WorldWideScience

Sample records for drug development highlighted

  1. Research Highlights: Helping Adolescents Resist Drugs

    National Research Council Canada - National Science Library

    2000-01-01

    Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills...

  2. Highlights of the SSC Site Development Plan

    International Nuclear Information System (INIS)

    Sanford, J.R.

    1991-10-01

    This paper summarizes highlights of the Site Development Plan for the Superconducting Super Collider Laboratory. The Plan, sometimes called a Master Plan, was prepared by the architectural and engineering firm for the Laboratory: Parsons Brinckerhoff/Morrison Knudsen (PB/MK) working in association with CRSS. Their task was to interpret the SSC project needs in the context of the Ellis County, Texas site. The team effort was under the direction of Lewis May from CRSS, guided by Robert Sims from the SSC Laboratory. Conceptual drawings are presented in this report

  3. FY2015 ceramic fuels development annual highlights

    Energy Technology Data Exchange (ETDEWEB)

    Mcclellan, Kenneth James [Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

    2015-09-22

    Key challenges for the Advanced Fuels Campaign are the development of fuel technologies to enable major increases in fuel performance (safety, reliability, power and burnup) beyond current technologies, and development of characterization methods and predictive fuel performance models to enable more efficient development and licensing of advanced fuels. Ceramic fuel development activities for fiscal year 2015 fell within the areas of 1) National and International Technical Integration, 2) Advanced Accident Tolerant Ceramic Fuel Development, 3) Advanced Techniques and Reference Materials Development, and 4) Fabrication of Enriched Ceramic Fuels. High uranium density fuels were the focus of the ceramic fuels efforts. Accomplishments for FY15 primarily reflect the prioritization of identification and assessment of new ceramic fuels for light water reactors which have enhanced accident tolerance while also maintaining or improving normal operation performance, and exploration of advanced post irradiation examination techniques which will support more efficient testing and qualification of new fuel systems.

  4. FY2016 Ceramic Fuels Development Annual Highlights

    Energy Technology Data Exchange (ETDEWEB)

    Mcclellan, Kenneth James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-01-24

    Key challenges for the Advanced Fuels Campaign are the development of fuel technologies to enable major increases in fuel performance (safety, reliability, power and burnup) beyond current technologies, and development of characterization methods and predictive fuel performance models to enable more efficient development and licensing of advanced fuels. Ceramic fuel development activities for fiscal year 2016 fell within the areas of 1) National and International Technical Integration, 2) Advanced Accident Tolerant Ceramic Fuel Development, 3) Advanced Techniques and Reference Materials Development, and 4) Fabrication of Enriched Ceramic Fuels. High uranium density fuels were the focus of the ceramic fuels efforts. Accomplishments for FY16 primarily reflect the prioritization of identification and assessment of new ceramic fuels for light water reactors which have enhanced accident tolerance while also maintaining or improving normal operation performance, and exploration of advanced post irradiation examination techniques which will support more efficient testing and qualification of new fuel systems.

  5. A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

    Science.gov (United States)

    Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, Mc.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

    2017-04-01

    There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

  6. Some highlights of research and development at AECL

    International Nuclear Information System (INIS)

    Langford, W.J.; Rae, H.K.

    1980-06-01

    The research and development programs of AECL have as their goal the strengthening of the knowledge and ability necessary to achieve national objectives in the field of nuclear energy. These objectives include a nuclear reactor system appropriate to Canada's industrial capabilities, now realized, and the extension of that system, through scientific and technological development, to serve the nation's needs for the forseeable future. The Company's programs are carefully integrated and focused to use the available funding to maximum advantage. The research facilities on which the program depends are among the best in the world, and support a full spectrum of research from fundamental nuclear physics to full-scale power reactor component irradiation and testing. In this report it has only been possible to high-light some important facets of the programs in each of the principal areas currently employing our energies. (auth)

  7. Developments in theranostic agents - some highlights of COST TD1004

    International Nuclear Information System (INIS)

    Mikolajczak, R.

    2015-01-01

    Full text of publication follows. The COST Action TD1004 Theragnostics Imaging and Therapy: an Action to Develop Novel Nano-sized Systems for Imaging-Guided Drug Delivery started in October 2011 within the Chemistry and Molecular Sciences and Technologies domain committee. The main objective of the Action is to increase the knowledge of imaging-guided drug delivery procedures and to apply this knowledge to the development of theranostic agents through an interdisciplinary approach that involves chemists, biologists, imaging and pharmaceutical technologists. This Action consists of five complementary Working Groups: (WG1) Imaging reporters for theranostic agents, (WG2) Nano-carriers for theranostic agents, (WG3) Preparation and selection of targeting vectors, (WG4) Theranostic agents responsive to endogenous and external stimuli, (WG5) Set-up of preclinical theranostic protocols. Investigations devoted to the design, synthesis, physico-chemical characterization and testing of imaging reporters tailored for theranostic applications are carried out. Interesting results have been obtained for the different imaging modalities addressing sensitivity (MRI), efficient tracers' labelling (PET, SPECT, radiotherapy), multiplex detection (Optical Imaging). Some results appear particularly worth to be noted: novel chelator system for Sc radionuclides and for MRI, macrocyclic ligands containing bis(phosphonate) side arm(s) yielding excellent systems for the coordination of Ga-68, applications of this and other PET isotopes (e.g. 64 Cu, 95 Nb) for 'theranostic' applications (with 90 Y, 177 Lu or 223,225 Ra, 225 Ac, 212 Pb, 213 Bi) using peptides, affibodies, antibodies as well as various nano-carriers. In the MRI field, where the sensitivity is the key-issue, it has been shown that innovative systems, based on Gd, may allow the in vivo visualization of cellular targeting and may serve as multimodal probes. The results from the research activities carried out in the

  8. Drug development in neuropsychopharmacology.

    Science.gov (United States)

    Fritze, Jürgen

    2008-03-01

    Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

  9. Metabonomics and drug development.

    Science.gov (United States)

    Ramana, Pranov; Adams, Erwin; Augustijns, Patrick; Van Schepdael, Ann

    2015-01-01

    Metabolites as an end product of metabolism possess a wealth of information about altered metabolic control and homeostasis that is dependent on numerous variables including age, sex, and environment. Studying significant changes in the metabolite patterns has been recognized as a tool to understand crucial aspects in drug development like drug efficacy and toxicity. The inclusion of metabonomics into the OMICS study platform brings us closer to define the phenotype and allows us to look at alternatives to improve the diagnosis of diseases. Advancements in the analytical strategies and statistical tools used to study metabonomics allow us to prevent drug failures at early stages of drug development and reduce financial losses during expensive phase II and III clinical trials. This chapter introduces metabonomics along with the instruments used in the study; in addition relevant examples of the usage of metabonomics in the drug development process are discussed along with an emphasis on future directions and the challenges it faces.

  10. Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

    Directory of Open Access Journals (Sweden)

    January Weiner 3rd

    2016-08-01

    Full Text Available In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

  11. OECD's Development Co-Operation Report highlights critical role of ...

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

    2018-02-14

    Feb 14, 2018 ... A global data divide persists today in developing countries. ... From a data perspective, this involves working together with ... This will entail emphasizing soft skills including leadership, change management, strategic thinking, ...

  12. Highlights of 50 years of nuclear fuel development

    International Nuclear Information System (INIS)

    Simnad, M.T.

    1989-01-01

    The development of nuclear fuels since the discovery of nuclear fission is briefly surveyed in this paper. The fabrication of the uranium fuel for the first nuclear pile, CP-1, is described. The research and development studies and fabrication of the different types of nuclear fuels for the variety of research and power reactors are reviewed. The important factors involved to achieve low fuel-cycle costs and reliable performance in the fuel elements are discussed in the historical context. 10 refs

  13. Highlights of 50 years of nuclear fuels developments

    International Nuclear Information System (INIS)

    Simnad, M.T.

    1989-01-01

    The development of nuclear fuels since the discovery of nuclear fission is briefly surveyed in this paper. The fabrication of the uranium fuel for the first nuclear pile, CP-1, is described. The research and development studies and fabrication of the different types of nuclear fuels for the variety of research and power reactors are reviewed. The important factors involved to achieve low fuel cycle costs and reliable performance in the fuel elements are discussed in the historical context

  14. Nuclear platform research and development - 2008-09 highlights

    International Nuclear Information System (INIS)

    Sadhankar, R.R.

    2009-08-01

    The Nuclear Platform R and D Program has lead responsibility for the maintenance and further development of the CANDU intellectual property covering the safety, licensing and design basis for nuclear facilities. The Nuclear Platform R and D Program is part of the Research and Technology Operation (RTO) unit of AECL and is managed through the Research and Development division, which has responsibility for maintaining and enhancing the knowledge and technology base. The RTO is also responsible for managing AECL's nuclear facilities and infrastructure (including laboratories and R and D facilities), the nuclear waste management program and other legacy liabilities (e.g., decommissioning) to demonstrate and grow shareholder value. The Nuclear Platform also provides the technology base from which new products and services can be developed to meet customer needs (including ACR and commercial products and services). (author)

  15. State Petroleum Enterprises in developing countries. [Conference highlights

    Energy Technology Data Exchange (ETDEWEB)

    Constantinou, C

    1978-10-01

    The growth in production and consumption of Petroleum in the developing countries has been accompanied by the establishment of State Petroleum Enterprises with the task of undertaking exploration, production, transportation, refining and marketing. Participants at a United Nations Conference exchanged experiences in the organization, management, and activities of State Petroleum Enterprises and reviewed co-operative arrangements among themselves. A central clearinghouse to aid technology transfer and training experience to less-developed countries was proposed. The conference also stressed that cooperation between state enterprises should be expanded in the future at both the bilateral and regional levels. It was felt that the conference provided an impressive demonstration of the growing role of State Petroleum Enterprises as effective instruments of national petroleum and economic development and emphasized the increasing role they must play in the world economy. 10 references. (SAC)

  16. Hydro-Quebec: research and development highlights 1998

    International Nuclear Information System (INIS)

    1999-01-01

    1998 confirmed once again that any planning in R and D must take into consideration unforeseen events. Actions are measured against their profitability, and R and D must contribute to increasing a company's competitive edge by providing it with new sources of revenue, by ensuring that it benefits from real savings and coming up with the best possible solutions to its technological problems. Hydro-Quebec's results attest to the fact that R and D is an investment that contributes to the utility's profitability. Whether trying to reduce maintenance costs through robot systems or cameras, improving injection methods for repairing dams, developing monitoring systems or new devices aimed at increasing the availability of equipment or reducing the environmental impact of its installations, the company's R and D projects have helped maintain its position as a world leader in the generation and transmission of hydroelectric power. The company is counting on technological innovation to boost the revenues of th e utility's business units. Examples include the work done to optimize the management of energy reserves, increase the network's load-flow capacity and flexibility, generate an electrical supply that meets international standards, and offer alternative distribution system solutions. Other projects involve improving turbine efficiency by modelling fluid flow, devising methods for forecasting natural inflows, analyzing losses in saturation transformers, developing the intelligent power system, and studying transient stability in real time, load frequency control, and customized power quality. Further projects are aimed at developing technologies and services that increase client loyalty and expand the client base such as research into energy management for low income clients, use of geothermal energy, new applications for electrotechnologies, electromagnetic compatibility, drive power and applications of lignin

  17. Hydro-Quebec: research and development highlights 1998

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-07-01

    1998 confirmed once again that any planning in R and D must take into consideration unforeseen events. Actions are measured against their profitability, and R and D must contribute to increasing a company's competitive edge by providing it with new sources of revenue, by ensuring that it benefits from real savings and coming up with the best possible solutions to its technological problems. Hydro-Quebec's results attest to the fact that R and D is an investment that contributes to the utility's profitability. Whether trying to reduce maintenance costs through robot systems or cameras, improving injection methods for repairing dams, developing monitoring systems or new devices aimed at increasing the availability of equipment or reducing the environmental impact of its installations, the company's R and D projects have helped maintain its position as a world leader in the generation and transmission of hydroelectric power. The company is counting on technological innovation to boost the revenues of the utility's business units. Examples include the work done to optimize the management of energy reserves, increase the network's load-flow capacity and flexibility, generate an electrical supply that meets international standards, and offer alternative distribution system solutions. Other projects involve improving turbine efficiency by modelling fluid flow, devising methods for forecasting natural inflows, analyzing losses in saturation transformers, developing the intelligent power system, and studying transient stability in real time, load frequency control, and customized power quality. Further projects are aimed at developing technologies and services that increase client loyalty and expand the client base such as research into energy management for low income clients, use of geothermal energy, new applications for electrotechnologies, electromagnetic compatibility, drive power and applications of lignin.

