useful basis for drug development. This article summarizes recent progress in the development of PTK inhibitors and demonstrates their potential use in the treatment of disease.

  6. [Current Trend of Drug Development for Neglected Tropical Diseases (NTDs)].

    PubMed

    Kita, Kiyoshi

    2016-01-01

    EBOLA hemorrhagic fever, a typical emerging infectious disease, began in December 2013 in the southern part of Guinea, and killed more than 11000 people by the end of June, 2015. In addition to emerging/re-emerging diseases and the 3 major infectious diseases i.e. HIV/AIDS, tuberculosis and malaria, neglected tropical diseases (NTDs) have recently become important tropical diseases of the poor. It is remarkable that Japan succeeded in the eradication of malaria and other tropical diseases, which include lymphatic filariasis and schistosomiasis. However, despite these achievements, it is important to sustain our efforts when we consider global health. This review highlights the significance of elimination and/or control of NTDs, and then introduces the current situation of drug development activities in Japan, which are aimed towards combating tropical infectious diseases. They include studies on a novel drug target, the "mitochondrial NADH-fumarate reductase system (Fumarate respiration)" composed of complex I, rhodoquinone and complex II, which plays an important role in the anaerobic energy metabolism of many helminths such as Ascaris suum. An additional interesting finding highlighted herein is that ascofuranone, a recently developed anti-African trypanosome drug, shows specific inhibition of fumarate respiration in Echinococcus multilocularis mitochondria. PMID:26831795

  7. Development of natural anti-tumor drugs by microorganisms.

    PubMed

    Chang, Chia-Che; Chen, Wei-Chuan; Ho, Tsing-Fen; Wu, Ho-Shing; Wei, Yu-Hong

    2011-05-01

    Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as β-carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed. PMID:21277252

  8. Functional GI disorders: from animal models to drug development

    PubMed Central

    Mayer, E A; Bradesi, S; Chang, L; Spiegel, B M R; Bueller, J A; Naliboff, B D

    2014-01-01

    Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man. PMID:17965064

  9. Drug Development and Challenges for Neuromuscular Clinical Trials.

    PubMed

    El Mouelhi, Mohamed

    2016-03-01

    Drug development process faces many challenges, including those encountered in clinical trials for neuromuscular diseases. Drug development is a lengthy and highly costly process. Out of 10 compounds entering first study in man (phase 1), only one compound reaches the market after an average of 14 years with a cost of $2.7 billion. Nevertheless, according to the Centers for Medicare and Medicaid services, prescription drugs constituted only 9 % of each health care dollar spent in USA in 2013. Examples of challenges encountered in neuromuscular clinical trials include lack of validated patient-reported outcome tools, blinding issues, and the use of placebo in addition to lack of health authority guidance for orphan diseases. Patient enrollment challenge is the leading cause of missed clinical trial deadlines observed in about 80 % of clinical trials, resulting in delayed availability of potentially life-saving therapies. Another specific challenge introduced by recent technology is the use of social media and risk of bias. Sharing personal experiences while in the study could easily introduce bias among patients that would interfere with accurate interpretation of collected data. To minimize this risk, recent neuromuscular studies incorporate as an inclusion criterion the patient's agreement not to share any of study experiences through social media with other patients during the study conduct. Consideration of these challenges will allow timely response to the high unmet medical needs for many neuromuscular diseases. PMID:26691331

  10. Development and application of an automated solution stability assay for drug discovery.

    PubMed

    Di, Li; Kerns, Edward H; Chen, Hong; Petusky, Susan L

    2006-02-01

    Screening of solution stability provides an early alert on potential liabilities of drug candidates so that strategies can be developed to overcome the challenges. A fully automated solution stability assay has been developed to accelerate traditional manual operation. The assay uses the advanced capabilities of a high-performance liquid chromatography instrument that is present in many pharmaceutical research laboratories. The samples are prepared automatically by a temperature-controlled autosampler. The samples are delivered to the stability matrices, mixed, incubated, and injected at selected time points during the reaction time course. This automated process occurs without operator intervention, thus allowing 96 experiments to be run with 0.5 h of a scientist's time compared to 8 h for the same study when performed manually. Automation not only eliminates the manual operation but also improves accuracy and throughput. The assay protocol has been optimized to achieve homogenous mixing and eliminate carryover. The assay is robust, flexible, and high throughput. It can be used to study stability for a large number of samples under multiple incubation conditions and has a wide range of applications in drug discovery and development, such as screening compound stability in biological assay media, obtaining a stability-pH profile, surveying compound stability in physiological fluids, and performing development forced degradation and excipient compatibility. PMID:16234336

  11. Temporal Development of Auroral Acceleration Potentials: High-Altitude Evolutionary Sequences, Drivers and Consequences

    NASA Astrophysics Data System (ADS)

    Hull, A. J.; Wilber, M.; Chaston, C.; Bonnell, J.; Mozer, F.; McFadden, J.; Goldstein, M.; Fillingim, M.

    2007-12-01

    The region above the auroral acceleration region is an integral part of the auroral zone electrodynamic system. At these altitudes (≥ 3 Re) we find the source plasma and fields that determine acceleration processes occurring at lower altitudes, which play a key role in the transport of mass and energy into the ionosphere. Dynamic changes in these high-altitude regions can affect and/or control lower-altitude acceleration processes according to how field-aligned currents and specific plasma sources form and decay and how they are spatially distributed, and through magnetic configuration changes deeper in the magnetotail. Though much progress has been made, the time development and consequential effects of the high-altitude plasma and fields are still not fully understood. We present Cluster multi-point observations at key instances within and above the acceleration region (> 3 RE) of evolving auroral arc current systems. Results are presented from events occurring under different conditions, such as magnetospheric activity, associations with density depletions or gradients, and Alfvenic turbulence. A preliminary survey, primarily at or near the plasma sheet boundary, indicates quasi- static up-down current pair systems are at times associated with density depletions and other instances occur in association with density gradients. The data suggest that such quasi-static current systems may be evolving from structured Alfvenic current systems. We will discuss the temporal development of auroral acceleration potentials, plasma and currents, including quasi-static system formation from turbulent systems of structured Alfvenic field-aligned currents, density depletion and constituent reorganization of the source and ionospheric plasma that transpire in such systems. Of particular emphasis is how temporal changes in magnetospheric source plasma and fields affect the development of auroral acceleration potentials at lower altitudes.

  12. Generic drugs: international trends and policy developments in Australia.

    PubMed

    Lofgren, Hans

    2004-01-01

    Public and private third-party payers in many countries encourage or mandate the use of generic drugs. This article examines the development of generics policy in Australia, against the background of a description of international trends in this area, and related experiences of reference pricing programs. The Australian generics market remains underdeveloped due to a historical legacy of small Pharmaceutical Benefits Scheme price differentials between originator brands and generics. It is argued that policy measures open to the Australian government can be conceived as clustering around two different approaches: incremental changes within the existing regulatory framework, or a shift towards a high volume/low price role of generics which would speed up the delivery of substantial cost savings, and could provide enhanced scope for the financing of new, patented drugs. PMID:15362295

  13. Development of a drug and alcohol information survey.

    PubMed

    Gough, H G

    1985-04-01

    Psychological measurement in regard to using drugs, alcohol, or other substances should attend to personological, attitudinal, and informational factors. Standardized tests are available for assessing personological and attitudinal variables, but not for knowledge. To develop a test of information, 45 multiple-choice items were correlated with total and part scores in samples of 132 men and 71 women; 35 items with significant (p less than .05) coefficients and other desirable properties were retained for a Drug and Alcohol Information Survey (DAIS). For 33 male and 36 female college students participating in an intensive psychological assessment program, scores on the DAIS were positively associated with (1) ratings of modernity, sensation seeking, originality, and nonorderliness; (2) personality scales for status propensity, sociability, social presence, and rebelliousness; and (3) a nonverbal test of field-independent cognitive ability. High scorers on the DAIS also reported more frequent use of marijuana, alcohol, and tobacco than did students with low scores. PMID:3875571

  14. Development of an Acoustic Droplet Vaporization, Ultrasound Drug Delivery Emulsion

    NASA Astrophysics Data System (ADS)

    Fabiilli, Mario L.; Sebastian, Ian E.; Fowlkes, J. Brian

    2010-03-01

    Many therapeutic applications of ultrasound (US) include the use of pefluorocarbon (PFC) microbubbles or emulsions. These colloidal systems can be activated in the presence of US, which in the case of emulsions, results in the production of bubbles—a process known as acoustic droplet vaporization (ADV). ADV can be used as a drug delivery mechanism, thereby yielding the localized release of toxic agents such a chemotherapeutics. In this work, emulsions that contain PFC and chlorambucil, a chemotherapy drug, are formulated using albumin or lipid shells. For albumin droplets, the oil phase—which contained CHL—clearly enveloped the PFC phase. The albumin emulsion also displayed better retention of CHL in the absence of US, which was evaluated by incubating Chinese hamster ovary cells with the various formulations. Thus, the developed emulsions are suitable for further testing in ADV-induced release of CHL.

  15. Methoprene and protein supplements accelerate reproductive development and improve mating success of male tephritid flies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have been studying the physiological mechanisms responsible for coordination of reproductive maturity and sex pheromone communication in males of tephritid flies in order to develop methods for acceleration of reproductive maturity among sterilized males. Our studies revealed that the juvenile ho...

  16. Future Development Of The Flerov Laboratory Accelerator Complex (Project DRIBs-III)

    NASA Astrophysics Data System (ADS)

    Gulbekian, G. G.; Dmitriev, S. N.; Itkis, M. G.; Oganessian, Yu. Ts.; Popeko, A. G.

    2010-04-01

    Future development of the FLNR accelerator complex (project DRIBs-III) includes modernization of existing cyclotrons, construction of a new experimental hall, creation of a new high current cyclotron and of next generation experimental set-ups. Realization of the project is planned for 2010-2016.

  17. Accelerating the Early Numeracy Development of Kindergartners with Limited Working Memory Skills through Remedial Education

    ERIC Educational Resources Information Center

    Toll, Sylke W. M.; Van Luit, Johannes E. H.

    2013-01-01

    Background: Young children with limited working memory skills are a special interest group among all children that score below average on early numeracy tests. This study examines the effect of accelerating the early numeracy development of these children through remedial education, by comparing them with children with typically working memory…

  18. Accelerated Professional Development and Peer Consultation: Two Strategies for Continuing Professional Education for Nurses.

    ERIC Educational Resources Information Center

    Hart, Gail; Clinton, Michael; Edwards, Helen; Evans, Katie; Lunney, Paul; Posner, Natasha; Tooth, Barbara; Weir, Derek; Ryan, Yoni

    2000-01-01

    A comparison was made of accelerated professional development (APD) for nurses (n=64), involving peer consultation and reflective practice, and peer consultation alone (n=30). Although APD participants had a higher completion rate, improvements in caregiver behaviors and work environment were not significantly different. (SK)

  19. Accelerating the Development of Expertise: A Step-Change in Social Science Research Capacity Building

    ERIC Educational Resources Information Center

    Wray, Alison; Wallace, Mike

    2011-01-01

    It is argued that future research capacity building for the social sciences needs to incorporate methods to accelerate the acquisition by researchers of holistic expertise relevant to their roles as researchers and as developers of others. An agenda is presented, based on a model of learning that highlights missing elements of current provision,…

  20. The introduction of new drugs into anaesthetic practice: a perspective in pharmaceutical development and regulation.

    PubMed

    Gilron, I

    1995-06-01

    This article reviews the process by which new drugs are introduced into anaesthetic practice with particular emphasis on pharmaceutical development and government regulation. After a brief overview of the drug development process, new trends in drug development are discussed including implementation of pharmacokinetic, pharmacodynamic and toxicokinetic studies in both preclinical and human phases of drug evaluation. A synopsis of the drug regulatory process is provided and, in particular, the problem of unapproved drug use in anaesthesia is discussed. Ethical issues regarding physician-industry interactions are highlighted by examples of conflict of interest in anaesthesia. The processes of drug development and regulation require much effort and cooperation between clinicians, pharmaceutical manufacturers and government regulators to achieve a common goal; the development and utilization of safe and effective drugs. A fundamental understanding of these processes may further facilitate optimal drug utilization and the active involvement of anaesthetists in the drug development process. PMID:7628033

  1. Quantitative bioanalysis: an integrated approach for drug discovery and development

    NASA Astrophysics Data System (ADS)

    Ong, Voon S.; Cook, Kevin L.; Kosara, Christine M.; Brubaker, William F.