  18. Hanford Site Protective Barrier Development Program: Fiscal year 1990 highlights

    International Nuclear Information System (INIS)

    Cadwell, L.L.

    1991-09-01

    The Hanford Site Protective Barrier Development Program was jointly developed by Pacific Northwest Laboratory (PNL) and Westinghouse Hanford Company (WHC) to design and test an earthen cover system(s) that can be used to inhibit water infiltration; plant, animal, and human intrusion; and wind and water erosion. The joint PNL/WHC program was initiated in FY 1986. To date, research findings support the initial concepts of barrier designs for the Hanford Site. A fine-soil surface is planned to partition surface water into runoff and temporary storage. Transpiration by vegetation that grows in the fine-soil layer will return stored water to the atmosphere as will surface evaporation. A capillary break created by the interface of the fine-soil layer and coarser textured materials below will further limit the downward migration of surface water, making it available over a longer period of time for cycling to the atmosphere. Should water pass the interface, it will drain laterally through a coarse textured sand/gravel layer. Tested barrier designs appear to work adequately to prevent drainage under current and postulated wetter-climate (added precipitation) conditions. Wind and water erosion tasks are developing data to predict the extent of erosion on barrier surfaces. Data collected during the last year confirm the effectiveness of small burrowing animals in removing surface water. Water infiltrating through burrows of larger mammals was subsequently lost by natural processes. Natural analog and climate change studies are under way to provide credibility for modeling the performance of barrier designs over a long period of time and under shifts in climate. 10 refs., 30 figs

  19. Hanford Site Protective Barrier Development Program: Fiscal year 1990 highlights

    Energy Technology Data Exchange (ETDEWEB)

    Cadwell, L.L. (ed.)

    1991-09-01

    The Hanford Site Protective Barrier Development Program was jointly developed by Pacific Northwest Laboratory (PNL) and Westinghouse Hanford Company (WHC) to design and test an earthen cover system(s) that can be used to inhibit water infiltration; plant, animal, and human intrusion; and wind and water erosion. The joint PNL/WHC program was initiated in FY 1986. To date, research findings support the initial concepts of barrier designs for the Hanford Site. A fine-soil surface is planned to partition surface water into runoff and temporary storage. Transpiration by vegetation that grows in the fine-soil layer will return stored water to the atmosphere as will surface evaporation. A capillary break created by the interface of the fine-soil layer and coarser textured materials below will further limit the downward migration of surface water, making it available over a longer period of time for cycling to the atmosphere. Should water pass the interface, it will drain laterally through a coarse textured sand/gravel layer. Tested barrier designs appear to work adequately to prevent drainage under current and postulated wetter-climate (added precipitation) conditions. Wind and water erosion tasks are developing data to predict the extent of erosion on barrier surfaces. Data collected during the last year confirm the effectiveness of small burrowing animals in removing surface water. Water infiltrating through burrows of larger mammals was subsequently lost by natural processes. Natural analog and climate change studies are under way to provide credibility for modeling the performance of barrier designs over a long period of time and under shifts in climate. 10 refs., 30 figs.

  20. Highlights from Drug Use Among American High School Students 1975-1977.

    Science.gov (United States)

    Johnston, Lloyd D.; And Others

    The current prevalence of drug use among American high school seniors and the trends in use since 1975 are the two major topics treated. Also reported are prevailing attitudes and beliefs among seniors concerning various types of drug use. Eleven separate classes of drugs are distinguished: marihuana (including hashish), inhalants, hallucinogens,…

  1. Melatonergic drugs in development

    Directory of Open Access Journals (Sweden)

    Carocci A

    2014-09-01

    Full Text Available Alessia Carocci,1 Alessia Catalano,1 Maria Stefania Sinicropi2 1Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, Bari, 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy Abstract: 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. Keywords: MT1/MT2 ligands, circadian rhythms, melatonin 

  2. Melatonergic drugs in development.

    Science.gov (United States)

    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.

  3. Drug development for neurodevelopmental disorders

    DEFF Research Database (Denmark)

    Berry-Kravis, Elizabeth M; Lindemann, Lothar; Jønch, Aia E

    2018-01-01

    Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal ge......, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led...... to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has...... been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical...

  4. Drug Development Process

    Science.gov (United States)

    ... Preclinical Research Preclinical Research Drugs undergo laboratory and animal testing to answer basic questions about safety. More Information ... Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products

  5. Quantitative decisions in drug development

    CERN Document Server

    Chuang-Stein, Christy

    2017-01-01

    This book offers a high-level treatise of evidence-based decisions in drug development. Because of the inseparable relationship between designs and decisions, a good portion of this book is devoted to the design of clinical trials. The book begins with an overview of product development and regulatory approval pathways. It then discusses how to incorporate prior knowledge into study design and decision making at different stages of drug development. The latter include selecting appropriate metrics to formulate decisions criteria, determining go/no-go decisions for progressing a drug candidate to the next stage and predicting the effectiveness of a product. Lastly, it points out common mistakes made by drug developers under the current drug-development paradigm. The book offers useful insights to statisticians, clinicians, regulatory affairs managers and decision-makers in the pharmaceutical industry who have a basic understanding of the drug-development process and the clinical trials conducted to support dru...

  6. Quantifying The Food And Drug Administration's rulemaking delays highlights the need for transparency.

    Science.gov (United States)

    Hwang, Thomas J; Avorn, Jerry; Carpenter, Daniel; Kesselheim, Aaron S

    2014-02-01

    The Food and Drug Administration (FDA) frequently uses its rulemaking process to establish or modify the way it regulates drugs, medical devices, and other medical products. The federal agency's rulemaking is controversial because of its perceived complexity, lack of transparency, and lengthy duration. To shed light on the FDA's rulemaking process, we examined the evolution of significant rules that the agency published during 2000-12 for drugs, devices, and other medical products. We found that the rules' median time to finalization was 7.3 years, with the pre-rule phase and postreview deliberation within the FDA accounting for the majority of that time. Rules that involved mandatory cost-benefit analyses were associated with an additional delay of approximately two years. We also found that longer review times were significantly associated with a reduction in the stringency of final rules, compared to the originally proposed versions. We recommend improving FDA's rulemaking by allocating additional resources to increase efficiency and by embarking on initiatives to promote transparency by the FDA and other parts of the executive branch.

  7. Drug Development Pipeline

    Science.gov (United States)

    ... molecule that contains genetic instructions to make proteins. Delivery of CFTR-encoded mRNA would allow the lung cells to create normally functioning CFTR protein, regardless of an individual’s specific CFTR gene mutation. This drug is delivered via inhalation. Editas This program is ...

  8. Drug development and manufacturing

    Science.gov (United States)

    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.

  9. Phase II clinical development of new drugs

    CERN Document Server

    Ting, Naitee; Ho, Shuyen; Cappelleri, Joseph C

    2017-01-01

    This book focuses on how to appropriately plan and develop a Phase II program, and how to design Phase II clinical trials and analyze their data. It provides a comprehensive overview of the entire drug development process and highlights key questions that need to be addressed for the successful execution of Phase II, so as to increase its success in Phase III and for drug approval. Lastly it warns project team members of the common potential pitfalls and offers tips on how to avoid them.

  10. Metallomics in drug development

    DEFF Research Database (Denmark)

    Nguyen, Trinh Thi Nhu Tam; Ostergaard, Jesper; Stürup, Stefan

    2013-01-01

    in plasma. A detection limit of 41 ng/mL of platinum and a precision of 2.1 % (for 10 µg/mL of cisplatin standard) were obtained. Simultaneous measurements of phosphorous and platinum allows the simultaneous monitoring of the liposomes, liposome-encapsulated cisplatin, free cisplatin and cisplatin bound...... to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before...

  11. Nuclear imaging drug development tools

    International Nuclear Information System (INIS)

    Buchanan, L.; Jurek, P.; Redshaw, R.

    2007-01-01

    This article describes the development of nuclear imaging as an enabling technology in the pharmaceutical industry. Molecular imaging is maturing into an important tool with expanding applications from validating that a drug reaches the intended target through to market launch of a new drug. Molecular imaging includes anatomical imaging of organs or tissues, computerized tomography (CT), magnetic resonance imaging (MRI) and ultrasound.

  12. Obesity and Pediatric Drug Development.

    Science.gov (United States)

    Vaughns, Janelle D; Conklin, Laurie S; Long, Ying; Zheng, Panli; Faruque, Fahim; Green, Dionna J; van den Anker, John N; Burckart, Gilbert J

    2018-05-01

    There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population. © 2018, The American College of Clinical Pharmacology.

  13. Drug discovery and developments in developing countries ...

    African Journals Online (AJOL)

    the major burden being in developing countries. Many of ... The driving force for drug discovery and development by pharmaceutical firms ... world and particularly in the third world countries ..... GFHR (2000) Global Forum for Health Research:.

  14. BBG Highlights

    Data.gov (United States)

    Broadcasting Board of Governors — BBG Highlights is a monthly summary of the BBG's accomplishments and news and developments affecting the Agency's work. Now, for the first time, this monthly update...

  15. Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.

    Science.gov (United States)

    Dubé, Marie-Pierre; de Denus, Simon; Tardif, Jean-Claude

    2016-02-01

    Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.

  16. Research Ethics and Commercial Drug Development: When Integrity Threatens Profitability

    Directory of Open Access Journals (Sweden)

    Bélisle Pipon, Jean-Christophe

    2016-05-01

    Full Text Available This case, based on personal experiences and on those found in the literature, highlights the delicate tension faced by drug development companies having to balance research integrity and their profitability.

  17. Adolescent Brain Development and Drugs

    Science.gov (United States)

    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…

  18. Surrogacy in antiviral drug development

    Science.gov (United States)

    Shaunak, Sunil; Davies, Donald S

    2002-01-01

    The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therapeutic intervention have started to give way to the use of an increasing number of surrogate markers. Using a combination of these markers, it is now possible to measure and monitor the pathogen as well as the host's response. Nowhere is this better exemplified in virology than in the field of AIDS. We have utilized the advances in pathogenesis and new antiretroviral drug development to: develop a new class of drugs which block the entry of HIV-1 into cells.develop a new approach for effectively delivering these drugs to those tissues in which most viral replication takes place. Over the last 10 years, our work has progressed from concept to clinical trial. Our laboratory based evaluation of the new molecules developed as well as our clinical evaluation of their safety and efficacy have had to respond and adapt to the rapid changes taking place in AIDS research. This paper discusses the problems encountered and the lessons learnt. PMID:12100230

  19. Drug Development for Metastasis Prevention.

    Science.gov (United States)

    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.