    2004-11-01

    An integrated approach to quantitative bioanalysis, incorporating turbulent flow chromatography (TFC) with mass spectrometric detection, was developed to support in-house drug discovery and development efforts. Activities such as metabolic stability screening and pharmacokinetic characterization support are carried out on a single unified platform. Two different TFC column-switching configurations, parallel and serial, are presented. The first, a parallel TFC column configuration, is capable of high-throughput analysis but carryover can reach as high as 0.24%. The characteristics of the instrument operating in the parallel configuration are provided for analysis of samples generated during in vitro metabolic stability assessments, a key screen during the lead optimization phase of drug discovery. Operating in this configuration, the system has the capability of performing on-line solid phase extraction and analysis of approximately 400 samples containing phosphate-buffered saline in approximately 14 h. The second, a serial TFC column configuration, was used to perform direct plasma injection analysis. The advantage of the serial configuration is the relatively low carryover (<0.040%) observed due to increased number of valve washes; however these extra washes lead to increased injection cycle times. A method developed using the serial TFC column configuration for the determination of dihydropyridines in plasma samples is given as an example. Analytical performance criteria examined during method development and validation included linearity, accuracy, precision, and recovery. The robustness of the technique was demonstrated by applying the method in the analysis of over 2500 plasma samples generated during preclinical drug development studies. Further, combined analysis of plasma and brain tissue was performed using acetonitrile precipitation as sample pretreatment for both matrices.

  2. Cancer Drug Development: New Targets for Cancer Treatment.

    PubMed

    Curt

    1996-01-01

    cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of

  3. Helicon Plasma Injector and Ion Cyclotron Acceleration Development in the VASIMR Experiment

    NASA Technical Reports Server (NTRS)

    Squire, Jared P.; Chang, Franklin R.; Jacobson, Verlin T.; McCaskill, Greg E.; Bengtson, Roger D.; Goulding, Richard H.

    2000-01-01

    In the Variable Specific Impulse Magnetoplasma Rocket (VASIMR) radio frequency (rf) waves both produce the plasma and then accelerate the ions. The plasma production is done by action of helicon waves. These waves are circular polarized waves in the direction of the electron gyromotion. The ion acceleration is performed by ion cyclotron resonant frequency (ICRF) acceleration. The Advanced Space Propulsion Laboratory (ASPL) is actively developing efficient helicon plasma production and ICRF acceleration. The VASIMR experimental device at the ASPL is called VX-10. It is configured to demonstrate the plasma production and acceleration at the 10kW level to support a space flight demonstration design. The VX-10 consists of three electromagnets integrated into a vacuum chamber that produce magnetic fields up to 0.5 Tesla. Magnetic field shaping is achieved by independent magnet current control and placement of the magnets. We have generated both helium and hydrogen high density (>10(exp 18) cu m) discharges with the helicon source. ICRF experiments are underway. This paper describes the VX-10 device, presents recent results and discusses future plans.

  4. Strategy and planning for chemopreventive drug development: clinical development plans II.

    PubMed

    Kelloff, G J; Crowell, J A; Hawk, E T; Steele, V E; Lubet, R A; Boone, C W; Covey, J M; Doody, L A; Omenn, G S; Greenwald, P; Hong, W K; Parkinson, D R; Bagheri, D; Baxter, G T; Blunden, M; Doeltz, M K; Eisenhauer, K M; Johnson, K; Knapp, G G; Longfellow, D G; Malone, W F; Nayfield, S G; Seifried, H E; Swall, L M; Sigman, C C

    1996-01-01

    This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs. PMID:9154168

  5. Paediatric drug development: the impact of evolving regulations.

    PubMed

    Turner, M A; Catapano, M; Hirschfeld, S; Giaquinto, C

    2014-06-01

    Children deserve medicines that are adapted to their needs. The need to include children in drug development has been recognised increasingly over the past few decades. Legal and regulatory frameworks are well established in the EU and US. The amount of work done to study medicines for children is significantly greater than it was 10 years go. Proof-of-concept has been demonstrated for all segments of the paediatric drug development pipeline. It is now time to examine how the practice of developing medicines for children has evolved within those frameworks and to determine how that work should be generalised. This review describes the development of medicines for children and critically appraises the work that has been done within those frameworks. Significant effort is needed to realize the potential provided by the current regulatory framework. Using the work programme of the Global Research in Paediatrics (GRiP) Network of Excellence as a template we outline current work and future growing points. PMID:24556465

  6. DEVELOPING THE PHYSICS DESIGN FOR NDCX-II, A UNIQUE PULSE-COMPRESSING ION ACCELERATOR

    SciTech Connect

    Friedman, A.; Barnard, J. J.; Cohen, R. H.; Grote, D. P.; Lund, S. M.; Sharp, W. M.; Faltens, A.; Henestroza, E.; Jung, J-Y.; Kwan, J. W.; Lee, E. P.; Leitner, M. A.; Logan, B. G.; Vay, J.-L.; Waldron, W. L.; Davidson, R.C.; Dorf, M.; Gilson, E.P.; Kaganovich, I.

    2009-07-20

    The Heavy Ion Fusion Science Virtual National Laboratory(a collaboration of LBNL, LLNL, and PPPL) is using intense ion beams to heat thin foils to the"warm dense matter" regime at<~;; 1 eV, and is developing capabilities for studying target physics relevant to ion-driven inertial fusion energy. The need for rapid target heating led to the development of plasma-neutralized pulse compression, with current amplification factors exceeding 50 now routine on the Neutralized Drift Compression Experiment (NDCX). Construction of an improved platform, NDCX-II, has begun at LBNL with planned completion in 2012. Using refurbished induction cells from the Advanced Test Accelerator at LLNL, NDCX-II will compress a ~;;500 ns pulse of Li+ ions to ~;;1 ns while accelerating it to 3-4 MeV over ~;;15 m. Strong space charge forces are incorporated into the machine design at a fundamental level. We are using analysis, an interactive 1D PIC code (ASP) with optimizing capabilities and centroid tracking, and multi-dimensional Warpcode PIC simulations, to develop the NDCX-II accelerator. This paper describes the computational models employed, and the resulting physics design for the accelerator.

  7. Accelerated stress testing of thin film solar cells: Development of test methods and preliminary results

    NASA Technical Reports Server (NTRS)

    Lathrop, J. W.

    1985-01-01

    If thin film cells are to be considered a viable option for terrestrial power generation their reliability attributes will need to be explored and confidence in their stability obtained through accelerated testing. Development of a thin film accelerated test program will be more difficult than was the case for crystalline cells because of the monolithic construction nature of the cells. Specially constructed test samples will need to be fabricated, requiring committment to the concept of accelerated testing by the manufacturers. A new test schedule appropriate to thin film cells will need to be developed which will be different from that used in connection with crystalline cells. Preliminary work has been started to seek thin film schedule variations to two of the simplest tests: unbiased temperature and unbiased temperature humidity. Still to be examined are tests which involve the passage of current during temperature and/or humidity stress, either by biasing in the forward (or reverse) directions or by the application of light during stress. Investigation of these current (voltage) accelerated tests will involve development of methods of reliably contacting the thin conductive films during stress.

  8. Developing The Physics Desing for NDCS-II, A Unique Pulse-Compressing Ion Accelerator

    SciTech Connect

    Friedman, A; Barnard, J J; Cohen, R H; Grote, D P; Lund, S M; Sharp, W M; Faltens, A; Henestroza, E; Jung, J; Kwan, J W; Lee, E P; Leitner, M A; Logan, B G; Vay, J -; Waldron, W L; Davidson, R C; Dorf, M; Gilson, E P; Kaganovich, I

    2009-09-24

    The Heavy Ion Fusion Science Virtual National Laboratory (a collaboration of LBNL, LLNL, and PPPL) is using intense ion beams to heat thin foils to the 'warm dense matter' regime at {approx}< 1 eV, and is developing capabilities for studying target physics relevant to ion-driven inertial fusion energy. The need for rapid target heating led to the development of plasma-neutralized pulse compression, with current amplification factors exceeding 50 now routine on the Neutralized Drift Compression Experiment (NDCX). Construction of an improved platform, NDCX-II, has begun at LBNL with planned completion in 2012. Using refurbished induction cells from the Advanced Test Accelerator at LLNL, NDCX-II will compress a {approx}500 ns pulse of Li{sup +} ions to {approx} 1 ns while accelerating it to 3-4 MeV over {approx} 15 m. Strong space charge forces are incorporated into the machine design at a fundamental level. We are using analysis, an interactive 1D PIC code (ASP) with optimizing capabilities and centroid tracking, and multi-dimensional Warpcode PIC simulations, to develop the NDCX-II accelerator. This paper describes the computational models employed, and the resulting physics design for the accelerator.

  9. In silico machine learning methods in drug development.

    PubMed

    Dobchev, Dimitar A; Pillai, Girinath G; Karelson, Mati

    2014-01-01

    Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases. PMID:25262800

  10. Novel approaches in anti-arenaviral drug development

    SciTech Connect

    Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan

    2011-03-15

    Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies.

  11. Support Tools in Formulation Development for Poorly Soluble Drugs.

    PubMed

    Fridgeirsdottir, Gudrun A; Harris, Robert; Fischer, Peter M; Roberts, Clive J

    2016-08-01

    The need for solubility enhancement through formulation is a well-known but still problematic issue because of the numbers of poorly water-soluble drugs in development. There are several possible routes that can be taken to increase the bioavailability of drugs intended for immediate-release oral formulation. The best formulation strategy for any given drug will depend on numerous factors, including required dose, shelf life, manufacturability, and the properties of the active pharmaceutical ingredient (API). Choosing an optimal formulation and manufacturing route for a new API is therefore not a straightforward process. Currently, there are several approaches that are used in the pharmaceutical industry to select the best formulation strategy. These differ in complexity and efficiency, but most try to predict which route will best suit the API based on selected molecular parameters such as molecular weight, lipophilicity (logP), and solubility. These methods range from using no tools, trial and error methods through a variety of complex tools from small in vitro or in vivo experiments or high throughput screening, guidance maps, and decision trees to the most complex methods based on computational modelling tools. This review aims to list available support tools and explain how they are used. PMID:27368122

  12. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery.

    PubMed

    Peterson, J Thomas

    2004-01-01

    Collagen turnover is a slow process on a biologic timescale with a t$\\\\frac12$ of 20-27 days that is mediated primarily by the matrix metalloproteinases (MMPs). Low collagen metabolism is not due to an intrinsically low Km of MMPs, but rather due to a highly regulated system of activity. Despite the stability of collagen and MMPs, the articles in this special addition illustrate the importance of this enzyme family in the disease process leading to congestive heart failure. Like MMPs, drug development is a tightly regulated process, and the successful turnover of MMP inhibitors into a marketed drug has also been a slow process on a pharmaceutical timescale. Since the discovery of the archetypal MMP (type 1 collagenase) over four decades ago by Gross and Lapierre, most major pharmaceutical companies have had MMP inhibitor programs for a variety of indications. Despite decades of research, tens of thousands of compounds synthesized and screened, and billions of dollars spent in clinical studies-Periostat (doxycycline hyclate, CollaGenex Pharmaceuticals Inc.) is the only collagenase inhibitor to be successfully launched. In addition, Periostat's approval is currently limited to periodontal disease. This article focuses on some of the lessons to be learned from the failure of so many MMP inhibitors across so many indications, and what potential exists for MMP inhibitors as a drug class, especially for heart failure. PMID:14739769

  13. Analysis of requirements for accelerating the development of geothermal energy resources in California

    NASA Technical Reports Server (NTRS)

    Fredrickson, C. D.