  20. Towards a sustainable system of drug development

    NARCIS (Netherlands)

    Moors, Ellen H.M.; Cohen, Adam F.; Schellekens, Huub

    2014-01-01

    Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development

  1. Transcriptomic changes in the pre-implantation uterus highlight histotrophic nutrition of the developing marsupial embryo.

    Science.gov (United States)

    Whittington, Camilla M; O'Meally, Denis; Laird, Melanie K; Belov, Katherine; Thompson, Michael B; McAllan, Bronwyn M

    2018-02-05

    Early pregnancy is a critical time for successful reproduction; up to half of human pregnancies fail before the development of the definitive chorioallantoic placenta. Unlike the situation in eutherian mammals, marsupial pregnancy is characterised by a long pre-implantation period prior to the development of the short-lived placenta, making them ideal models for study of the uterine environment promoting embryonic survival pre-implantation. Here we present a transcriptomic study of pre-implantation marsupial pregnancy, and identify differentially expressed genes in the Sminthopsis crassicaudata uterus involved in metabolism and biosynthesis, transport, immunity, tissue remodelling, and uterine receptivity. Interestingly, almost one quarter of the top 50 genes that are differentially upregulated in early pregnancy are putatively involved in histotrophy, highlighting the importance of nutrient transport to the conceptus prior to the development of the placenta. This work furthers our understanding of the mechanisms underlying survival of pre-implantation embryos in the earliest live bearing ancestors of mammals.

  2. Prodrug Strategy in Drug Development

    Directory of Open Access Journals (Sweden)

    Hajnal Kelemen

    2016-09-01

    Full Text Available Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability, used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation. Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

  3. Hanford Site Permanent Isolation Surface Barrier Development Program: Fiscal year 1992 and 1993 highlights

    International Nuclear Information System (INIS)

    Cadwell, L.L.; Link, S.O.; Gee, G.W.

    1993-09-01

    The Hanford Site Permanent Isolation Surface Barrier Development Program was jointly developed by the Pacific Northwest Laboratory and Westinghouse Hanford Company to design and test an earthen cover system that can be used to inhibit water infiltration; plant, animal, and human intrusion; and wind and water erosion. Kaiser Engineers Hanford Company provided engineering design support for the program. Work on barrier design has been under way at Hanford for nearly 10 years. The comprehensive development of a long-term barrier, formerly the Hanford Site Protective Barrier Development Program, was initiated in FY 1986, and a general field-tested design is expected to be completed by FY 1998. Highlights of efforts in FY 1992 and FY 1993 included the resumption of field testing, the completion of the prototype barrier design, and the convening of an external peer review panel, which met twice with the barrier development team. The review panel provided helpful guidance on current and future barrier development activities, while commending the program for its significant technical contributions to innovative barrier technology development

  4. Developments in platinum anticancer drugs

    Science.gov (United States)

    Tylkowski, Bartosz; Jastrząb, Renata; Odani, Akira

    2018-01-01

    Platinum compounds represent one of the great success stories of metals in medicine. Following the unexpected discovery of the anticancer activity of cisplatin (Fig. 1) in 1965 by Prof. Rosenberg [1], a large number of its variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. Although cisplatin has been in use for over four decades, new and more effective platinum-based therapeutics are finally on the horizon. A wide introduction to anticancer studies is given by the authors of the previous chapter. This chapter aims at providing the readers with a comprehensive and in-depth understanding of recent developments of platinum anticancer drugs and to review the state of the art. The chapter is divided into two parts. In the first part we present a historical aspect of platinum and its complexes, while in the second part we give an overview of developments in the field of platinum anticancer agents.

  5. Transcriptomic analysis highlights epigenetic and transcriptional regulation during zygotic embryo development of Pinus pinaster.

    Science.gov (United States)

    de Vega-Bartol, José J; Simões, Marta; Lorenz, W Walter; Rodrigues, Andreia S; Alba, Rob; Dean, Jeffrey F D; Miguel, Célia M

    2013-08-30

    It is during embryogenesis that the plant body plan is established and the meristems responsible for all post-embryonic growth are specified. The molecular mechanisms governing conifer embryogenesis are still largely unknown. Their elucidation may contribute valuable information to clarify if the distinct features of embryo development in angiosperms and gymnosperms result from differential gene regulation. To address this issue, we have performed the first transcriptomic analysis of zygotic embryo development in a conifer species (Pinus pinaster) focusing our study in particular on regulatory genes playing important roles during plant embryo development, namely epigenetic regulators and transcription factors. Microarray analysis of P. pinaster zygotic embryogenesis was performed at five periods of embryo development from early developing to mature embryos. Our results show that most changes in transcript levels occurred in the first and the last embryo stage-to-stage transitions, namely early to pre-cotyledonary embryo and cotyledonary to mature embryo. An analysis of functional categories for genes that were differentially expressed through embryogenesis highlighted several epigenetic regulation mechanisms. While putative orthologs of transcripts associated with mechanisms that target transposable elements and repetitive sequences were strongly expressed in early embryogenesis, PRC2-mediated repression of genes seemed more relevant during late embryogenesis. On the other hand, functions related to sRNA pathways appeared differentially regulated across all stages of embryo development with a prevalence of miRNA functions in mid to late embryogenesis. Identification of putative transcription factor genes differentially regulated between consecutive embryo stages was strongly suggestive of the relevance of auxin responses and regulation of auxin carriers during early embryogenesis. Such responses could be involved in establishing embryo patterning. Later in

  6. Development and Optimization of controlled drug release ...

    African Journals Online (AJOL)

    The aim of this study is to develop and optimize an osmotically controlled drug delivery system of diclofenac sodium. Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active drugs. Drug delivery from these systems, to a large extent, is independent of the physiological factors ...

  7. Orphan drugs: trends and issues in drug development.

    Science.gov (United States)

    Rana, Proteesh; Chawla, Shalini

    2018-04-12

    Research in rare diseases has contributed substantially toward the current understanding in the pathophysiology of the common diseases. However, medical needs of patients with rare diseases have always been neglected by the society and pharmaceutical industries based on their small numbers and unprofitability. The Orphan Drug Act (1983) was the first serious attempt to address the unmet medical needs for patients with rare diseases and to provide impetus for the pharmaceutical industry to promote orphan drug development. The process of drug development for rare diseases is no different from common diseases but involves significant cost and infrastructure. Further, certain aspect of drug research may not be feasible for the rare diseases. The drug-approving authority must exercise their scientific judgment and ensure due flexibility while evaluating data at various stages of orphan drug development. The emergence of patent cliff combined with the government incentives led the pharmaceutical industry to realize the good commercial prospects in developing an orphan drug despite the small market size. Indeed, many drugs that were given orphan designation ended up being blockbusters. The orphan drug market is projected to reach $178 billion by 2020, and the prospects of research and development in rare diseases appears to be quite promising and rewarding.

  8. Highlights from panel discussion on key issues for future developments in microwave processing

    International Nuclear Information System (INIS)

    Gac, F.D.; Iskander, M.F.

    1992-01-01

    This paper reports on highlights from a panel discussion on Key Issues for Future Development in Microwave Processing. Although the panelists represented a mix of individuals from government, academia, and industry, only one aspect of industry was represented, namely microwave system manufacturers. For further panel discussions, it is recommended that the materials manufacturing (i.e., microwave user) sector also be represented. Three important points emerged from the panel discussion. The first deals with the credibility and usability of information, be it dielectric property measurements, experimental procedures, or microwave processing results. Second, a considerable communication and education gap continues to exist between the materials community and microwave engineers. Finally, a more realistic approach should be taken in identifying where microwave processing makes sense

  9. Hanford Site Long-term Surface Barrier Development Program: Fiscal year 1994 highlights

    International Nuclear Information System (INIS)

    Petersen, K.L.; Link, S.O.; Gee, G.W.

    1995-08-01

    The Hanford Site Surface Barrier Development Program was organized in 1985 to test the effectiveness of various barrier designs in minimizing the effects of water infiltration; plant, animal and human intrusion; and wind and water erosion on buried wastes, plus preventing or minimizing the emanation of noxious gases. A team of scientists from the Pacific Northwest Laboratory (PNL) and engineers from Westinghouse Hanford Company (WHC) direct the barrier development effort. ICF Kaiser Hanford Company, in conjunction with WHC and PNL, developed design drawings and construction specifications for a 5-acre prototype barrier. The highlight of efforts in FY 1994 was the construction of the prototype barrier. The prototype barrier was constructed on the Hanford Site at the 200 BP-1 Operable Unit of the 200 East Area. Construction was completed in August 1994 and monitoring instruments are being installed so experiments on the prototype barrier can begin in FY 1995. The purpose of the prototype barrier is to provide insights and experience with issues regarding barrier design, construction, and performance that have not been possible with individual tests and experiments conducted to date. Additional knowledge and experience was gained in FY 1994 on erosion control, physical stability, water infiltration control, model testing, Resource Conservation and Recovery Act (RCRA) comparisons, biointrusion control, long-term performance, and technology transfer

  10. Promoting positive youth development and highlighting reasons for living in Northwest Alaska through digital storytelling.

    Science.gov (United States)

    Wexler, Lisa; Gubrium, Aline; Griffin, Megan; DiFulvio, Gloria

    2013-07-01

    Using a positive youth development framework, this article describes how a 3-year digital storytelling project and the 566 digital stories produced from it in Northwest Alaska promote protective factors in the lives of Alaska Native youth and serve as digital "hope kits," a suicide prevention approach that emphasizes young people's reasons for living. Digital stories are short, participant-produced videos that combine photos, music, and voice. We present process data that indicate the ways that digital stories serve as a platform for youth to reflect on and represent their lives, important relationships and achievements. In so doing, youth use the digital storytelling process to identify and highlight encouraging aspects of their lives, and develop more certain and positive identity formations. These processes are correlated with positive youth health outcomes. In addition, the digital stories themselves serve as reminders of the young people's personal assets--their reasons for living--after the workshop ends. Young people in this project often showed their digital stories to those who were featured positively within as a way to strengthen these interpersonal relationships. Evaluation data from the project show that digital storytelling workshops and outputs are a promising positive youth development approach. The project and the qualitative data demonstrate the need for further studies focusing on outcomes related to suicide prevention.

  11. Status of SINQ, the only MW spallation neutron source-highlighting target development and industrial applications

    International Nuclear Information System (INIS)

    Wagner, Werner; Dai, Yong; Glasbrenner, Heike; Grosse, Mirco; Lehmann, Eberhard

    2006-01-01

    SINQ is a continuous spallation neutron source, driven by PSI's 590 MeV proton accelerator. Receiving a stable proton current of 1.3 mA, SINQ is the presently most powerful accelerator-driven facility worldwide. Besides the primary designation of SINQ to serve as user facility for neutron scattering and neutron imaging, PSI seeks to play a leading role in the development of the facility, focusing on spallation targets and materials research for high-dose radiation environments. Accompanying these activities, SINQ has established several projects serving a more general, profound development towards high-power spallation targets: the most prominent ones being SINQ Target Irradiation Program (STIP) and megawatt pilot experiment for a liquid metal target (MEGAPIE), complemented by LiSoR and VIMOS. Within the user program, SINQ is aspiring to attract an appropriate contingent of industrial applications. The paper highlights the potential for industrial applications by means of selected examples from strain mapping and neutron imaging

  12. Symposium Highlights

    International Nuclear Information System (INIS)

    Owen-Whitred, K.