    1978-01-01

    Various resource data are presented showing that geothermal energy has the potential of satisfying a singificant part of California's increasing energy needs. General factors slowing the development of geothermal energy in California are discussed and required actions to accelerate its progress are presented. Finally, scenarios for developing the most promising prospects in the state directed at timely on-line power are given. Specific actions required to realize each of these individual scenarios are identified.

  14. Understanding developmental pharmacodynamics: importance for drug development and clinical practice.

    PubMed

    Mulla, Hussain

    2010-08-01

    Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some antidepressants in children. GABA(A) receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the mu opioid receptor. An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual 'bottom up' (ontogeny knowledge driven) and 'top down' (pediatric pharmacokinetic-pharmacodynamic studies) approach. PMID

  15. Disciplined approach to drug discovery and early development.

    PubMed

    Plenge, Robert M

    2016-07-27

    Our modern health care system demands therapeutic interventions that improve the lives of patients. Unfortunately, decreased productivity in therapeutics research and development (R&D) has driven drug costs up while delivering insufficient value to patients. Here, I discuss a model of translational medicine that connects four components of the early R&D pipeline-causal human biology, therapeutic modality, biomarkers of target modulation, and proof-of-concept clinical trials. Whereas the individual components of this model are not new, technological advances and a disciplined approach to integrating all four areas offer hope for improving R&D productivity. PMID:27464747

  16. Orphan Nuclear Receptors as Targets for Drug Development

    PubMed Central

    Mukherjee, Subhajit

    2012-01-01

    Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994

  17. Biology-driven cancer drug development: back to the future

    PubMed Central

    2010-01-01

    Most of the significant recent advances in cancer treatment have been based on the great strides that have been made in our understanding of the underlying biology of the disease. Nevertheless, the exploitation of biological insight in the oncology clinic has been haphazard and we believe that this needs to be enhanced and optimized if patients are to receive maximum benefit. Here, we discuss how research has driven cancer drug development in the past and describe how recent advances in biology, technology, our conceptual understanding of cell networks and removal of some roadblocks may facilitate therapeutic advances in the (hopefully) near future. PMID:20385032

  18. Effects of Antitumor Drug Sorafenib on Chick Embryo Development.

    PubMed

    Cheng, Yi-Sen; Wang, Xiao-Yu; Wang, Guang; Li, Yan; Chen, Yue-Lei; Chuai, Man-Li; Lee, Kenneth Ka Ho; Ding, Xiao-Yan; Yang, Xue-Song

    2015-07-01

    Sorafenib has been used as an oral anti-cancer drug because of its ability to inhibit tumor growth. However, the pharmacological effect of sorafenib is still the lack of in vivo experimental evidence. Tumor and embryonic cells share some similar features, so we investigated the effects of sorafenib on the development of gastrulating chick embryos. We found that sorafenib exposure was markedly attributed to the number of embryonic cell in proliferation and apoptosis. We also detected sorafenib significantly interfered with epithelial-mesenchymal transition (EMT). Furthermore, sorafenib treatment impaired the production and migration of neural crest cells. PMID:25810088

  19. Antiviral Drugs Specific for Coronaviruses in Preclinical Development

    PubMed Central

    Adedeji, Adeyemi O.; Sarafianos, Stefan G.

    2014-01-01

    Coronaviruses are positive stranded RNA viruses that cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses impeded the development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), and more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), has impelled the development of such drugs. This review focuses on some newly identified SARS-CoV inhibitors, with known mechanisms of action and their potential to inhibit the novel MERS-CoV. The clinical development of optimized versions of such compounds could be beneficial for the treatment and control of SARS-CoV, the current MERS-CoV and other future SARS-like epidemics. PMID:24997250

  20. Alzheimer's disease drug development based on Computer-Aided Drug Design.

    PubMed

    Zeng, Huahui; Wu, Xiangxiang

    2016-10-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the excessive deposition of amyloids in the brain. The pathological features mainly include the extracellular amyloid plaques and intracellular neurofibrillary tangles, which are the production of amyloid precursor protein (APP) processed by the α-, β- and γ-secretases. Based on the amyloid cascade hypotheses of AD, a large number of amyloid-β agents and secretase inhibitors against AD have been recently developed by using computational methods. This review article describes pathophysiology of AD and the structure of the Aβ plaques, β- and γ-secretases, and discusses the recent advances in the development of the amyloid agents for AD therapy and diagnosis by using Computer-Aided Drug Design approach. PMID:26415837

  1. Recent developments in the application of electron accelerators for polymer processing

    NASA Astrophysics Data System (ADS)

    Chmielewski, A. G.; Al-Sheikhly, M.; Berejka, A. J.; Cleland, M. R.; Antoniak, M.

    2014-01-01

    There are now over 1700 high current, electron beam (EB) accelerators being used world-wide in industrial applications, most of which involve polymer processing. In contrast to the use of heat, which transfers only about 5-10% of input energy into energy useful for materials modification, radiation processing is very energy efficient, with 60% or more of the input energy to an accelerator being available for affecting materials. Historic markets, such as the crosslinking of wire and cable jacketing, of heat shrinkable tubings and films, of partial crosslinking of tire components and of low-energy EB to cure or dry inks and coatings remain strong. Accelerator manufacturers have made equipment more affordable by down-sizing units while maintaining high beam currents. Very powerful accelerators with 700 kW output have made X-ray conversion a practical alternative to the historic use of radioisotopes, mainly cobalt-60, for applications as medical device sterilization. New EB end-uses are emerging, such as the development of nano-composites and nano-gels and the use of EB processing to facilitate biofuel production. These present opportunities for future research and development.

  2. Application of Biomarkers in the Development of Drugs Intended for the Treatment of Osteoarthritis

    PubMed Central

    Kraus, Virginia Byers; Burnett, Bruce; Coindreau, Javier; Cottrell, Susan; Eyre, David; Gendreau, Michael; Gardiner, Jennifer; Garnero, Patrick; Hardin, John; Henrotin, Yves; Heinegård, Dick; Ko, Amy; Lohmander, Stefan; Matthews, Gloria; Menetski, Joseph; Moskowitz, Roland; Persiani, Stefano; Poole, Robin; Rousseau, Jean Charles; Todman, Martin

    2013-01-01

    Objective Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007–2009 at the behest of the Osteoarthritis Research Society International (OARSI FDA initiative). Results This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within one to two years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are

  3. Progress In Plasma Accelerator Development for Dynamic Formation of Plasma Liners

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Eskridge, Richard; Martin, Adam; Smith, James; Lee, Michael; Cassibry, Jason T.; Griffin, Steven; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    An experimental plasma accelerator for magnetic target fusion (MTF) applications under development at the NASA Marshall Space Flight Center is described. The accelerator is a coaxial pulsed plasma thruster (Figure 1). It has been tested experimentally and plasma jet velocities of approx.50 km/sec have been obtained. The plasma jet has been photographed with 10-ns exposure times to reveal a stable and repeatable plasma structure (Figure 2). Data for velocity profile information has been obtained using light pipes and magnetic probes embedded in the gun walls to record the plasma and current transit respectively at various barrel locations. Preliminary spatially resolved spectral data and magnetic field probe data are also presented. A high speed triggering system has been developed and tested as a means of reducing the gun "jitter". This jitter is being characterized and future work for second generation "ultra-low jitter" gun development is being identified.

  4. A Wind-Tunnel Investigation of the Development of Lift on Wings in Accelerated Longitudinal Motion

    NASA Technical Reports Server (NTRS)

    Turner, Thomas R.

    1960-01-01

    An investigation was made in the Langley 300 MPH 7- by 10-foot tunnel to determine the development of lift on a wing during a simulated constant-acceleration catapult take-off. The investigation included models of a two-dimensional wing, an unswept wing having an aspect ratio of 6, a 35 deg. swept wing having an aspect ratio of 3.05, and a 60 deg. delta wing having an aspect ratio of 2.31. All the wings investigated developed at least 90 percent of their steady-state lift in the first 7 chord lengths of travel. The development of lift was essentially independent of the acceleration when based on chord lengths traveled, and was in qualitative agreement with theory.

  5. The Role of Neoadjuvant Trials in Drug Development for Solid Tumors.

    PubMed

    Funt, Samuel A; Chapman, Paul B

    2016-05-15

    The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR. PMID:26842238

  6. Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development.

    PubMed

    He, Yan; Ho, Chris

    2015-10-01

    Amorphous solid dispersion (ASD) can accelerate a project by improving dissolution rate and solubility, offering dose escalation flexibility and excipient acceptance for toxicology studies, as well as providing adequate preclinical and clinical exposure. The prerequisite physicochemical properties for a compound to form a stable ASD are glass-forming ability and low-crystallization tendency, which can be assessed using computational tools and experimental methods. Polymer excipient screening by in silico miscibility prediction and experimental screening techniques is discussed. Improved technologies for polymer screening with minimal quantity of drug substance, and the scalability of ASD from bench to commercial are reviewed. Considerations of in vitro evaluations, preclinical animal selection, and the translation of the preclinical results to clinical studies are also discussed. Better understanding of how polymers improve the stability of the amorphous phase in the solid state and how ASD improves bioavailability have facilitated the applications of ASD ranging from discovery research to preclinical development and further to commercialization. With the understanding of how ASDs are currently used in the pharmaceutical industry and what challenges remain to be solved, ASD can be applied to solve drug formulation problems at given research and development stages. PMID:26175316

  7. Titanium MEMS Technology Development for Drug Delivery and Microfluidic Applications

    NASA Astrophysics Data System (ADS)

    Khandan, Omid

    The use of microelectromechanical systems (MEMS) technology in medical and biological applications has increased dramatically in the past decade due to the potential for enhanced sensitivity, functionality, and performance associated with the miniaturization of devices, as well as the market potential for low-cost, personalized medicine. However, the utility of such devices in clinical medicine is ultimately limited due to factors associated with prevailing micromachined materials such as silicon, as it poses concerns of safety and reliability due to its intrinsically brittle properties, making it prone to catastrophic failure. Recent advances in titanium (Ti) micromachining provides an opportunity to create devices with enhanced safety and performance due to its proven biocompatibility and high fracture toughness, which causes it to fail by means of graceful, plasticity-based deformation. Motivated by this opportunity, we discuss our efforts to advance Ti MEMS technology in two ways: 1) Through the development of titanium-based microneedles (MNs) that seek to provide a safer, simpler, and more efficacious means of ocular drug delivery, and 2) Through the advancement of Ti anodic bonding for future realization of robust microfluidic devices for photocatalysis applications. As for the first of these thrusts, we show that MN devices with in-plane geometry and through-thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings can be fabricated utilizing Ti deep reactive ion etching (Ti DRIE). Our mechanical testing and finite element analysis (FEA) results suggest that these devices possess sufficient stiffness for reliable corneal insertion. Our MN coating studies show that, relative to solid MNs of identical shank dimension, fenestrated devices can increase drug carrying capacity by 5-fold. Furthermore, we demonstrate that through-etched fenestrations provide a protective cavity for delivering

  8. Implications and limitations of cellular reprogramming for psychiatric drug development.

    PubMed

    Tobe, Brian T D; Brandel, Michael G; Nye, Jeffrey S; Snyder, Evan Y

    2013-01-01

    Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics. PMID:24232258

  9. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

    PubMed

    Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing

    2016-04-01

    Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition. PMID:27045656

  10. 78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-31

    ...The Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) is seeking input from the public on the following topics related to antibacterial drug development: Potential new study designs, proposed priorities for CDER guidances, and strategies intended to slow the rate of emerging resistance to antibacterial drugs. The purpose of this notice is to request......