    2015-01-01

    Overview/Highlights: To begin, I'd like to take a moment to highlight some of the novel elements of this Symposium as compared to those that have been held in the past. For the first time ever, this Symposium was organized around five concurrent sessions, covering over 300 papers and presentations. These sessions were complemented by an active series of exhibits put on by vendors, universities, ESARDA, INMM, and Member State Support Programmes. We also had live demonstrations throughout the week on everything from software to destructive analysis to instrumentation, which provided the participants the opportunity to see recent developments that are ready for implementation. I'm sure you all had a chance to observe - and, more importantly, interact with - the electronic Poster, or ePoster format used this past week. This technology was used here for the first time ever by the IAEA, and I'm sure was a first for many of us as well. The ePoster format allowed participants to interact with the subject matter, and the subject matter experts, in a dynamic, engaging way. In addition to the novel technology used here, I have to say that having the posters strategically embedded in the sessions on the same topic, by having each poster author introduce his or her topic to the assembled group in order to lure us to the poster area during the breaks, was also a novel and highly effective technique. A final highlight I'd like to touch on in terms of the Symposium organization is the diversity of participation. This chart shows the breakdown by geographical distribution for the Symposium, in terms of participants. There are no labels, so don't try to read any, I simply wanted to demonstrate that we had great representation in terms of both the Symposium participants in general and the session chairs more specifically-and on that note, I would just mention here that 59 Member States participated in the Symposium. But what I find especially interesting and

  13. Orphan drug: Development trends and strategies

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2010-01-01

    Full Text Available 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.

  14. NMR spectroscopy and drug development

    International Nuclear Information System (INIS)

    Craik, D.; Munro, S.

    1990-01-01

    The use of nuclear magnetic resonance (NMR) spectroscopy for structural and conformational studies on drug molecules, the three-dimensional investigation of proteins structure and their interactions with ligands are discussed. In-vivo NMR studies of the effects of drugs on metabolism in perfused organs and whole animals are also briefly presented. 5 refs., ills

  15. Pediatric Melanoma and Drug Development

    Directory of Open Access Journals (Sweden)

    Klaus Rose

    2018-03-01

    Full Text Available Importance—Pediatric melanoma occurs, albeit rarely. Should patients be treated by today’s medical standards, or be subjected to medically unnecessary clinical studies? Observations—We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in www.clinicaltrials.gov and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale. Regulatory authorities define children by chronological age, not physiologically. Newborns’ organs are immature but they develop and mature rapidly. Separate proof of efficacy in underage patients is justified formally/regulatorily but lacks medical sense. Children—especially post-puberty—and adults vis-a-vis medications are physiologically very similar. Two adolescent melanoma studies were terminated in 2016 because of waning recruitment, while five studies in pediatric melanoma and other solid tumors, triggered by European Union pediatric investigation plans, continue recruiting worldwide. Conclusions and Relevance—Regulatory-demanded pediatric melanoma studies are medically superfluous. Melanoma patients of all ages should be treated with effective combination treatment. Babies need special attention. Children need dose-finding and pharmacokinetic studies but adolescents metabolize and respond to drugs similarly to adults. Institutional Review Boards/ethics committees should suspend ongoing questionable pediatric melanoma studies and reject newly submitted questionable studies.

  16. Use of SPring-8 in drug development

    International Nuclear Information System (INIS)

    Nishijima, Kazumi

    2006-01-01

    Protein structure analysis consortium was established by 21 drug companies and has analyzed protein structures using the beam line BL32B2 of SPring-8 since September in 2002. Outline of the protein structure analysis consortium, contribution of SPring-8 to drug development, and the present status and future of use of SPring-8 are stated. For examples of structure analysis, the human nuclear enzyme (PARP-1) fragment complex crystal structure, human ISG20, human dipeptidine peptidase IV, human cMDH, chromatin binding human nuclear enzyme complex, change of structure of each step of tyrosine activation of bacteria tyrosine tRNA synthetase are described. Contribution of analysis of protein structure and functions to drug development, development process of new drug, drug screening using compounds database on the basis of the three dimensional structure of receptor active site, genome drug development, and the effects of a target drug on the market are explained. (S.Y.)

  17. Pharmacometrics in early clinical drug development

    NARCIS (Netherlands)

    Keizer, R.J.

    2010-01-01

    Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and to reduce attrition rates on the route from drug discovery to approval. This field of drug research, which builds heavily on

  18. Antimalarial Drug: From its Development to Deface.

    Science.gov (United States)

    Barik, Tapan Kumar

    2015-01-01

    Wiping out malaria is now the global concern as about three billion people are at risk of malaria infection globally. Despite of extensive research in the field of vaccine development for malaria, till now, no effective vaccine is available for use and hence only antimalarial drugs remain our best hope for both treatment and prevention of malaria. However, emergence and spread of drug resistance has been a major obstacle for the success of malaria elimination globally. This review will summarize the information related to antimalarial drugs, drug development strategies, drug delivery through nanoparticles, few current issues like adverse side effects of most antimalarial drugs, non availability of drugs in the market and use of fake/poor quality drugs that are hurdles to malaria control. As we don't have any other option in the present scenario, we have to take care of the existing tools and make them available to almost all malaria affected area.

  19. Positron emission tomography in drug development

    International Nuclear Information System (INIS)

    Rubin, R. H.; Fischman, A. J.

    1997-01-01

    There are four kinds of measurements that can be carried out with positron emission tomography (PET) that can contribute significantly to the process of drug development: pharmacodynamic measurement of tissue metabolism influenced by a given drug; precise measurements of tissue blood flow; tissue pharmacokinetics of a given drug following administration of a particular dose; and the temporal course of ligand-receptor interaction. One or more of these measurements can greatly improve the decision making involved in determining the appropriate dose of a drug, the clinical situations in which a drug might be useful, and the linkage of pharmacokinetics with pharmacodynamics, which is at the heart of effective drug development. The greater the potential of a particular compound as a therapeutic agent, the greater the potential for PET to contribute to the drug development process

  20. AEB highlights

    International Nuclear Information System (INIS)

    1975-01-01

    AEB HIGHLIGHTS is a half-yearly report reflecting the most important recent achievements of the various Research and Technical Divisions of the Atomic Energy Board. It appears alternately in English and Afrikaans [af

  1. AEB highlights

    International Nuclear Information System (INIS)

    1977-01-01

    AEB HIGHLIGHTS is a half yearly report reflecting the most important recent achievements of the various Research and Technical Divisions of the Atomic Energy Board. It appears alternately in English and Afrikaans [af

  2. Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development.

    Science.gov (United States)

    Wickström, Henrika; Hilgert, Ellen; Nyman, Johan O; Desai, Diti; Şen Karaman, Didem; de Beer, Thomas; Sandler, Niklas; Rosenholm, Jessica M

    2017-11-21

    Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

  3. Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles—A Platform for Drug Development

    Directory of Open Access Journals (Sweden)

    Henrika Wickström

    2017-11-01

    Full Text Available Mesoporous silica nanoparticles (MSNs have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV and poorly permeable (BCS class III, IV drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI surface functionalized MSNs, as well as drug-free and drug-loaded MSN–PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

  4. New Zealand’s Drug Development Industry

    Directory of Open Access Journals (Sweden)

    Christopher Carswell

    2013-09-01

    Full Text Available 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.

  5. Drug development for airway diseases: looking forward

    NARCIS (Netherlands)

    Holgate, Stephen; Agusti, Alvar; Strieter, Robert M.; Anderson, Gary P.; Fogel, Robert; Bel, Elisabeth; Martin, Thomas R.; Reiss, Theodore F.

    2015-01-01

    Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations

  6. Molecular science for drug development and biomedicine.

    Science.gov (United States)

    Zhong, Wei-Zhu; Zhou, Shu-Feng

    2014-11-04

    With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken place in molecular science, particularly in the areas associated with drug development and biomedicine, both experimental and theoretical. The current thematic issue was launched with the focus on the topic of "Molecular Science for Drug Development and Biomedicine", in hopes to further stimulate more useful techniques and findings from various approaches of molecular science for drug development and biomedicine.[...].

  7. Brookhaven highlights

    International Nuclear Information System (INIS)

    Rowe, M.S.; Belford, M.; Cohen, A.; Greenberg, D.; Seubert, L.

    1993-01-01

    This report highlights the research activities of Brookhaven National Laboratory during the period dating from October 1, 1992 through September 30, 1993. There are contributions to the report from different programs and departments within the laboratory. These include technology transfer, RHIC, Alternating Gradient Synchrotron, physics, biology, national synchrotron light source, applied science, medical science, advanced technology, chemistry, reactor physics, safety and environmental protection, instrumentation, and computing and communications

  8. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

    Science.gov (United States)

    Azam, Mohammad; Nardi, Valentina; Shakespeare, William C.; Metcalf, Chester A.; Bohacek, Regine S.; Wang, Yihan; Sundaramoorthi, Raji; Sliz, Piotr; Veach, Darren R.; Bornmann, William G.; Clarkson, Bayard; Dalgarno, David C.; Sawyer, Tomi K.; Daley, George Q.

    2006-01-01

    Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. PMID:16754879

  9. Development Impact Assessment Highlights Co-benefits of GHG Mitigation Actions

    Energy Technology Data Exchange (ETDEWEB)

    2016-06-01

    This EC-LEDS document describes the Development Impact Assessment (DIA) process that explores interactions between development goals and the low emission development strategies. DIA aims to support informed decision-making by considering how policies and programs intended to meet one goal may impact other development priorities. Enhancing Capacity for Low Emission Development Strategies (EC-LEDS) is a flagship U.S. government-led effort that assists countries in developing and implementing LEDS. The program enhances partner country efforts by providing targeting technical assistance and building a shared global knowledge base on LEDS. is a flagship U.S. government-led effort that assists countries in developing and implementing LEDS. The program enhances partner country efforts by providing targeting technical assistance and building a shared global knowledge base on LEDS.

  10. DEVELOPMENT AND REGISTRATION OF CHIRAL DRUGS

    NARCIS (Netherlands)

    WITTE, DT; ENSING, K; FRANKE, JP; DEZEEUW, RA

    1993-01-01

    In this review we describe the impact of chirality on drug development and registration in the United States, Japan and the European Community. Enantiomers may have differences in their pharmacological profiles, and, therefore, chiral drugs ask for special analytical and pharmacological attention

  11. Modeling and simulation for medical product development and evaluation : highlights from the FDA-C-Path-ISOP 2013 workshop

    NARCIS (Netherlands)

    Romero, Klaus; Sinha, Vikram; Allerheiligen, Sandra; Danhof, Meindert; Pinheiro, Jose; Kruhlak, Naomi; Wang, Yaning; Wang, Sue-Jane; Sauer, John-Michael; Marier, J. F.; Corrigan, Brian; Rogers, James; Heerspink, H. J. Lambers; Gumbo, Tawanda; Vis, Peter; Watkins, Paul; Morrison, Tina; Gillespie, William; Gordon, Mark Forrest; Stephenson, Diane; Hanna, Debra; Pfister, Marc; Lalonde, Richard; Colatsky, Thomas

    2014-01-01

    Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for

  12. Corporate sustainability and inclusive development: highlights from international business and management research

    NARCIS (Netherlands)

    Kourula, A.; Pisani, N.; Kolk, A.

    Sustainability has attracted increasing attention from business scholars as corporations have started to take more responsibility for their environmental, social, and development impacts. In this review, we focus on the latest sustainability-related research published in the international business

  13. Development and Evaluation of Chronotherapeutic Drug Delivery ...

    African Journals Online (AJOL)

    Conclusion: The developed system is capable of releasing the drug after a 4-h lag period. However ... concentration would be at its maximum level, ... spheronizer (Caleva MBS, UK)operating at .... capsules show that the color intensity of the.

  14. Use of biomarkers in ALS drug development and clinical trials.

    Science.gov (United States)

    Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert

    2015-05-14

    The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. A combined experimental and in silico characterization to highlight additional structural features and properties of a potentially new drug

    Science.gov (United States)

    Bastos, Isadora T. S.; Costa, Fanny N.; Silva, Tiago F.; Barreiro, Eliezer J.; Lima, Lídia M.; Braz, Delson; Lombardo, Giuseppe M.; Punzo, Francesco; Ferreira, Fabio F.; Barroso, Regina C.

    2017-10-01

    LASSBio-1755 is a new cycloalkyl-N-acylhydrazone parent compound designed for the development of derivatives with antinociceptive and anti-inflammatory activities. Although single crystal X-ray diffraction has been considered as the golden standard in structure determination, we successfully used X-ray powder diffraction data in the structural determination of new synthesized compounds, in order to overcome the bottle-neck due to the difficulties experienced in harvesting good quality single crystals of the compounds. We therefore unequivocally assigned the relative configuration (E) to the imine double bond and a s-cis conformation of the amide function of the N-acylhydrazone compound. These features are confirmed by a computational analysis performed on the basis of molecular dynamics calculations, which are extended not only to the structural characteristics but also to the analysis of the anisotropic atomic displacement parameters, a further information - missed in a typical powder diffraction analysis. The so inferred data were used to perform additional cycles of refinement and eventually generate a new cif file with additional physical information. Furthermore, crystal morphology prediction was performed, which is in agreement with the experimental images acquired by scanning electron microscopy, thus providing useful information on possible alternative paths for better crystallization strategies.

  16. Results at Mallik highlight progress in gas hydrate energy resource research and development

    Science.gov (United States)

    Collett, T.S.

    2005-01-01

    The recent studies that project the role of gas hydrates in the future energy resource management are reviewed. Researchers have long speculated that gas hydrates could eventually be a commercial resource for the future. A Joint Industry Project led by ChevronTexaco and the US Department of Energy is designed to characterize gas hydrates in the Gulf of Mexico. Countries including Japan, canada, and India have established large gas hydrate research and development projects, while China, Korea and Mexico are investigating the viability of forming government-sponsored gas hydrate research projects.

  17. Impact of biomarker development on drug safety assessment

    International Nuclear Information System (INIS)

    Marrer, Estelle; Dieterle, Frank

    2010-01-01

    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.

  18. Accessing external innovation in drug discovery and development.

    Science.gov (United States)

    Tufféry, Pierre

    2015-06-01

    A decline in the productivity of the pharmaceutical industry research and development (R&D) pipeline has highlighted the need to reconsider the classical strategies of drug discovery and development, which are based on internal resources, and to identify new means to improve the drug discovery process. Accepting that the combination of internal and external ideas can improve innovation, ways to access external innovation, that is, opening projects to external contributions, have recently been sought. In this review, the authors look at a number of external innovation opportunities. These include increased interactions with academia via academic centers of excellence/innovation centers, better communication on projects using crowdsourcing or social media and new models centered on external providers such as built-to-buy startups or virtual pharmaceutical companies. The buzz for accessing external innovation relies on the pharmaceutical industry's major challenge to improve R&D productivity, a conjuncture favorable to increase interactions with academia and new business models supporting access to external innovation. So far, access to external innovation has mostly been considered during early stages of drug development, and there is room for enhancement. First outcomes suggest that external innovation should become part of drug development in the long term. However, the balance between internal and external developments in drug discovery can vary largely depending on the company strategies.

  19. Development highlights of micro-nano technologies in the MENA region and pathways for initiatives to support and network

    NARCIS (Netherlands)

    Al-Rawashdeh, M.I.M.; Alfeeli, B.; Rawashdeh, A.M.; Hessel, V.

    2013-01-01

    Current developments in the field of micro-nano technologies in the Middle East and North Africa (MENA) region are highlighted. Firstly, the scientific outcome of micro-nano technologies from the MENA region is analyzed. Egypt and Saudi Arabia are the leading countries, with >50% of the total MENA

  20. Surgical virtual reality - highlights in developing a high performance surgical haptic device.

    Science.gov (United States)

    Custură-Crăciun, D; Cochior, D; Constantinoiu, S; Neagu, C

    2013-01-01

    Just like simulators are a standard in aviation and aerospace sciences, we expect for surgical simulators to soon become a standard in medical applications. These will correctly instruct future doctors in surgical techniques without there being a need for hands on patient instruction. Using virtual reality by digitally transposing surgical procedures changes surgery in are volutionary manner by offering possibilities for implementing new, much more efficient, learning methods, by allowing the practice of new surgical techniques and by improving surgeon abilities and skills. Perfecting haptic devices has opened the door to a series of opportunities in the fields of research,industry, nuclear science and medicine. Concepts purely theoretical at first, such as telerobotics, telepresence or telerepresentation,have become a practical reality as calculus techniques, telecommunications and haptic devices evolved,virtual reality taking a new leap. In the field of surgery barrier sand controversies still remain, regarding implementation and generalization of surgical virtual simulators. These obstacles remain connected to the high costs of this yet fully sufficiently developed technology, especially in the domain of haptic devices. Celsius.

  1. Counterfeit drugs and medical devices in developing countries

    Directory of Open Access Journals (Sweden)

    Glass BD

    2014-03-01

    Full Text Available Beverley D GlassSchool of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD, AustraliaAbstract: The World Health Organization has reported that counterfeit medicines potentially make up more than 50% of the global drug market, with a significant proportion of these fake products being encountered in developing countries. This occurrence is attributed to a lack of effective regulation and a weak enforcement capacity existing in these countries, with an increase in this trade resulting from the growing size and sophistication of drug counterfeiters. In addition, due to both cost and lack of availability of medicines, consumers in developing countries are more likely to seek out these inexpensive options. The World Health Organization is mindful of the impact of counterfeit drugs on consumer confidence in health care systems, health professionals, the supply chain, and genuine suppliers of medicines and medical devices. Antibiotics, antituberculosis drugs, and antimalarial and antiretroviral drugs are frequently targeted, with reports of 60% of the anti-infective drugs in Asia and Africa containing active pharmaceutical ingredients outside their pharmacopoeial limits. This has obvious public health implications of increasing drug resistance and negating all the efforts that have already gone into the provision of medicines to treat these life threatening conditions in the developing world. This review, while focusing on counterfeit medicines and medical devices in developing countries, will present information on their impact and how these issues can be addressed by regulation and control of the supply chain using technology appropriate to the developing world. The complexity of the problem will also be highlighted in terms of the definition of counterfeit and substandard medicines, including gray pharmaceuticals. Although this issue presents as a global public health problem, outcomes in developing countries where counterfeit

  2. 2013 Highlights

    International Nuclear Information System (INIS)

    2014-01-01

    The annual report gives a summary overview of key research and development activities at the Belgian Nuclear Research Centre SCK-CEN in 2013. The report discusses progress and main achievements in the following areas: reactor safety, radioactive waste and decommissioing, radiation protection, the BR2 reactor, nuclear fuel research, raduioactivity and the environment and medical applications with emphasis on dosimetry.

  3. 2014 Highlights

    International Nuclear Information System (INIS)

    2015-01-01

    The annual report gives a summary overview of key research and development activities at the Belgian Nuclear Research Centre SCK-CEN in 2014. The report discusses progress and main achievements in the following areas: reactor safety, radioactive waste and decommissioning, radiation protection, the BR2 reactor, nuclear fuel research, radioactivity and the environment and medical applications with emphasis on dosimetry.

  4. TRPV3 in Drug Development

    Directory of Open Access Journals (Sweden)

    Lisa M. Broad

    2016-09-01

    Full Text Available 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.

  5. Austrian highlights

    International Nuclear Information System (INIS)

    Jones, Simon

    2001-01-01

    An overview of recent development in the Austrian hydroelectric industry is presented, and details of the installed capacity, the Austrian government's power market reform package, and the promotion of small-scale hydroelectric power plants are given. The operation of Verbund - Austria's largest power generator and distributor - and the restructuring of the Verbund's main Austrian Hydro Power (AHP) generating group are discussed. The export of power, the joint venture of Verbund with CIR Energia in Italy to market power to commercial and industrial users, and the controversy surrounding the Freudenau run-of-the river plant which successfully tested a matrix turbine are reported

  6. Brookhaven highlights

    Energy Technology Data Exchange (ETDEWEB)

    Rowe, M.S.; Cohen, A.; Greenberg, D.; Seubert, L. (eds.)

    1992-01-01

    This publication provides a broad overview of the research programs and efforts being conducted, built, designed, and planned at Brookhaven National Laboratory. This work covers a broad range of scientific disciplines. Major facilities include the Alternating Gradient Synchrotron (AGS), with its newly completed booster, the National Synchrotron Light Source (NSLS), the High Flux Beam Reactor (HFBR), and the RHIC, which is under construction. Departments within the laboratory include the AGS department, accelerator development, physics, chemistry, biology, NSLS, medical, nuclear energy, and interdepartmental research efforts. Research ranges from the pure sciences, in nuclear physics and high energy physics as one example, to environmental work in applied science to study climatic effects, from efforts in biology which are a component of the human genome project to the study, production, and characterization of new materials. The paper provides an overview of the laboratory operations during 1992, including staffing, research, honors, funding, and general laboratory plans for the future.

  7. Brookhaven highlights

    International Nuclear Information System (INIS)

    Rowe, M.S.; Cohen, A.; Greenberg, D.; Seubert, L.

    1992-01-01

    This publication provides a broad overview of the research programs and efforts being conducted, built, designed, and planned at Brookhaven National Laboratory. This work covers a broad range of scientific disciplines. Major facilities include the Alternating Gradient Synchrotron (AGS), with its newly completed booster, the National Synchrotron Light Source (NSLS), the High Flux Beam Reactor (HFBR), and the RHIC, which is under construction. Departments within the laboratory include the AGS department, accelerator development, physics, chemistry, biology, NSLS, medical, nuclear energy, and interdepartmental research efforts. Research ranges from the pure sciences, in nuclear physics and high energy physics as one example, to environmental work in applied science to study climatic effects, from efforts in biology which are a component of the human genome project to the study, production, and characterization of new materials. The paper provides an overview of the laboratory operations during 1992, including staffing, research, honors, funding, and general laboratory plans for the future

  8. Development Considerations for Nanocrystal Drug Products.

    Science.gov (United States)

    Chen, Mei-Ling; John, Mathew; Lee, Sau L; Tyner, Katherine M

    2017-05-01

    Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

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

    Directory of Open Access Journals (Sweden)

    Hyeong-Min Lee

    2016-01-01

    Full Text Available 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.