  11. Developing an Occupational Drug Abuse Program: Considerations and Approaches. Services Research Monograph Series.

    ERIC Educational Resources Information Center

    Stephen, Mae; Prentice, Robert

    This monograph, developed as a guide for companies interested in establishing drug abuse programs, begins with a brief summary of studies assessing the extent and costs of employee drug use. The next section addresses some practical and conceptual issues about establishing a drug abuse program. Suggestions for implementing a drug abuse program are…

  12. High performance computing for drug development on K computer

    NASA Astrophysics Data System (ADS)

    Fujitani, Hideaki; Shinoda, Keiko; Yamashita, Takefumi; Kodama, Tatsuhiko

    2013-08-01

    Massively parallel computations (MP-CAFEE) ware developed to calculate absolute binding free energies of small molecules bound to a protein by all-atom molecular dynamics. It uses the nonequilibrium work measurement and Bennett acceptance ratio methods to calculate the free energy difference between the bound and unbound states. The FUJI force field was developed in order to assign force field parameters to arbitrary organic molecules in a unified manner including proteins and nucleic acids. Its dihedral parameters agree with the torsion energy profiles calculated by high-level ab initio molecular orbital theory for the model systems of protein backbone. Comparing with various force fields it agrees well with recent observations by vibrational spectroscopy on Ramachandran angle's population of alanine dipeptide in water. MP-CAFEE with FUJI force field has an efficient parallel algorithm and enough accuracy for computer aided drug design.

  13. Twin-Screw Extruder and Pellet Accelerator Integration Developments for ITER

    SciTech Connect

    Meitner, Steven J; Baylor, Larry R; Combs, Stephen Kirk; Fehling, Dan T; Foust, Charles R; McGill, James M; Rasmussen, David A; Maruyama, So

    2011-01-01

    The ITER pellet injection system consisting of a twinscrew frozen hydrogen isotope extruder, coupled to a combination solenoid actuated pellet cutter and pneumatic pellet accelerator, is under development at the Oak Ridge National Laboratory. A prototype extruder has been built to produce a continuous solid deuterium extrusion and will be integrated with a secondary section, where pellets are cut, chambered, and launched with a single-stage pneumatic accelerator into the plasma through a guide tube. This integrated pellet injection system is designed to provide 5 mm fueling pellets, injected at a rate up to 10 Hz, or 3 mm edge localized mode (ELM) triggering pellets, injected at higher rates up to 20 Hz. The pellet cutter, chamber mechanism, and the solenoid operated pneumatic valve for the accelerator are optimized to provide pellet velocities between 200-300 m/s to ensure high pellet survivability while traversing the inner wall fueling guide tubes, and outer wall ELMpacing guide tubes. This paper outlines the current twin-screwextruder design, pellet accelerator design, and the integrationrequired for both fueling and ELM pacing pellets.

  14. The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America.

    PubMed

    Arnold, Renée J G; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico

    2015-01-01

    Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries. PMID:25844162

  15. The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America

    PubMed Central

    Arnold, Renée J.G.; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico

    2015-01-01

    Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries. PMID:25844162

  16. Formulation and development of gastroretentive drug delivery system for ofloxacin.

    PubMed

    Ali, J; Hasan, S; Ali, M

    2006-09-01

    The aim of the present study was to develop a delivery system wherein the retention of ofloxacin could be achieved for increased local action in gastric region against Helicobacter pylori infection. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in citrate phosphate buffer (pH 3). The hydrodynamically balanced capsules were prepared by physical mixing of various grades of HPMC and poly(ethylene oxide) (PEO) alone as well as in combinations. Cellulose acetate pthalate, liquid paraffin, and ethyl cellulose were used as release modifiers so as to maintain release of drug over a period of 12 h. The capsules prepared with PEOWSR 60K and drug coated with 2.5% ethyl cellulose gave the best in vitro percentage release and were taken as the optimized formulations. Various grades of Eudragit and PEO were used in combination for formulating floating microspheres using solvent diffusion technique for preparation of multiple unit system. The use of two different solvents (dichloromethane and ethanol) that differed in the rate of diffusion led to formation of a hollow core in the microspheres, which was partially responsible for the flotation ability. The in vitro release of the floating capsules and microspheres was found to be 96.02% and 95.83% in 12 h, respectively. Both the dosage forms follow Higuchi model for release from formulations. By fitting the in vitro release data of single unit dosage form into zero-order, first-order, and Higuchi model, it could be concluded that the release followed Higuchi model, as the correlation coefficient (R2 value) was higher than those in the other two release models. In both cases of single and multiple unit dosage form, R2 values for Higuchi model were found to be good, showing that drug release followed non-Fickian diffusion mechanism. PMID:17003848

  17. Priority research areas to accelerate the development of practical ultraconductive copper conductors

    SciTech Connect

    Lee, Dominic F.; Burwell, Malcolm; Stillman, H.

    2015-09-01

    This report documents the findings at an Ultraconductive Copper Strategy Meeting held on March 11, 2015 in Washington DC. The aim of this meeting was to bring together researchers of ultraconductive copper in the U.S. to identify and prioritize critical non-proprietary research activities that will enhance the understanding in the material and accelerate its development into practical conductors. Every effort has been made to ensure that the discussion and findings are accurately reported in this document.

  18. Development of an accelerated reliability test schedule for terrestrial solar cells

    NASA Technical Reports Server (NTRS)

    Lathrop, J. W.; Prince, J. L.

    1981-01-01

    An accelerated test schedule using a minimum amount of tests and a minimum number of cells has been developed on the basis of stress test results obtained from more than 1500 cells of seven different cell types. The proposed tests, which include bias-temperature, bias-temperature-humidity, power cycle, thermal cycle, and thermal shock tests, use as little as 10 and up to 25 cells, depending on the test type.

  19. Development of a photovoltaic module qualification test based on combined-environment accelerated stress data

    NASA Astrophysics Data System (ADS)

    Trenchard, S. E.; Royal, E.; Anderson, R. T.

    The U.S. Coast Guard has developed a qualification test to screen photovoltaic modules for utilization on marine aids to navigation. The test is based on a combined-environment of hot and cold saltwater immersion and air pressurization. The test has demonstrated a very high acceleration factor and excellent correlation of electrical failures with modules in a concurrent real-time marine exposure.

  20. Development of a photovoltaic module qualification test based on combined-environment accelerated stress data

    NASA Technical Reports Server (NTRS)

    Trenchard, S. E.; Royal, E.; Anderson, R. T.

    1982-01-01

    The U.S. Coast Guard has developed a qualification test to screen photovoltaic modules for utilization on marine aids to navigation. The test is based on a combined-environment of hot and cold saltwater immersion and air pressurization. The test has demonstrated a very high acceleration factor and excellent correlation of electrical failures with modules in a concurrent real-time marine exposure.

  1. Requirements and Development of an Acceleration Measurement System for International Space Station Microgravity Science Payloads

    NASA Technical Reports Server (NTRS)

    Sutliff, Thomas J.

    1997-01-01

    The International Space Station is being developed by NASA and international partners as a versatile user platform to allow long term on-orbit investigations of a variety of scientific and technology arenas. In particular, scientific studies are planned within a research class known as microgravity science in areas such as biotechnology, combustion, fluid physics, and materials sciences. An acceleration measurement system is in development to aid such research conducted in the on-orbit conditions of apparent weightlessness. This system provides a general purpose acceleration measurement capability in support of these payloads and investigators. Such capability allows for systematic study of scientific phenomena by obtaining information regarding the local accelerations present during experiment operations. Preparations for implementing this flight measurement system involves two distinct stages: requirements development prior to initiating the design activity, and the design activity itself. This paper defines the requirements definition approach taken, provides an overview of the results of the requirements phase, and outlines the initial design considerations being addressed for this measurement system. Some preliminary engineering approaches are also described.

  2. Developing a Dissociative Nanocontainer for Peptide Drug Delivery.

    PubMed

    Kelly, Patrick; Anand, Prachi; Uvaydov, Alexander; Chakravartula, Srinivas; Sherpa, Chhime; Pires, Elena; O'Neil, Alison; Douglas, Trevor; Holford, Mandë

    2015-10-01

    The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB) models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP) reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid) is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers. PMID:26473893

  3. Human cytomegalovirus and transplantation: drug development and regulatory issues.

    PubMed

    McIntosh, Megan; Hauschild, Benjamin; Miller, Veronica

    2016-01-01

    Cytomegalovirus (CMV) infection is highly prevalent worldwide and can cause serious disease among immunocompromised individuals, including persons with HIV and transplant recipients on immunosuppressive therapies. It can also result in congenital cytomegalovirus when women are infected during pregnancy. Treatment and prevention of CMV in solid organ and haematopoietic stem cell transplant recipients is accomplished in one of three ways: (1) prophylactic therapy to prevent CMV viraemia; (2) pre-emptive therapy for those with low levels of replicating virus; and (3) treatment for established disease. Despite the high prevalence of CMV, there are few available approved drug therapies, and those that are available are hampered by toxicity and less-than-optimal efficacy. New therapies are being developed and tested; however, inconsistency in standardisation of virus levels and questions about potential endpoints in clinical trials present regulatory hurdles that must be addressed. This review covers the current state of CMV therapy, drugs currently under investigation, and clinical trial issues and questions that are in need of resolution. PMID:27482453

  4. Developing a Dissociative Nanocontainer for Peptide Drug Delivery

    PubMed Central

    Kelly, Patrick; Anand, Prachi; Uvaydov, Alexander; Chakravartula, Srinivas; Sherpa, Chhime; Pires, Elena; O’Neil, Alison; Douglas, Trevor; Holford, Mandë

    2015-01-01

    The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB) models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP) reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid) is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers. PMID:26473893

  5. DEVELOPING DRUGS FOR CORE SOCIAL AND COMMUNICATION IMPAIRMENT IN AUTISM

    PubMed Central

    Posey, David J.; Erickson, Craig A.; McDougle, Christopher J.