  10. Drug development: from concept to marketing!

    Science.gov (United States)

    Tamimi, Nihad A M; Ellis, Peter

    2009-01-01

    Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

  11. Success rates for product development strategies in new drug development.

    Science.gov (United States)

    Dahlin, E; Nelson, G M; Haynes, M; Sargeant, F

    2016-04-01

    While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008

  12. Challenges in developing drugs for primary headaches

    DEFF Research Database (Denmark)

    Schytz, Henrik Winther; Hargreaves, Richard; Ashina, Messoud

    2017-01-01

    This review considers the history of drug development in primary headaches and discusses challenges to the discovery of innovative headache therapeutics. Advances in headache genetics have yet to translate to new classes of therapeutics and there are currently no clear predictive human biomarkers...... for any of the primary headaches that can guide preventative drug discovery and development. Primary headache disorder subtypes despite common phenotypic presentation are undoubtedly heterogeneous in their pathophysiology as judged by the variability of response to headache medicines. Sub......, despite having promising effects in basic pain models, have not delivered efficacy in the clinic. Future efforts may triage novel physiological mediators using human experimental models of headache pain to support drug discovery strategies that target active pathways pharmacologically....

  13. A Trojan horse in drug development

    DEFF Research Database (Denmark)

    Christensen, Søren Brøgger; Skytte, Dorthe Mondrup; Denmeade, Samuel R

    2009-01-01

    Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 s...

  14. Has molecular imaging delivered to drug development?

    Science.gov (United States)

    Murphy, Philip S.; Patel, Neel; McCarthy, Timothy J.

    2017-10-01

    Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

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

    Science.gov (United States)

    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.

  16. Mixed WTO ruling on generic drug development.

    Science.gov (United States)

    Elliott, R

    2000-01-01

    On 17 March 2000, the World Trade Organization upheld the provision in Canada's patent laws that allows generic drug manufacturers to develop (but not sell) their cheaper versions of patented medicines before the 20-year patients expire. The decision prevents pharmaceutical companies from enjoying market monopolies beyond their patent terms, avoiding what would otherwise be even lengthier delays in the sale of cheaper, generic drugs in Canada. This decision is of significance not only to Canada, but also to other WTO member countries and to all individuals who use pharmaceutical products. However, the decision is not all positive: the WTO also ruled that Canada is violating international agreements by letting generic manufacturers stockpile their versions of patented drugs before patents expire. This article explains the issues, the arguments, and the decision.

  17. Heterocyclic Scaffolds: Centrality in Anticancer Drug Development.

    Science.gov (United States)

    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.

  18. Multi-target drugs: the trend of drug research and development.

    Science.gov (United States)

    Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

    2012-01-01

    Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

  19. Drug development against tuberculosis: Impact of alkaloids.

    Science.gov (United States)

    Mishra, Shardendu K; Tripathi, Garima; Kishore, Navneet; Singh, Rakesh K; Singh, Archana; Tiwari, Vinod K

    2017-09-08

    Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. 75 FR 32482 - Investigational New Drug Applications; Co-development of Investigational Drugs

    Science.gov (United States)

    2010-06-08

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0247] 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...

  1. Effects of Psychostimulant Drugs on Developing Brain

    Directory of Open Access Journals (Sweden)

    Ibrahim Durukan

    2013-08-01

    Full Text Available Although psychostimulants have been used for the treatment of attention deficit hyperactivity disorder for approximately 70 years, little is known about the long term effects of these drugs on developing brain. The observable effects of psychostimulants are influenced by the timing of exposure, the age of examination after drug exposure and sex. Preclinical studies point out that chronic psychostimulant exposure before adolescence cause reverse sensitization or tolerance and this leads to reduction in stimulant effectiveness in adolesecence and adulthood. Preclinical studies show the potential long term effects of psychostimulants. But it is necessary to investigate the relationship between preclinical effects and clinical practice. A developmental approach is needed to understand the impact of pediatric medications on the brain that includes assessment at multiple ages to completely characterize the long term effects of these medications. The aim of this paper is to review the effects of psychostimulants on developing brain.

  2. AMS in drug development at GSK

    International Nuclear Information System (INIS)

    Young, G.C.; Ellis, W.J.

    2007-01-01

    A history of the use of AMS in GSK studies spanning the last 8 years (1998-2005) is presented, including use in pilot studies through to clinical, animal and in vitro studies. A brief summary of the status of GSK's in-house AMS capability is outlined and views on the future of AMS in GSK are presented, including potential impact on drug development and potential advances in AMS technology

  3. Nonimaging detectors in drug development and approval.

    Science.gov (United States)

    Wagner, H N

    2001-07-01

    Regulatory applications for imaging biomarkers will expand in proportion to the validation of specific parameters as they apply to individual questions in the management of disease. This validation is likely to be applicable only to a particular class of drug or a single mechanism of action. Awareness among the world's regulatory authorities of the potential for these emerging technologies is high, but so is the cost to the sponsor (including the logistics of including images in a dossier), and therefore the pharmaceutical industry must evaluate carefully the potential benefit of each technology for its drug development programs, just as the authorities must consider carefully the extent to which the method is valid for the use to which the applicant has put it. For well-characterized tracer systems, it may be possible to design inexpensive cameras that make rapid assessments.

  4. Animal Migraine Models for Drug Development

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  5. Drugs in development for Parkinson's disease: an update.

    Science.gov (United States)

    Johnston, Tom H; Brotchie, Jonathan M

    2006-01-01

    The current development of emerging pharmacological treatments for Parkinson's disease (PD), front preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The alpha2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal' synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and alpha-synuclein oligomerization inhibitors, remain in development.

  6. Deep Burn: Development of Transuranic Fuel for High-Temperature Helium-Cooled Reactors- Monthly Highlights September 2010

    International Nuclear Information System (INIS)

    Snead, Lance Lewis; Besmann, Theodore M.; Collins, Emory D.; Bell, Gary L.

    2010-01-01

    The DB Program monthly highlights report for August 2010, ORNL/TM-2010/184, was distributed to program participants by email on September 17. This report discusses: (1) Core and Fuel Analysis - (a) Core Design Optimization in the HTR (high temperature helium-cooled reactor) Prismatic Design (Logos), (b) Core Design Optimization in the HTR Pebble Bed Design (INL), (c) Microfuel analysis for the DB HTR (INL, GA, Logos); (2) Spent Fuel Management - (a) TRISO (tri-structural isotropic) repository behavior (UNLV), (b) Repository performance of TRISO fuel (UCB); (3) Fuel Cycle Integration of the HTR (high temperature helium-cooled reactor) - Synergy with other reactor fuel cycles (GA, Logos); (4) TRU (transuranic elements) HTR Fuel Qualification - (a) Thermochemical Modeling, (b) Actinide and Fission Product Transport, (c) Radiation Damage and Properties; (5) HTR Spent Fuel Recycle - (a) TRU Kernel Development (ORNL), (b) Coating Development (ORNL), (c) Characterization Development and Support, (d) ZrC Properties and Handbook; and (6) HTR Fuel Recycle - (a) Graphite Recycle (ORNL), (b) Aqueous Reprocessing, (c) Pyrochemical Reprocessing METROX (metal recovery from oxide fuel) Process Development (ANL).

  7. Contraceptive issues of youth and adolescents in developing countries: highlights from the Philippines and other Asian countries.

    Science.gov (United States)

    Alesna-Llanto, Emma; Raymundo, Corazon M

    2005-10-01

    This article highlights contraceptive issues in Asia, home to some 700 million adolescents. It starts with a description of the socio-cultural milieu of adolescents in South and Southeast Asia, their knowledge and use of contraceptives, the myriad barriers to access, and the many innovative programs to broaden contraceptive availability. The reproductive health needs of adolescents in poor countries cannot be solved by merely supplying them with contraceptives--these needs can only be fully addressed in the context of gender equality, poverty alleviation and the conviction that investing in the reproductive health of adolescents is a most urgent priority. Investing in the reproductive health of adolescents will have an impact not only on birth and abortion rates, maternal health, and the spread of STI/HIV but also on the demographics and economic development of the region--and beyond.

  8. Developing the Next Generation of International Safeguards and Nonproliferation Experts: Highlights of Select Activities at the National Laboratories

    Energy Technology Data Exchange (ETDEWEB)

    Reed, J; Mathews, C; Kirk, B; Lynch, P; Doyle, J; Meek, E; Pepper, S; Metcalf, R

    2010-03-31

    With many safeguards experts in the United States at or near retirement age, and with the growing and evolving mission of international safeguards, attracting and educating a new generation of safeguards experts is an important element of maintaining a credible and capable international safeguards system. The United States National Laboratories, with their rich experience in addressing the technical and policy challenges of international safeguards, are an important resource for attracting, educating, and training future safeguards experts. This presentation highlights some of the safeguards education and professional development activities underway at the National Laboratories. These include university outreach, summer courses, internships, mid-career transition, knowledge retention, and other projects. The presentation concludes with thoughts on the challenge of interdisciplinary education and the recruitment of individuals with the right balance of skills and backgrounds are recruited to meet tomorrow's needs.

  9. The development and maintenance of drug addiction.

    Science.gov (United States)

    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.

  10. Model-assisted analysis of spatial and temporal variations in fruit temperature and transpiration highlighting the role of fruit development.

    Science.gov (United States)

    Nordey, Thibault; Léchaudel, Mathieu; Saudreau, Marc; Joas, Jacques; Génard, Michel

    2014-01-01

    Fruit physiology is strongly affected by both fruit temperature and water losses through transpiration. Fruit temperature and its transpiration vary with environmental factors and fruit characteristics. In line with previous studies, measurements of physical and thermal fruit properties were found to significantly vary between fruit tissues and maturity stages. To study the impact of these variations on fruit temperature and transpiration, a modelling approach was used. A physical model was developed to predict the spatial and temporal variations of fruit temperature and transpiration according to the spatial and temporal variations of environmental factors and thermal and physical fruit properties. Model predictions compared well to temperature measurements on mango fruits, making it possible to accurately simulate the daily temperature variations of the sunny and shaded sides of fruits. Model simulations indicated that fruit development induced an increase in both the temperature gradient within the fruit and fruit water losses, mainly due to fruit expansion. However, the evolution of fruit characteristics has only a very slight impact on the average temperature and the transpiration per surface unit. The importance of temperature and transpiration gradients highlighted in this study made it necessary to take spatial and temporal variations of environmental factors and fruit characteristics into account to model fruit physiology.

  11. Model-assisted analysis of spatial and temporal variations in fruit temperature and transpiration highlighting the role of fruit development.

    Directory of Open Access Journals (Sweden)

    Thibault Nordey

    Full Text Available Fruit physiology is strongly affected by both fruit temperature and water losses through transpiration. Fruit temperature and its transpiration vary with environmental factors and fruit characteristics. In line with previous studies, measurements of physical and thermal fruit properties were found to significantly vary between fruit tissues and maturity stages. To study the impact of these variations on fruit temperature and transpiration, a modelling approach was used. A physical model was developed to predict the spatial and temporal variations of fruit temperature and transpiration according to the spatial and temporal variations of environmental factors and thermal and physical fruit properties. Model predictions compared well to temperature measurements on mango fruits, making it possible to accurately simulate the daily temperature variations of the sunny and shaded sides of fruits. Model simulations indicated that fruit development induced an increase in both the temperature gradient within the fruit and fruit water losses, mainly due to fruit expansion. However, the evolution of fruit characteristics has only a very slight impact on the average temperature and the transpiration per surface unit. The importance of temperature and transpiration gradients highlighted in this study made it necessary to take spatial and temporal variations of environmental factors and fruit characteristics into account to model fruit physiology.

  12. Mind the gap : predicting cardiovascular risk during drug development

    NARCIS (Netherlands)

    Chain, Anne S. Y.

    2012-01-01

    Cardiovascular safety issues, specifically drug-induced QT/QTc-interval prolongation, remain a major cause of drug attrition during clinical development and is one of the main causes for post-market drug withdrawals accounting for 15-34% of all drug discontinuation. Given the potentially fatal

  13. Highlights of recent developments and trends in cancer nanotechnology research--view from NCI Alliance for Nanotechnology in Cancer.

    Science.gov (United States)

    Hull, L C; Farrell, D; Grodzinski, P

    2014-01-01

    Although the incidence of cancer and cancer related deaths in the United States has decreased over the past two decades due to improvements in early detection and treatment, cancer still is responsible for a quarter of the deaths in this country. There is much room for improvement on the standard treatments currently available and the National Cancer Institute (NCI) has recognized the potential for nanotechnology and nanomaterials in this area. The NCI Alliance for Nanotechnology in Cancer was formed in 2004 to support multidisciplinary researchers in the application of nanotechnology to cancer diagnosis and treatment. The researchers in the Alliance have been productive in generating innovative solutions to some of the central issues of cancer treatment including how to detect tumors earlier, how to target cancer cells specifically, and how to improve the therapeutic index of existing chemotherapies and radiotherapy treatments. Highly creative ideas are being pursued where novelty in nanomaterial development enables new modalities of detection or therapy. This review highlights some of the innovative materials approaches being pursued by researchers funded by the NCI Alliance. Their discoveries to improve the functionality of nanoparticles for medical applications includes the generation of new platforms, improvements in the manufacturing of nanoparticles and determining the underlying reasons for the movement of nanoparticles in the blood. © 2013.

  14. Nurses' Views Highlight a Need for the Systematic Development of Patient Safety Culture in Forensic Psychiatry Nursing.

    Science.gov (United States)

    Kuosmanen, Anssi; Tiihonen, Jari; Repo-Tiihonen, Eila; Eronen, Markku; Turunen, Hannele

    2017-11-04

    Although forensic nurses work with the most challenging psychiatric patients and manifest a safety culture in their interactions with patients, there have been few studies on patient safety culture in forensic psychiatric nursing. The aim of this qualitative study was to describe nurses' views of patient safety culture in their working unit and daily hospital work in 2 forensic hospitals in Finland. Data were collected over a period of 1 month by inviting nurses to answer an open-ended question in an anonymous Web-based questionnaire. A qualitative inductive analysis was performed on nurses' (n = 72) written descriptions of patient safety culture in state-owned forensic hospitals where most Finnish forensic patients are treated. Six main themes were identified: "systematization of an open and trusting communication culture," "visible and close interaction between managers and staff," "nonpunitive responses to errors, learning and developing," "balancing staff and patient perspectives on safety culture," "operational safety guidelines," and "adequate human resources to ensure safety." The findings highlight the influence of the prevailing culture on safety behaviors and outcomes for both healthcare workers and patients. Additionally, they underline the importance of an open culture with open communication and protocols.

  15. Novel approaches in anti-arenaviral drug development

    International Nuclear Information System (INIS)

    Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan

    2011-01-01

    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.

  16. Highlighting the evidence gap: how cost-effective are interventions to improve early childhood nutrition and development?

    Science.gov (United States)

    Batura, Neha; Hill, Zelee; Haghparast-Bidgoli, Hassan; Lingam, Raghu; Colbourn, Timothy; Kim, Sungwook; Sikander, Siham; Pulkki-Brannstrom, Anni-Maria; Rahman, Atif; Kirkwood, Betty; Skordis-Worrall, Jolene

    2015-07-01

    There is growing evidence of the effectiveness of early childhood interventions to improve the growth and development of children. Although, historically, nutrition and stimulation interventions may have been delivered separately, they are increasingly being tested as a package of early childhood interventions that synergistically improve outcomes over the life course. However, implementation at scale is seldom possible without first considering the relative cost and cost-effectiveness of these interventions. An evidence gap in this area may deter large-scale implementation, particularly in low- and middle-income countries. We conduct a literature review to establish what is known about the cost-effectiveness of early childhood nutrition and development interventions. A set of predefined search terms and exclusion criteria standardized the search across five databases. The search identified 15 relevant articles. Of these, nine were from studies set in high-income countries and six in low- and middle-income countries. The articles either calculated the cost-effectiveness of nutrition-specific interventions (n = 8) aimed at improving child growth, or parenting interventions (stimulation) to improve early childhood development (n = 7). No articles estimated the cost-effectiveness of combined interventions. Comparing results within nutrition or stimulation interventions, or between nutrition and stimulation interventions was largely prevented by the variety of outcome measures used in these analyses. This article highlights the need for further evidence relevant to low- and middle-income countries. To facilitate comparison of cost-effectiveness between studies, and between contexts where appropriate, a move towards a common outcome measure such as the cost per disability-adjusted life years averted is advocated. Finally, given the increasing number of combined nutrition and stimulation interventions being tested, there is a significant need for evidence of cost

  17. A Development of Hybrid Drug Information System Using Image Recognition

    Directory of Open Access Journals (Sweden)

    HwaMin Lee

    2015-04-01

    Full Text Available In order to prevent drug abuse or misuse cases and avoid over-prescriptions, it is necessary for medicine taker to be provided with detailed information about the medicine. In this paper, we propose a drug information system and develop an application to provide information through drug image recognition using a smartphone. We designed a contents-based drug image search algorithm using the color, shape and imprint of drug. Our convenient application can provide users with detailed information about drugs and prevent drug misuse.

  18. Open source biotechnology : A drug for developing countries' health problems?

    NARCIS (Netherlands)

    Schellekens, M.H.M.

    2008-01-01

    In developing countries, many people suffer from diseases for which there are no drugs or for which drugs exist that they cannot afford because they are too expensive. The advent of genomics has sparked the idea that new drugs can be more easily developed and that genomics thus could lessen the

  19. Nonstructural Proteins of Alphavirus—Potential Targets for Drug Development

    Directory of Open Access Journals (Sweden)

    Farhana Abu Bakar

    2018-02-01

    Full Text Available Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors.

  20. Personalized Medicine: Pharmacogenomics and Drug Development

    Directory of Open Access Journals (Sweden)

    Somayeh Mirsadeghi

    2017-03-01

    Full Text Available Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient’s genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.

  1. The role of radiolabelled compounds in preclinical drug development

    International Nuclear Information System (INIS)

    Hawkins, D.R.

    1988-01-01

    The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

  2. Do national drug policies influence antiretroviral drug prices? Evidence from the Southern African Development community.

    Science.gov (United States)

    Liu, Yao; Galárraga, Omar

    2017-03-01

    The efficacy of low- and middle-income countries’ (LMIC) national drug policies in managing antiretroviral (ARV) pharmaceutical prices is not well understood. Though ARV drug prices have been declining in LMIC over the past decade, little research has been done on the role of their national drug policies. This study aims to (i) analyse global ARV prices from 2004 to 2013 and (ii) examine the relationship of national drug policies to ARV prices. Analysis of ARV drug prices utilized data from the Global Price Reporting Mechanism from the World Health Organization (WHO). Ten of the most common ARV drugs (first-line and second-line) were selected. National drug policies were also assessed for 12 countries in the South African Development Community (SADC), which self-reported their policies through WHO surveys. The best predictor of ARV drug price was generic status—the generic versions of 8 out of 10 ARV drugs were priced lower than branded versions. However, other factors such as transaction volume, HIV prevalence, national drug policies and PEPFAR/CHAI involvement were either not associated with ARV drug price or were not consistent predictors of price across different ARV drugs. In the context of emerging international trade agreements, which aim to strengthen patent protections internationally and potentially delay the sale of generic drugs in LMIC, this study shines a spotlight on the importance of generic drugs in controlling ARV prices. Further research is needed to understand the impact of national drug policies on ARV prices.

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

    DEFF Research Database (Denmark)

    Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

    2014-01-01

    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......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...

  4. Investigating Nature's Mysteries for Drug Development

    Science.gov (United States)

    More than half of the drugs approved to treat cancer come from a natural product or a natural product prototype. Scientists in NCI-Frederick's Natural Products Branch are exploring ways to harness chemicals produced by marine invertebrates, other animals, plants, and microbes for cancer drug discovery.

  5. Development, use and evaluation of drugs

    DEFF Research Database (Denmark)

    Hansen, E H; Launsø, Laila

    1987-01-01

    . Drugs offer a standard solution to health problems independent of the individuals' social life. Thus drugs become a tool which function in agreement with the disintegrated and achievement-orientated approach to disease as it is organized today. In general the statements in this article are not limited...

  6. Radiocarbon mass spectrometry for drug development

    International Nuclear Information System (INIS)

    Ulrich, Schulze-Konig Tim

    2011-01-01

    Full text: Radiocarbon has a huge potential as a tracer for metabolism studies in humans. By using Accelerator Mass Spectrometry (AMS) for its detection, a unique sensitivity is reached reducing required radiation doses to a negligible level. Until recently, a widespread use of AMS in biomedical research was impeded by the high complexity of the instrument, time-consuming sample preparation, and a limited availability of measurement capacity. Over the last few years, tremendous progress has been achieved in the reduction of size and complexity of AMS instruments. It allowed designing a compact AMS system, dubbed BioMICADAS to address the needs of biomedical users. For more than two years, this system is in successful operation at a commercial service provider for the pharmaceutical industry. A further drastic simplification of radiocarbon mass spectrometers seems possible and could establish a regular usage of this technology in drug development. However, to reach this goal a better integration of AMS into the workflow of bioanalytical laboratories will be necessary. For this purpose, CO 2 accepting ion sources may be a key, since they enable an almost automated sample preparation. The status of radiocarbon AMS in biomedical research and its perspective will be discussed

  7. Male central hypogonadism secondary to exogenous androgens: a review of the drugs and protocols highlighted by the online community of users for prevention and/or mitigation of adverse effects.

    Science.gov (United States)

    Karavolos, Stamatios; Reynolds, Michael; Panagiotopoulou, Nikoletta; McEleny, Kevin; Scally, Michael; Quinton, Richard

    2015-05-01

    Androgen- or anabolic steroid-induced hypogonadism (ASIH) is no longer confined to professional athletes; its prevalence amongst young men and teenagers using androgens and/or anabolic steroids (AASs) is rising fast, and those affected can experience significant symptoms. Clinicians are increasingly encountering demanding, well-informed men affected by ASIH, yet lacking authoritative information on the subject may struggle to project a credible message. In this article, we overview the methods and drugs that men use in an attempt to counteract ASIH (with a view to either preventing its onset, or reversing it once it has developed) and summarize the scientific evidence underpinning these. The main channel for obtaining these drugs is the Internet, where they can be readily sourced without a valid prescription. An Internet search using relevant terms revealed a huge number of websites providing advice on how to buy and use products to counteract ASIH. Drugs arising repeatedly in our search included human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The quality and accuracy of the online information was variable, but review of medical literature also highlighted a lack of scientific data to guide clinical practice. It is important for clinicians to be aware of the AAS user's self-treatment strategies with regard to ASIH side-effect mitigation. By ensuring that they are well-informed, clinicians are more likely to retain the credibility and trust of AAS users, who will in turn likely be more open to engage with appropriate management. © 2014 John Wiley & Sons Ltd.