    2008-01-01

    SYNOPSIS There are many challenges to studying drug effects on core social and language impairment in autism. Drugs such as fenfluramine, naltrexone, and secretin do not appear to be efficacious for these core symptoms. Risperidone has led to improvement in some aspects of social relatedness when used to treat irritability in autism. More research is needed on the utility of selective serotonin reuptake inhibitors, cholinergic drugs, glutamatergic drugs, and oxytocin for core autistic symptoms. PMID:18775370

  6. The trade-off between maturation and growth during accelerated development in frogs.

    PubMed

    Mueller, Casey A; Augustine, Starrlight; Kooijman, Sebastiaan A L M; Kearney, Michael R; Seymour, Roger S

    2012-09-01

    Developmental energetics are crucial to a species' life history and ecology but are poorly understood from a mechanistic perspective. Traditional energy and mass budgeting does not distinguish between costs of growth and maturation, making it difficult to account for accelerated development. We apply a metabolic theory that uniquely considers maturation costs (Dynamic Energy Budget theory, DEB) to interpret empirical data on the energetics of accelerated development in amphibians. We measured energy use until metamorphosis in two related frogs, Crinia georgiana and Pseudophryne bibronii. Mass and energy content of fresh ova were comparable between the species. However, development to metamorphosis was 1.7 times faster in C. georgiana while P. bibronii produced nine times the dry biomass at metamorphosis and had lower mass-specific oxygen requirements. DEB theory explained these patterns through differences in ontogenetic energy allocation to maturation. P. bibronii partitioned energy in the same (constant) way throughout development whereas C. georgiana increased the fraction of energy allocated to maturation over growth between hatching and the onset of feeding. DEB parameter estimation for additional, direct-developing taxa suggests that a change in energy allocation during development may result from a selective pressure to increase development rate, and not as a result of development mode. PMID:22613786

  7. Development of a Dielectric-Loaded Accelerator Test Facility Based on an X-Band Magnicon Amplifier

    SciTech Connect

    Gold, S. H.; Fliflet, A. W.; Kinkead, A. K.; Gai, W.; Power, J. G.; Konecny, R.; Jing, C.; Tantawi, S. G.; Nantista, C. D.; Hu, Y.; Du, X.; Tang, C.; Lin, Y.; Bruce, R. W.; Bruce, R. L.; Lewis, D. III

    2006-01-03

    The Naval Research Laboratory (NRL) and Argonne National Laboratory (ANL), in collaboration with the Stanford Linear Accelerator Center (SLAC), are developing a dielectric-loaded accelerator (DLA) test facility powered by the 11.424-GHz magnicon amplifier that was developed jointly by NRL and Omega-P, Inc. Thus far, DLA structures developed by ANL have been tested at the NRL Magnicon Facility without injected electrons, including tests of alumina and magnesium calcium titanate structures at gradients up to {approx}8 MV/m. The next step is to inject electrons in order to build a compact DLA test accelerator. The Accelerator Laboratory of Tsinghua University in Beijing, China has developed a 5-MeV electron injector for the accelerator, and SLAC is developing a means to combine the two magnicon output arms, and to drive the injector and an accelerator section with separate control of the power ratio and relative phase. Also, RWBruce Associates, working with NRL, is developing a means to join ceramic tubes to produce long accelerating sections using a microwave brazing process. The installation and commissioning of the first dielectric-loaded test accelerator, including injector, DLA structure, and spectrometer, should take place within the next year.

  8. The Development of Cognitive Schemas about Drugs among Preschoolers.

    ERIC Educational Resources Information Center

    Zucker, Robert A.; And Others

    This paper reviews several studies on preschoolers' perceptions of alcohol and drug use. The studies make five main points: (1) the process of socialization to alcohol and drug involvement begins earlier than adolescence, and involves the ability to identify alcohol and drugs by name, class, and smell; (2) the process of socialization involves…

  9. Can Accelerators Accelerate Learning?

    NASA Astrophysics Data System (ADS)

    Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.

    2009-03-01

    The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ) [1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.

  10. Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation.

    PubMed

    Verma, Sanjay; Rudraraju, Varma S

    2015-02-01

    The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months. PMID:25190361

  11. Developing drugs for the developing world: an economic, legal, moral, and political dilemma.

    PubMed

    Resnik, D B

    2001-05-01

    This paper discusses the economic, legal, moral, and political difficulties in developing drugs for the developing world. It argues that large, global pharmaceutical companies have social responsibilities to the developing world, and that they may exercise these responsibilities by investing in research and development related to diseases that affect developing nations, offering discounts on drug prices, and initiating drug giveaways. However, these social responsibilities are not absolute requirements and may be balanced against other obligations and commitments in light of economic, social, legal, political, and other conditions. How a company decides to exercise its social responsibilities to the developing world depends on (1) the prospects for a reasonable profit and (2) the prospects for a productive business environment. Developing nations can either help or hinder the pharmaceutical industry's efforts to exercise social responsibility through various policies and practices. To insure that companies can make a reasonable profit, developing nations should honor pharmaceutical product patents and adhere to international intellectual property treaties, such as the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement. To insure the companies have a good business environment, developing nations should try to promote the rule of law, ethical business practices, stable currencies, reliable banking systems, free and open markets, democracy, and other conditions conducive to business. Overall, this paper advocates for reciprocity and cooperation between pharmaceutical companies and developing nations to address the problem of developing drugs for the developing world. In pursuing this cooperative approach, developing nations may use a variety of other techniques to encourage pharmaceutical companies to act responsibly, such as subsidizing pharmaceutical research, helping to design and implement research protocols, providing a guaranteed market, and

  12. [Chapter 2. Transitions in drug-discovery technology and drug-development in Japan (1980-2010)].

    PubMed

    Sakakibara, Noriko; Yoshioka, Ryuzo; Matsumoto, Kazuo

    2014-01-01

    In 1970s, the material patent system was introduced in Japan. Since then, many Japanese pharmaceutical companies have endeavored to create original in-house products. From 1980s, many of the innovative products were small molecular drugs and were developed using powerful medicinal-chemical technologies. Among them were antibiotics and effective remedies for the digestive organs and circulatory organs. During this period, Japanese companies were able to launch some blockbuster drugs. At the same time, the pharmaceutical market, which had grown rapidly for two decades, was beginning to level off. From the late 1990s, drug development was slowing down due to the lack of expertise in biotechnology such as genetic engineering. In response to the circumstances, the research and development on biotechnology-based drugs such as antibody drugs have become more dynamic and popular at companies than small molecule drugs. In this paper, the writers reviewed in detail the transitions in drug discovery and development between 1980 and 2010. PMID:25272636

  13. Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy

    PubMed Central

    Nau, Gerard J.; Ross, Ted M.; Evans, Thomas G.; Chakraborty, Krishnendu; Empey, Kerry M.; Flynn, JoAnne L.

    2014-01-01

    Pulmonary diseases and infections are among the top contributors to human morbidity and mortality worldwide, and despite the successful history of vaccines and antimicrobial therapeutics, infectious disease still presents a significant threat to human health. Effective vaccines are frequently unavailable in developing countries, and successful vaccines have yet to be developed for major global maladies, such as tuberculosis. Furthermore, antibiotic resistance poses a growing threat to human health. The “Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy” session of the 2013 Pittsburgh International Lung Conference highlighted several recent and current studies related to treatment and prevention of antibiotic-resistant bacterial infections, highly pathogenic influenza, respiratory syncytial virus, and tuberculosis. Research presented here focused on novel antimicrobial therapies, new vaccines that are either in development or currently in clinical trials, and the potential for immunomodulatory therapies. These studies are making important contributions to the areas of microbiology, virology, and immunology related to pulmonary diseases and infections and are paving the way for improvements in the efficacy of vaccines and antimicrobials. PMID:25148426

  14. Challenges and future in vaccines, drug development, and immunomodulatory therapy.

    PubMed

    Kling, Heather M; Nau, Gerard J; Ross, Ted M; Evans, Thomas G; Chakraborty, Krishnendu; Empey, Kerry M; Flynn, JoAnne L

    2014-08-01

    Pulmonary diseases and infections are among the top contributors to human morbidity and mortality worldwide, and despite the successful history of vaccines and antimicrobial therapeutics, infectious disease still presents a significant threat to human health. Effective vaccines are frequently unavailable in developing countries, and successful vaccines have yet to be developed for major global maladies, such as tuberculosis. Furthermore, antibiotic resistance poses a growing threat to human health. The "Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy" session of the 2013 Pittsburgh International Lung Conference highlighted several recent and current studies related to treatment and prevention of antibiotic-resistant bacterial infections, highly pathogenic influenza, respiratory syncytial virus, and tuberculosis. Research presented here focused on novel antimicrobial therapies, new vaccines that are either in development or currently in clinical trials, and the potential for immunomodulatory therapies. These studies are making important contributions to the areas of microbiology, virology, and immunology related to pulmonary diseases and infections and are paving the way for improvements in the efficacy of vaccines and antimicrobials. PMID:25148426

  15. Development of an essential drugs list for Bosnia and Herzegovina.

    PubMed Central

    Carballo, M; Serdarevic, D; Zulic, I

    1997-01-01

    Part of the impact of the war in ex-Yugoslavia and especially Bosnia and Herzegovina was to limit the supply of therapeutic drugs they had used before the war. The difficulties encountered made the health care system temporarily dependent on humanitarian assistance agencies which applied the concept of essential drugs; and, after initial difficulties, national health staff adapted to the need to prescribe from a very limited range of drugs. Meanwhile, national drug policy and procurement and prescribing practices were reviewed by working groups and a national List of Essential Drugs was drawn up by national experts with international support. This list has now been passed into legislation. PMID:9227382

  16. [Cytochrome P450 enzymes and microbial drug development - A review].

    PubMed

    Li, Zhong; Zhang, Wei; Li, Shengying

    2016-03-01

    Cytochrome P450 enzymes broadly exist in animals, plants and microorganisms. This superfamily of monooxygenases holds the greatest diversity of substrate structures and catalytic reaction types among all enzymes. P450 enzymes play important roles in natural product biosynthesis. In particular, P450 enzymes are capable of catalyzing the regio- and stereospecific oxidation of non-activated C-H bonds in complex organic compounds under mild conditions, which overrides many chemical catalysts. This advantage thus warrants their great potential in microbial drug development. In this review, we introduce a variety of P450 enzymes involved in natural product biosynthesis; provide a brief overview on protein engineering, biotransformation and practical application of P450 enzymes; and discuss the limits, challenges and prospects of industrial application of P450 enzymes. PMID:27382792

  17. An approach to the development of drugs for appetite disorders.

    PubMed

    Morley, J E

    1989-01-01

    This review covers some modern concepts in the development of drugs to treat appetite disorders. Specific attention is paid to the peripheral satiety system and the role of gastrointestinal peptides such as cholecystokinin in the pathogenesis of satiety. Alterations in neuropeptide Y and/or peptide YY are suggested to play a role in the pathophysiology of bulimia. Corticotropin-releasing factor is a putative candidate peptide involved in anorexia nervosa. The serotonin reuptake inhibitors fenfluramine and fluoxetene decrease weight in obese subjects. Endogenous opioids modulate the choice of palatable foods. Anorexia in the old appears to be related to a decrease in opioid feeding drive and an excess of the satiety action of cholecystokinin. Other agents involved in weight regulation include those which alter gastric emptying, increase thermogenesis, or modulate fat cell metabolism. It should be stressed that many neurotransmitters that modulate appetite also alter other behaviors, increasing their propensity to produce side effects. PMID:2573002

  18. Regenerative Medicine: Transforming the Drug Discovery and Development Paradigm

    PubMed Central

    Karathanasis, Sotirios K.

    2014-01-01

    Despite the explosion of knowledge in basic biological processes controlling tissue regeneration and the growing interest in repairing/replacing diseased tissues and organs through various approaches (e.g., small and large molecule therapeutics, stem cell injection, tissue engineering), the pharmaceutical industry (pharma) has been reluctant to fully adopt these technologies into the traditional drug discovery and research and development (R&D) process. In this article, I discuss knowledge-base gaps and other possible factors that may delay full incorporation of these innovations in pharma R&D. I hope that this discussion will illuminate key issues that currently limit synergistic relationships between pharma and academic institutions and may even stimulate initiation of such collaborative research. PMID:25085955

  19. Fabry Disease – Current Treatment and New Drug Development

    PubMed Central

    Motabar, Omid; Sidransky, Ellen; Goldin, Ehud; Zheng, Wei

    2010-01-01

    Fabry disease is a rare inherited lysosomal storage disorder caused by a partial or complete deficiency of α-galactosidase A (GLA), resulting in the storage of excess cellular glycosphingolipids. Enzyme replacement therapy is available for the treatment of Fabry disease, but it is a costly, intravenous treatment. Alternative therapeutic approaches, including small molecule chaperone therapy, are currently being explored. High throughput screening (HTS) technologies can be utilized to discover other small molecule compounds, including non-inhibitory chaperones, enzyme activators, molecules that reduce GLA substrate, and molecules that activate GLA gene promoters. This review outlines the current therapeutic approaches, emerging treatment strategies, and the process of drug discovery and development for Fabry disease. PMID:21127742

  20. Multi-regional clinical trials and global drug development.

    PubMed

    Shenoy, Premnath

    2016-01-01

    Drug development has been globalized, and multi-regional clinical trial (MRCT) for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such as USA, EU-Japan, and China have issued guidance documents in respect of MRCT's. Lack of harmonization in the design and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International conference on hormonisation (ICH) has initiated the process for having a harmonized guidance document on MRCT. This document is likely to be issued in early 2017. PMID:27141471

  1. [Effect of drug preparation combinations on intrauterine development].

    PubMed

    Bariliak, I R

    1977-01-01

    On the 13th day of pregnancy chloridine (50 mg/kg) or 6-mercaptopurine (60 mg/kg) was administered to rats. Thirty minutes before this the anomals received insulin (40 IU/kg), pentoxyl (100 mg/kg), ethonium (15 mg/kg), dimexide (5500 mg/kg), or magnesium sulphate (250 mg/kg). Oi the 20th day of preganancy the animals were sacrificed. While chloridine and 6-mercaptopurine caused abnormal development in all live embryos, their damaging (teratogenic and embryolethal) and action was sharply reduced when teratogens were used in combination with other drugs. The author feels that the normalizing effect of the study agents is due to the influence of these compounds on the functioning of the lysosome-segregational system. PMID:923784

  2. Multi-regional clinical trials and global drug development

    PubMed Central

    Shenoy, Premnath

    2016-01-01

    Drug development has been globalized, and multi-regional clinical trial (MRCT) for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such as USA, EU-Japan, and China have issued guidance documents in respect of MRCT's. Lack of harmonization in the design and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International conference on hormonisation (ICH) has initiated the process for having a harmonized guidance document on MRCT. This document is likely to be issued in early 2017. PMID:27141471

  3. A comparison of physiochemical property profiles of development and marketed oral drugs.

    PubMed

    Wenlock, Mark C; Austin, Rupert P; Barton, Patrick; Davis, Andrew M; Leeson, Paul D

    2003-03-27

    The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed. The aim is to identify the trends in physiochemical properties that favor a drug's successful passage through clinical development and on to the market. Two libraries were created, one of current development oral drugs and one of marketed oral drugs. Statistical analysis of the two showed that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean molecular weight of marketed oral drugs. It is also clear that the most lipophilic compounds are being discontinued from development. PMID:12646035

  4. Addiction and the potential for therapeutic drug development.

    PubMed

    Janssen, P A

    1994-01-01

    Therapeutic drug development in alcoholism could be targeted at any of the following: direct antagonism, substitution, treatment of abstinence, enhancement of aversion, modification of biodisposition, or craving. Ritanserin is a potent, centrally acting, highly selective 5-HT1C/2 antagonist which, in addition to having a sleep-regulating and anti-depression/anti-axiety effect, displays a unique pharmacological action in several animal paradigms of substance abuse which assess drug-craving. In fact, the latter pharmacological action was demonstrated after initial clinical observations suggested an effect of ritanserin in the chronic withdrawal phase after detoxification from alcohol in patients. The results of a recent double-blind, placebo-controlled, trial indicated that ritanserin did not induce aversion to drink alcohol in normal volunteers who display social drinking, but are not suffering alcohol dependence. Currently, a full clinical development program of ritanserin in cocaine and alcohol abuse is ongoing. Three major double-blind, placebo-controlled trials in alcohol dependent patients are in progress. Patients of different severity levels, ranging from mild to very severe, are studied. The dosages of ritanserin tested (2.5 mg, 5 mg, and 10 mg o.d.) are known to be well tolerated and safe. Two trials aim for relapse prevention--clinically defined in one, biochemically defined in the other-, and one trial has improved (reduced) drinking behaviour as a therapeutic goal. This program, which involves close to 900 alcohol-dependent patients, is well under way, and is still picking up momentum. PMID:8032167

  5. Development of an ion beam analyzing system for the KBSI heavy-ion accelerator.

    PubMed

    Bahng, Jungbae; Hong, Jonggi; Park, Jin Yong; Kim, Seong Jun; Ok, Jung-Woo; Choi, Seyong; Shin, Chang Seouk; Yoon, Jang-Hee; Won, Mi-Sook; Lee, Byoung-Seob; Kim, Eun-San

    2016-02-01

    The Korea Basic Science Institute (KBSI) has been developing a heavy ion accelerator system to accelerate high current, multi-charge state ions produced by a 28 GHz superconducting electron cyclotron ion source. A beam analyzing system as a part of the low energy beam transport apparatus was developed to select charged particles with desirable charge states from the ion beams. The desired species of ion, which is generated and extracted from the ECR ion source including various ion particles, can be selected by 90° dipole electromagnet. Due to the non-symmetrical structure in the coil as well as the non-linear permeability of the yoke material coil, a three dimensional analysis was carried out to confirm the design parameters. In this paper, we present the experimental results obtained as result of an analysis of KBSI accelerator. The effectiveness of beam selection was confirmed during the test of the analyzing system by injecting an ion beam from an ECR ion source. PMID:26932105

  6. Development of an ion beam analyzing system for the KBSI heavy-ion accelerator

    NASA Astrophysics Data System (ADS)

    Bahng, Jungbae; Hong, Jonggi; Park, Jin Yong; Kim, Seong Jun; Ok, Jung-Woo; Choi, Seyong; Shin, Chang Seouk; Yoon, Jang-Hee; Won, Mi-Sook; Lee, Byoung-Seob; Kim, Eun-San

    2016-02-01

    The Korea Basic Science Institute (KBSI) has been developing a heavy ion accelerator system to accelerate high current, multi-charge state ions produced by a 28 GHz superconducting electron cyclotron ion source. A beam analyzing system as a part of the low energy beam transport apparatus was developed to select charged particles with desirable charge states from the ion beams. The desired species of ion, which is generated and extracted from the ECR ion source including various ion particles, can be selected by 90° dipole electromagnet. Due to the non-symmetrical structure in the coil as well as the non-linear permeability of the yoke material coil, a three dimensional analysis was carried out to confirm the design parameters. In this paper, we present the experimental results obtained as result of an analysis of KBSI accelerator. The effectiveness of beam selection was confirmed during the test of the analyzing system by injecting an ion beam from an ECR ion source.

  7. Update on the development of externally powered dielectric-loaded accelerating structures.

    SciTech Connect

    Jing, C.; Gai, W.; Konecny, R.; Power, J. G.; Liu, W.; Kanareykin, A.; Gold, S.; Kinkead, A. K.; High Energy Physics; EuclidTechlabs,; Naval Research Lab.; Icarus Research

    2009-01-01

    We report on recent progress in a program to develop an RF-driven Dielectric-Loaded Accelerating (DLA) structure, capable of supporting high gradient acceleration. Previous high power tests revealed that the earlier DLA structures suffered from multipactor and arcing at the dielectric joint. A few new DLA structures have been designed to alleviate this limitation including the coaxial coupler based DLA structure and the clamped DLA structure. These structures were recently fabricated and high power tested at the NRL X-band Magnicon facility. Results show the multipactor can be reduced by the TiN coating on the dielectric surface. Gradient of 15 MV/m has also been tested without dielectric breakdown in the test of the clamped DLA structure. Detailed results are reported, and future plans discussed.

  8. Testing Done for Lorentz Force Accelerators and Electrodeless Propulsion Technology Development

    NASA Technical Reports Server (NTRS)

    Pencil, Eric J.; Gilland, James H.; Arrington, Lynn A.; Kamhawi, Hani

    2004-01-01

    The NASA Glenn Research Center is developing Lorentz force accelerators and electrodeless plasma propulsion for a wide variety of space applications. These applications range from precision control of formation-flying spacecraft to primary propulsion for very high power interplanetary spacecraft. The specific thruster technologies being addressed are pulsed plasma thrusters, magnetoplasmadynamic thrusters, and helicon-electron cyclotron resonance acceleration thrusters. The pulsed plasma thruster mounted on the Earth Observing-1 spacecraft was operated successfully in orbit in 2002. The two-axis thruster system is fully incorporated in the attitude determination and control system and is being used to automatically counteract disturbances in the pitch axis of the spacecraft. Recent on-orbit operations have focused on extended operations to add flight operation time to the total accumulated thruster life. The results of the experiments pave the way for electric propulsion applications on future Earth-imaging satellites.

  9. Update on the Development of Externally Powered Dielectric-Loaded Accelerating Structures

    SciTech Connect

    Jing, C.; Kanareykin, A.; Gai, W.; Konecny, R.; Power, J. G.; Liu, W.; Gold, S. H.; Kinkead, A. K.

    2009-01-22

    We report on recent progress in a program to develop an RF-driven Dielectric-Loaded Accelerating (DLA) structure, capable of supporting high gradient acceleration. Previous high power tests revealed that the earlier DLA structures suffered from multipactor and arcing at the dielectric joint. A few new DLA structures have been designed to alleviate this limitation including the coaxial coupler based DLA structure and the clamped DLA structure. These structures were recently fabricated and high power tested at the NRL X-band Magnicon facility. Results show the multipactor can be reduced by the TiN coating on the dielectric surface. Gradient of 15 MV/m has also been tested without dielectric breakdown in the test of the clamped DLA structure. Detailed results are reported, and future plans discussed.

  10. Development of Wind-and-React Bi-2212 Accelerator Magnet Technology

    SciTech Connect

    Godeke, A.; Cheng, D.; Dietderich, D. R.; English, C. D.; Felice, H.; Hannaford, C. R.; Prestemon, S. O.; Sabbi, G.; Scanlan, R. M.; Hikichi, Y.; Nishioka, J.; Hasegawa, T.

    2007-08-28

    We report on the progress in our R&D program, targeted to develop the technology for the application of Bi2Sr2CaCu2Ox (Bi-2212) in accelerator magnets. The program uses subscale coils, wound from insulated cables, to study suitable materials, heat treatment homogeneity, stability, and effects of magnetic field and thermal and electro-magnetic loads. We have addressed material and reaction related issues and report on the fabrication, heat treatment, and analysis of subscale Bi-2212 coils. Such coils can carry a current on the order of 5000 A and generate, in various support structures, magnetic fields from 2.6 to 9.9 T. Successful coils are therefore targeted towards a hybrid Nb3Sn-HTS magnet which will demonstrate the feasibility of Bi-2212 for accelerator magnets, and open a new magnetic field realm, beyond what is achievable with Nb3Sn.

  11. Recent Progress in the Development of a Circular Ion Induction Accelerator for Space Charge Dominated Beams

    NASA Astrophysics Data System (ADS)

    Ahle, L.; Sangster, T. C.; Autrey, D.; Barnard, J.; Craig, G.; Friedman, A.; Grote, D. P.; Halaxa, E.; Hanks, R. L.; Hernandez, M.; Kirbie, H. C.; Logan, B. G.; Lund, S. M.; Mant, G.; Molvik, A.; Sharp, W.; Berners, D.; Eylon, S.; Judd, D. L.; Reginato, L.; Debeling, A.; Fritz, W.

    1998-11-01

    The Heavy Ion Fusion Group at Lawrence Livermore National Laboratory has been developing the world's first ion induction accelerator. This machine has recently been extended to 90 degress, or 10 half-lattice periods(HLP) with full beam transport. As part of this extension, two new diagnostic systems have been fully enabled, the Capacitive Beam Probes(C-probes) and the Gated Beam Imager(GBI). The C-probes measure the charge centroid of the beam in each HLP and the GBI measures emittance in both transverse planes. Output from both diagnostics will be presented. In addition, induction cores have been installed on five of the HLP's, in anticipation of the first attempts at acceleration. The status of these attempts will also be discussed.

  12. Development of an S-band accelerating structure with quasi-symmetric single-feed racetrack couplers

    NASA Astrophysics Data System (ADS)

    Heo, Hoon; Joo, Young-Do; Park, Yong-Jung; Kang, Heung-Sik; Lee, Heung-Soo; Oh, Kyoung-Min; Seo, Hyung-Seok; Noh, Sung-Ju

    2015-03-01

    We developed an S-band traveling-wave accelerating structure for the Pohang Accelerator Laboratory's X-ray free-electron laser (PAL-XFEL), and we fabricated and tested a full-scale prototype. In order to reduce the field asymmetry inside the coupler cavity, we used the SUPERFISH code and the CST MWS electromagnetic field solvers to design the constant-gradient traveling-wave accelerator to use quasi-symmetric single-feed racetrack couplers. The RF measurement results indicate that the accelerating gradient of the prototype structure is as high as 27 MV/m for an input RF power of 65 MW.

  13. 78 FR 32667 - Draft Guidance for Industry on Rheumatoid Arthritis: Developing Drug Products for Treatment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-31

    ...The Food and Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled ``Rheumatoid Arthritis: Developing Drug Products for Treatment.'' This guidance outlines FDA's current thinking on the principles of clinical development relevant to dose-selection and assessment of efficacy and safety to support the approval of drug products for the treatment of......

  14. 78 FR 66744 - Draft Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-06

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Pulmonary Tuberculosis... industry entitled ``Pulmonary Tuberculosis: Developing Drugs for Treatment.'' The purpose of the draft... tuberculosis. This guidance applies to the development of a single investigational drug as well as...

  15. 78 FR 40485 - Lung Cancer Patient-Focused Drug Development; Extension of Comment Period

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-05

    ... lung cancer patient-focused drug development. In the Federal Register of June 5, 2013 (78 FR 33581... In the Federal Register of June 5, 2013 (78 FR 33581), FDA announced an opportunity for public... HUMAN SERVICES Food and Drug Administration Lung Cancer Patient-Focused Drug Development; Extension...

  16. 77 FR 69634 - International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-20

    .... In the Federal Register of June 29, 2011 (76 FR 38187), FDA published a notice announcing the... Development and Manufacture of Drug Substances; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled ``Q11 Development and Manufacture of Drug Substances.'' The guidance was prepared under...

  17. Development of polymer-polysaccharide hydrogels for controlling drug delivery

    NASA Astrophysics Data System (ADS)

    Baldwin, Aaron David

    The use of polymers as biomaterials has evolved over the past several decades, encompassing an expanding synthetic toolbox and many bio-mimetic approaches. Both synthetic and natural polymers have been used as components for biomaterials as their unique chemical structures can provide specific functions for desired applications. Of these materials, heparin, a highly sulfated naturally occurring polysaccharide, has been investigated extensively as a core component in drug delivery platforms and tissue engineering. The goal of this work was to further explore the use of heparin via conjugation with synthetic polymers for applications in drug delivery. We begin by investigating low molecular weight heparin (LMWH), a depolymerized heparin that is used medicinally in the prevention of thrombosis by subcutaneous injection or intravenous drip. Certain disease states or disorders require frequent administration with invasive delivery modalities leading to compliance issues for individuals on prolonged therapeutic courses. To address these issues, a long-term delivery method was developed for LMWH via subcutaneous injection of in situ hydrogelators. This therapy was accomplished by chemical modification of LMWH with maleimide functionality so that it may be crosslinked into continuous hydrogel networks with four-arm thiolated polyethylene glycol (PEG-SH). These hydrogels degrade via hydrolysis over a period of weeks and release bioactive LMWH with first-order kinetics as determined by in vitro and in vivo models, thus indicating the possibility of an alternative means of heparin delivery over current accepted methodologies. Evaluation of the maleimide-thiol chemistries applied in the LMWH hydrogels revealed reversibility for some conjugates under reducing conditions. Addition chemistries, such as maleimide-thiol reactions, are widely employed in biological conjugates and are generally accepted as stable. Here we show that the resulting succinimide thioether formed by the

  18. Increasing Spontaneous Retinal Activity before Eye Opening Accelerates the Development of Geniculate Receptive Fields

    PubMed Central

    Davis, Zachary W.; Chapman, Barbara

    2015-01-01

    Visually evoked activity is necessary for the normal development of the visual system. However, little is known about the capacity for patterned spontaneous activity to drive the maturation of receptive fields before visual experience. Retinal waves provide instructive retinotopic information for the anatomical organization of the visual thalamus. To determine whether retinal waves also drive the maturation of functional responses, we increased the frequency of retinal waves pharmacologically in the ferret (Mustela putorius furo) during a period of retinogeniculate development before eye opening. The development of geniculate receptive fields after receiving these increased neural activities was measured using single-unit electrophysiology. We found that increased retinal waves accelerate the developmental reduction of geniculate receptive field sizes. This reduction is due to a decrease in receptive field center size rather than an increase in inhibitory surround strength. This work reveals an instructive role for patterned spontaneous activity in guiding the functional development of neural circuits. SIGNIFICANCE STATEMENT Patterned spontaneous neural activity that occurs during development is known to be necessary for the proper formation of neural circuits. However, it is unknown whether the spontaneous activity alone is sufficient to drive the maturation of the functional properties of neurons. Our work demonstrates for the first time an acceleration in the maturation of neural function as a consequence of driving patterned spontaneous activity during development. This work has implications for our understanding of how neural circuits can be modified actively to improve function prematurely or to recover from injury with guided interventions of patterned neural activity. PMID:26511250

  19. Recent developments in rf superconductivity for high-brightness and high-gradient ion beam accelerators

    SciTech Connect

    Delayen, J.R.; Bohn, C.L.; Kennedy, W.L.; Nichols, G.L.; Roche, C.T.; Sagalovsky, L.

    1992-01-01

    Recent progress in on-going development program leading to the design of superconducting continuous-wave (cw) linear accelerators for high-brightness ion beams is reviewed. A new spoke-resonator geometry incorporating a half-wavelength resonant line was fabricated and tested. This geometry serves as the basis for the constituent cavities of a superconducting section being designed for high-current testing with a deuterium beam. Considerable progress has been made in the design of this section. A multi-phased program leading to the development of a superconducting radio-frequency quadrupole (SCRFQ) has been initiated. Design considerations and test results from the various activities are presented.

  20. Recent developments in rf superconductivity for high-brightness and high-gradient ion beam accelerators

    SciTech Connect

    Delayen, J.R.; Bohn, C.L.; Kennedy, W.L.; Nichols, G.L.; Roche, C.T.; Sagalovsky, L.

    1992-02-01

    Recent progress in on-going development program leading to the design of superconducting continuous-wave (cw) linear accelerators for high-brightness ion beams is reviewed. A new spoke-resonator geometry incorporating a half-wavelength resonant line was fabricated and tested. This geometry serves as the basis for the constituent cavities of a superconducting section being designed for high-current testing with a deuterium beam. Considerable progress has been made in the design of this section. A multi-phased program leading to the development of a superconducting radio-frequency quadrupole (SCRFQ) has been initiated. Design considerations and test results from the various activities are presented.

  1. Food and Drug Administration process for development and approval of drugs and radiopharmaceuticals: treatments in urologic oncology.

    PubMed

    Ning, Yang-Min; Maher, V Ellen

    2015-03-01

    Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA's role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years. PMID:25613202

  2. Sleep-wake mechanisms and drug discovery: sleep EEG as a tool for the development of CNS-acting drugs

    PubMed Central

    Staner, Luc

    2002-01-01

    Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT2A/C receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure. PMID:22034388

  3. Proteomics and biomarkers in clinical trials for drug development.

    PubMed

    Lee, Jung-min; Han, Jasmine J; Altwerger, Gary; Kohn, Elise C

    2011-11-18

    Proteomics allows characterization of protein structure and function, protein-protein interactions, and peptide modifications. It has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new therapeutic targets and possible indicators of response to and duration of therapy. The discovery, verification, and validation of novel biomarkers are critical in streamlining clinical development of targeted compounds, and directing rational treatments for patients whose tumors are dependent upon select signaling pathways. Studies are now underway in many diseases to examine the immune or inflammatory proteome, vascular proteome, cancer or disease proteome, and other subsets of the specific pathology microenvironment. Successful assay verification and biological validation of such biomarkers will speed development of potential agents to targetable dominant pathways and lead to selection of individuals most likely to benefit. Reconsideration of analytical and clinical trials methods for acquisition, examination, and translation of proteomics data must occur before we march further into future of drug development. PMID:21570499

  4. Education and Skills for Development in South Africa: Reflections on the Accelerated and Shared Growth Initiative for South Africa

    ERIC Educational Resources Information Center

    McGrath, S.; Akoojee, Salim

    2007-01-01

    In July 2005, President Mbeki announced the launch of the Accelerated and Shared Growth Initiative for South Africa (AsgiSA), a new development strategy designed to help the South African state meet the ANC's 2004 election pledges, namely: (1) halve unemployment; (2) halve poverty; (3) accelerate employment equity; and (4) improve broad-based…

  5. Developing a Molecular Roadmap of Drug-Food Interactions

    PubMed Central

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni; Kouskoumvekaki, Irene

    2015-01-01

    Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map. PMID:25668218

  6. Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

    PubMed Central

    Salvi, Vaibhav; Karnad, Dilip R; Panicker, Gopi Krishna; Kothari, Snehal

    2010-01-01

    Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a ‘thorough QT/QTc’ (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 PMID:19775279

  7. Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis

    PubMed Central

    Hoffmann, Georg F.

    2016-01-01

    Background Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations. Methods Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. Results Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). Conclusion Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation. PMID:27557111

  8. Development of hollow/porous floating beads of metoprolol for pulsatile drug delivery.

    PubMed

    Taranalli, Sangmesh S; Dandagi, Panchaxari M; Mastiholimath, Vinayak S

    2015-06-01

    The purpose of this work was to develop hollow calcium pectinate beads for floating pulsatile release of metoprolol tartrate intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads were prepared by simple process of acid-base reaction during ionotropic cross-linking using low methoxy pectin, xanthan gum, sodium carboxy methyl cellulose, guar gum, locust bean, gellan gum and calcium chloride as a cross-linking agent. Based on the preliminary studies optimized polymers were selected for formulation design with different polymers ratio concentrations. The obtained floating beads were studied for entrapment efficiency, buoyancy study, swelling index, surface morphology, in vitro release, stability studies and in vivo floating study. The floating beads obtained were porous, float up to 12-24 h. The radiological studies (X-rays) pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for hypertension. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. From the accelerated stability studies, it was observed that the formulations are quite stable. All formulations followed first-order release kinetics by diffusion mechanism. This approach suggested the use of hollow calcium pectinate microparticles as promising floating pulsatile drug delivery system for site- and time-specific release of drugs acting as per chronotherapy of diseases. PMID:24744159

  9. Stable isotope-resolved metabolomics and applications for drug development

    PubMed Central

    Fan, Teresa W-M.; Lorkiewicz, Pawel; Sellers, Katherine; Moseley, Hunter N.B.; Higashi, Richard M.; Lane, Andrew N.

    2012-01-01

    Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality. PMID:22212615

  10. Reactive metabolites in early drug development: predictive in vitro tools.

    PubMed

    Pelkonen, Olavi; Pasanen, Markku; Tolonen, Ari; Koskinen, Mikko; Hakkola, Jukka; Abass, Khaled; Laine, Jaana; Hakkinen, Merja; Juvonen, Risto; Auriola, Seppo; Storvik, Markus; Huuskonen, Pasi; Rousu, Timo; Rahikkala, Maiju

    2015-01-01

    Drug metabolism can result in the formation of highly reactive metabolites that are known to play a role in toxicity resulting in a significant proportion of attrition during drug development and clinical use. Thus, the earlier such reactivity was detected, the better. This review summarizes our multi-year project, together with pertinent literature, to examine a battery of in vitro tests capable of detecting the formation of reactive metabolites. Principal prerequisites for such tests were delineated: chemicals known/not known to cause tissue injury and produce reactive metabolites, activation system (mainly human-derived), small- and large-molecular targets (small-molecular trappers, peptides, proteins), analytical techniques (mass spectrometry), and cellular toxicity biomarkers. The current status of in vitro tools to detect reactive intermediates is the following: 1. Small-molecular trapping agents such glutathione or cyanide detect the production of reactive species with high sensitivity by proper MS technique. However, it seems that also putative "negatives" give rise to corresponding adducts. 2. Results from peptide and dG (DNA targeting) trapper studies are generally in line with those of small-molecular trappers, although also important differences exist. These two trapping platforms do not overlap. 3. It is anticipated that the in vitro adduct studies could be fully interpreted only in conjunction with toxicity biomarker (such as the Nrf2 pathway) information from whole cells or tissues. However, while there are tools to characterize the chemical liability and there are correlation between individual/integrated endpoints and toxicity, there are still severe gaps in understanding the mechanisms behind the link between reactive metabolites and adverse effects. PMID:25312212

  11. Accelerating vaccine development and deployment: report of a Royal Society satellite meeting

    PubMed Central

    Bregu, Migena; Draper, Simon J.; Hill, Adrian V. S.; Greenwood, Brian M.

    2011-01-01

    The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it. PMID:21893549

  12. Accelerating vaccine development and deployment: report of a Royal Society satellite meeting.

    PubMed

    Bregu, Migena; Draper, Simon J; Hill, Adrian V S; Greenwood, Brian M

    2011-10-12

    The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it. PMID:21893549

  13. Performance and Environmental Test Results of the High Voltage Hall Accelerator Engineering Development Unit

    NASA Technical Reports Server (NTRS)

    Kamhawi, Hani; Haag, Thomas; Huang, Wensheng; Shastry, Rohit; Pinero, Luis; Peterson, Todd; Mathers, Alex

    2012-01-01

    NASA Science Mission Directorate's In-Space Propulsion Technology Program is sponsoring the development of a 3.5 kW-class engineering development unit Hall thruster for implementation in NASA science and exploration missions. NASA Glenn and Aerojet are developing a high fidelity high voltage Hall accelerator that can achieve specific impulse magnitudes greater than 2,700 seconds and xenon throughput capability in excess of 300 kilograms. Performance, plume mappings, thermal characterization, and vibration tests of the high voltage Hall accelerator engineering development unit have been performed. Performance test results indicated that at 3.9 kW the thruster achieved a total thrust efficiency and specific impulse of 58%, and 2,700 sec, respectively. Thermal characterization tests indicated that the thruster component temperatures were within the prescribed material maximum operating temperature limits during full power thruster operation. Finally, thruster vibration tests indicated that the thruster survived the 3-axes qualification full-level random vibration test series. Pre and post-vibration test performance mappings indicated almost identical thruster performance. Finally, an update on the development progress of a power processing unit and a xenon feed system is provided.

  14. Developing a drug-like natural product library.

    PubMed

    Quinn, Ronald J; Carroll, Anthony R; Pham, Ngoc B; Baron, Paul; Palframan, Meredith E; Suraweera, Lekha; Pierens, Gregory K; Muresan, Sorel

    2008-03-01

    Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs. PMID:18257534

  15. WInd-and-react Bi-2212 coil development for accelerator magnets

    SciTech Connect

    Godeke, A.; Acosta, P.; Cheng, D.; Dietderich, D. R.; Mentink, M. G. T.; Prestemon, S. O.; Meinesz, M.; Hong, S.; Huang, Y.; Miao, H.; Parrell, J.; Sabbi, G.L.

    2009-10-13

    Sub-scale coils are being manufactured and tested at Lawrence Berkeley National Laboratory in order to develop wind-and-react Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub x} (Bi-2212) magnet technology for future graded accelerator magnet use. Previous Bi-2212 coils showed significant leakage of the conductors core constituents to the environment, which can occur during the partial melt reaction around 890 C in pure oxygen. The main origin of the observed leakage is intrinsic leakage of the wires, and the issue is therefore being addressed at the wire manufacturing level. We report on further compatibility studies, and the performance of new sub-scale coils that were manufactured using improved conductors. These coils exhibit significantly reduced leakage, and carry currents that are about 70% of the witness wire critical current (I{sub c}). The coils demonstrate, for the first time, the feasibility of round wire Bi-2212 conductors for accelerator magnet technology use. Successful high temperature superconductor coil technology will enable the manufacture of graded accelerator magnets that can surpass the, already closely approached, intrinsic magnetic field limitations of Nb-based superconducting magnets.

  16. Accelerator production of tritium plant design and supporting engineering development and demonstration work

    SciTech Connect

    Lisowski, P.W.

    1997-11-01

    Tritium is an isotope of hydrogen with a half life of 12.3 years. Because it is essential for US thermonuclear weapons to function, tritium must be periodically replenished. Since K reactor at Savannah River Site stopped operating in 1988, tritium has been recycled from dismantled nuclear weapons. This process is possible only as long as many weapons are being retired. Maintaining the stockpile at the level called for in the present Strategic Arms Reduction Treaty (START-I) will require the Department of Energy to have an operational tritium production capability in the 2005--2007 time frame. To make the required amount of tritium using an accelerator based system (APT), neutrons will be produced through high energy proton reactions with tungsten and lead. Those neutrons will be moderated and captured in {sup 3}He to make tritium. The APT plant design will use a 1,700 MeV linear accelerator operated at 100 mA. In preparation for engineering design, starting in October 1997 and subsequent construction, a program of engineering development and demonstration is underway. That work includes assembly and testing of the first 20 MeV of the low energy plant linac at 100 mA, high-energy linac accelerating structure prototyping, radiofrequency power system improvements, neutronic efficiency measurements, and materials qualifications.

  17. Vibration-Based Method Developed to Detect Cracks in Rotors During Acceleration Through Resonance

    NASA Technical Reports Server (NTRS)

    Sawicki, Jerzy T.; Baaklini, George Y.; Gyekenyesi, Andrew L.

    2004-01-01

    In recent years, there has been an increasing interest in developing rotating machinery shaft crack-detection methodologies and online techniques. Shaft crack problems present a significant safety and loss hazard in nearly every application of modern turbomachinery. In many cases, the rotors of modern machines are rapidly accelerated from rest to operating speed, to reduce the excessive vibrations at the critical speeds. The vibration monitoring during startup or shutdown has been receiving growing attention (ref. 1), especially for machines such as aircraft engines, which are subjected to frequent starts and stops, as well as high speeds and acceleration rates. It has been recognized that the presence of angular acceleration strongly affects the rotor's maximum response to unbalance and the speed at which it occurs. Unfortunately, conventional nondestructive evaluation (NDE) methods have unacceptable limits in terms of their application for online crack detection. Some of these techniques are time consuming and inconvenient for turbomachinery service testing. Almost all of these techniques require that the vicinity of the damage be known in advance, and they can provide only local information, with no indication of the structural strength at a component or system level. In addition, the effectiveness of these experimental techniques is affected by the high measurement noise levels existing in complex turbomachine structures. Therefore, the use of vibration monitoring along with vibration analysis has been receiving increasing attention.

  18. Advanced laser particle accelerator development at LANL: from fast ignition to radiation oncology

    SciTech Connect

    Flippo, Kirk A; Gaillard, Sandrine A; Offermann, D T; Cobble, J A; Schmitt, M J; Gautier, D C; Kwan, T J T; Montgomery, D S; Kluge, Thomas; Bussmann, Micheal; Bartal, T; Beg, F N; Gall, B; Geissel, M; Korgan, G; Kovaleski, S; Lockard, T; Malekos, S; Schollmeier, M; Sentoku, Y; Cowan, T E

    2010-01-01

    Laser-plasma accelerated ion and electron beam sources are an emerging field with vast prospects, and promise many superior applications in a variety of fields such as hadron cancer therapy, compact radioisotope generation, table-top nuclear physics, laboratory astrophysics, nuclear forensics, waste transmutation, SN M detection, and inertial fusion energy. LANL is engaged in several projects seeking to develop compact high current and high energy ion and electron sources. We are especially interested in two specific applications: ion fast ignition/capsule perturbation and radiation oncology in conjunction with our partners at the ForschungsZentrum Dresden-Rossendorf (FZD). Laser-to-beam conversion efficiencies of over 10% are needed for practical applications, and we have already shown inherent etliciencies of >5% from flat foils, on Trident using only a 5th of the intensity and energy of the Nova Petawatt. With clever target designs, like structured curved cone targets, we have also been able to achieve major ion energy gains, leading to the highest energy laser-accelerated proton beams in the world. These new target designs promise to help usher in the next generation of particle sources realizing the potential of laser-accelerated beams.

  19. Development of High Gradient Laser Wakefield Accelerators Towards Nuclear Detection Applications at LBNL

    SciTech Connect

    Geddes, Cameron G. R.; Gonsalves, Anthony J.; Lin Chen; Cormier-Michel, Estelle; Matlis, Nicholas H.; Panasenko, Dmitriy; Plateau, Guillaume R.; Schroeder, Carl B.; Toth, Csaba; Bruhwiler, David L.; Cary, John R.; Esarey, Eric H.; Nakamura, Kei; Bakeman, Mike; Leemans, Wim P.

    2009-03-10

    Compact high-energy linacs are important to applications including monochromatic gamma sources for nuclear material security applications. Recent laser wakefield accelerator experiments at LBNL demonstrated narrow energy spread beams, now with energies of up to 1 GeV in 3 cm using a plasma channel at low density. This demonstrates the production of GeV beams from devices much smaller than conventional linacs, and confirms the anticipated scaling of laser driven accelerators to GeV energies. Stable performance at 0.5 GeV was demonstrated. Experiments and simulations are in progress to control injection of particles into the wake and hence to improve beam quality and stability. Using plasma density gradients to control injection, stable beams at 1 MeV over days of operation, and with an order of magnitude lower absolute momentum spread than previously observed, have been demonstrated. New experiments are post-accelerating the beams from controlled injection experiments to increase beam quality and stability. Thomson scattering from such beams is being developed to provide collimated multi-MeV monoenergetic gamma sources for security applications from compact devices. Such sources can reduce dose to target and increase accuracy for applications including photofission and nuclear resonance fluorescence.

  20. Development of high gradient laser wakefield accelerators towards nuclear detection applications at LBNL

    SciTech Connect

    Geddes, Cameron GR; Bruhwiler, David L.; Cary, John R.; Esarey, Eric H.; Gonsalves, Anthony J.; Lin, Chen; Cormier-Michel, Estelle; Matlis, Nicholas H.; Nakamura, Kei; Bakeman, Mike; Panasenko, Dmitriy; Plateau, Guillaume R.; Schroeder, Carl B.; Toth, Csaba; Leemans, Wim P.

    2008-09-08

    Compact high-energy linacs are important to applications including monochromatic gamma sources for nuclear material security applications. Recent laser wakefield accelerator experiments at LBNL demonstrated narrow energy spread beams, now with energies of up to 1 GeV in 3 cm using a plasma channel at low density. This demonstrates the production of GeV beams from devices much smaller than conventional linacs, and confirms the anticipated scaling of laser driven accelerators to GeV energies. Stable performance at 0.5 GeV was demonstrated. Experiments and simulations are in progress to control injection of particles into the wake and hence to improve beam quality and stability. Using plasma density gradients to control injection, stable beams at 1 MeV over days of operation, and with an order of magnitude lower absolute momentum spread than previously observed, have been demonstrated. New experiments are post-accelerating the beams from controlled injection experiments to increase beam quality and stability. Thomson scattering from such beams is being developed to provide collimated multi-MeV monoenergetic gamma sources for security applications from compact devices. Such sources can reduce dose to target and increase accuracy for applications including photofission and nuclear resonance fluorescence.