  8. Targeting DNA repair systems in antitubercular drug development.

    Science.gov (United States)

    Minias, Alina; Brzostek, Anna; Dziadek, Jaroslaw

    2018-01-28

    Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development

    Directory of Open Access Journals (Sweden)

    Jan eStenvang

    2013-12-01

    Full Text Available Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

  10. The Development Impact of the Illegality of Drug Trade

    OpenAIRE

    Keefer, Philip; Loayza, Norman V.; Soares, Rodrigo R.

    2008-01-01

    This paper reviews the unintended consequences of the war on drugs, particularly for developing countries, and weighs them against the evidence regarding the efficacy of prohibition to curb drug use and trade. It reviews the available evidence and presents new results that indicate that prohibition has limited effects on drug prevalence and prices, most likely indicating a combination of i...

  11. Imaging biomarkers as surrogate endpoints for drug development

    International Nuclear Information System (INIS)

    Richter, Wolf S.

    2006-01-01

    The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates - thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of ''personalised medicine''. A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may - if properly validated - serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's ''critical path initiative''. (orig.)

  12. Development of novel alkylating drugs as anticancer agents.

    Science.gov (United States)

    Izbicka, Elzbieta; Tolcher, Anthony W

    2004-06-01

    Although conventional alkylating drugs have proven efficacy in the treatment of malignancies, the agents themselves are not selective. Therefore, non-specific alkylation of cellular nucleophilic targets may contribute to many of the observed toxic effects. Novel approaches to drug discovery have resulted in candidate agents that are focused on 'soft alkylation'--alkylators with greater target selectivity. This review highlights the discovery of small molecule drugs that bind to DNA with higher selectivity, act in a unique hypoxic tumor environment, or covalently bind specific protein targets overexpressed in cancer, such as topoisomerase II, glutathione transferase pi1, beta-tubulin and histone deacetylase.

  13. Investigation of toxic metabolites during drug development

    International Nuclear Information System (INIS)

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

    2005-01-01

    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

  14. The worldwide trend of using botanical drugs and strategies for developing global drugs.

    Science.gov (United States)

    Ahn, Kyungseop

    2017-03-01

    Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116].

  15. Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy

    Science.gov (United States)

    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

  16. Challenges and future in vaccines, drug development, and immunomodulatory therapy.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  18. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  19. A development perspective on adolescent drug abuse.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Recent advances in (therapeutic protein drug development [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    H.A. Daniel Lagassé

    2017-02-01

    Full Text Available Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016.

  2. Kinase-Centric Computational Drug Development

    NARCIS (Netherlands)

    Kooistra, Albert J.; Volkamer, Andrea

    2017-01-01

    Kinases are among the most studied drug targets in industry and academia, due to their involvement in a majority of cellular processes and, upon dysregulation, in a variety of diseases including cancer, inflammation, and autoimmune disorders. The high interest in this druggable protein family

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

    Directory of Open Access Journals (Sweden)

    Donglu Zhang

    2012-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-02-17

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

  5. Chemical synthesis, characterisation, analytical method development and control to promote exposure assessments and toxicological testing. Highlights from COMPARE

    Energy Technology Data Exchange (ETDEWEB)

    Bergman, Aa.; Malmberg, T.; Weiss, J. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry

    2004-09-15

    The issue of endocrine disruptor effects in wildlife and humans grow increasingly important during the 1990s'. As part of the focus on endocrine disruptors new contaminants and their metabolites were put forward for studies with endpoints related to hormone disruption. One such large group of chemicals and/or metabolites of neutral semi-persistent or persistent compounds was the substituted phenols, particularly the halogenated phenolic compounds (HPCs). Polychlorobiphenylols (OHPCBs) were reported to be strongly retained in human blood plasma in 1995 and this article was the first study to point out the general retention of several OH-PCBs in the plasma. The metabolic formation of OH-PCBs was well known and the specific blood retention had been reported for at least one PCB congener, 3,3',4,4'-tetrachlorobiphenyl (CB-77) in some previous studies. The identification of OH-PCBs being retained in blood and their specific binding to transthyretin (TTR) has formed much of the basis for two EU R and D programs, first RENCO and now COMPARE. The present report is aimed to highlight some of the results obtained within the COMPARE program mainly dealing with the chemical synthesis, characterisation and analytical aspects of HPCs.

  6. A two-pronged approach in leishmaniasis drug development in ...

    African Journals Online (AJOL)

    Nancy Kamau

    Trouiller P; Olliaro P; Torreele E;. Orbinski J; Laing R and Ford N. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet. 2002; 359: 2188–94. 9. Nwaka S and Ridley RG. Virtual drug discovery and development for neglected diseases through public-private partnerships.

  7. An active role for machine learning in drug development

    Science.gov (United States)

    Murphy, Robert F.

    2014-01-01

    Due to the complexity of biological systems, cutting-edge machine-learning methods will be critical for future drug development. In particular, machine-vision methods to extract detailed information from imaging assays and active-learning methods to guide experimentation will be required to overcome the dimensionality problem in drug development. PMID:21587249

  8. Delays in clinical development of neurological drugs in Japan.

    Science.gov (United States)

    Ikeda, Masayuki

    2017-06-28

    The delays in the approval and development of neurological drugs between Japan and other countries have been a major issue for patients with neurological diseases. The objective of this study was to analyze factors contributing to the delay in the launching of neurological drugs in Japan. We analyzed data from Japan and the US for the approval of 42 neurological drugs, all of which were approved earlier in the US than in Japan, and examined the potential factors that may cause the delay of their launch. Introductions of the 42 drugs in Japan occurred at a median of 87 months after introductions in the US. The mean review time of new drug applications for the 20 drugs introduced in Japan in January 2011 or later (15 months) was significantly shorter than that for the other 22 drugs introduced in Japan in December 2010 or earlier (24 months). The lag in the Japan's review time behind the US could not explain the approval delays. In the 31 of the 42 drugs, the application data package included overseas data. The mean review time of these 31 drugs (17 months) was significantly shorter than that of the other 11 drugs without overseas data (26 months). The mean approval lag behind the US of the 31 drugs (78 months) was also significantly shorter than that of the other 11 drugs (134 months). These results show that several important reforms in the Japanese drug development and approval system (e.g., inclusion of global clinical trial data) have reduced the delays in the clinical development of neurological drugs.

  9. [New drug development by innovative drug administration--"change" in pharmaceutical field].

    Science.gov (United States)

    Nagai, T

    1997-11-01

    New drug development can be made by providing products of higher "selectivity for the drug" for medical treatment. There are two ways for the approach to get higher "selectivity of drug": 1) discovery of new compounds with high selectivity of drug; 2) innovation of new drug administration, that is new formulation and/or method with high selectivity of drug by integration and harmonization of various hard/soft technologies. An extensive increase of biological information and advancement of surrounding science and technology may modify the situation as the latter overcomes the former in the 21 century. As the science and technology in the 21 century is said to be formed on "3H", that is, 1. hybrid; 2. hi-quality; 3. husbandry, the new drug development by innovative drug administration is exactly based on the science and technology of 3H. Its characteristic points are interdisciplinary/interfusion, international, of philosophy/ethics, and systems of hard/hard/heart. From these points of view, not only the advance of unit technology but also a revolution in thinking way should be "must" subjects. To organize this type of research well, a total research activity such as ROR (research on research) might take an important and efficient role. Here the key words are the "Optimization technology" and "Change in Pharmaceutical Fields." As some examples of new drug innovation, our trials on several topical mucosal adhesive dosage forms and parenteral administration of peptide drugs such as insulin and erythropoietin will be described.

  10. Reflection of successful anticancer drug development processes in the literature.

    Science.gov (United States)

    Heinemann, Fabian; Huber, Torsten; Meisel, Christian; Bundschus, Markus; Leser, Ulf

    2016-11-01

    The development of cancer drugs is time-consuming and expensive. In particular, failures in late-stage clinical trials are a major cost driver for pharmaceutical companies. This puts a high demand on methods that provide insights into the success chances of new potential medicines. In this study, we systematically analyze publication patterns emerging along the drug discovery process of targeted cancer therapies, starting from basic research to drug approval - or failure. We find clear differences in the patterns of approved drugs compared with those that failed in Phase II/III. Feeding these features into a machine learning classifier allows us to predict the approval or failure of a targeted cancer drug significantly better than educated guessing. We believe that these findings could lead to novel measures for supporting decision making in drug development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Challenges in orphan drug development and regulatory policy in China.

    Science.gov (United States)

    Cheng, Alice; Xie, Zhi

    2017-01-18

    While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China.

  12. IGC highlights 1988

    International Nuclear Information System (INIS)

    1989-01-01

    The major thrust of the research and development (R and D) activities of the Indira Gandhi Centre for Atomic Research (IGCAR), Kalpakkam is oriented towards mastering fast breeder reactor (FBR) technology. Towards this end, its current R and D activities are carried out in a wide variety of disciplines. Highlights of its R and D activities during 1988 are summarised under the headings: Reactor Engineering and Design, Reactor Physics and Safety, Materials Science and Technology, Sodium Chemistry and Technology, Fuel Reprocessing and Electronics and Instrumentation. The text is illustrated with a number of figures, graphs and coloured pictures. (M.G.B.). figs., tabs

  13. BARC highlights '88

    International Nuclear Information System (INIS)

    1989-01-01

    Highlights of research and development activities of the Bhabha Atomic Research Centre (BARC), Bombay during 1988 are presented in chapters entitled: Physical Sciences, Chemical Sciences, Materials and Materials Sciences, Radioisotopes, Reactors, Fuel Cycle, Radiological Safety and Protection, Electronics and Instrumentation, Engineering Services, and Life Sciences. Main thrust of the R and D activities of BARC is on nuclear power reactor technology and all stages of nuclear fuel cycle. Some activities are also in the frontier areas such as high temperature superconductivity and inertial confinement fusion. (M.G.B.). figs., tabs., coloured ills

  14. Highlights of the round table discussion on trends and future developments of the application of pressure to high Tc materials

    International Nuclear Information System (INIS)

    Chu, C.W.; Ayache, C.; Fietz, W.J.; Kourouklis, G.K.; Liarokapis, E.; Wijngaarden, R.

    1991-01-01

    A discussion of current trends and the future development of the application of pressure to high T c materials was initiated by a brief presentation by each panel member and followed by an active exchange among all participants in the Workshop. The current status of the study of high temperature superconductivity and the past, current, and future roles of pressure in that study were discussed

  15. Getting rid of the unwanted: highlights of developments and challenges of biobeneficiation of iron ore minerals-a review.

    Science.gov (United States)

    Adeleke, Rasheed A

    2014-12-01

    The quest for quality mineral resources has led to the development of many technologies that can be used to refine minerals. Biohydrometallurgy is becoming an increasingly acceptable technology worldwide because it is cheap and environmentally friendly. This technology has been successfully developed for some sulphidic minerals such as gold and copper. In spite of wide acceptability of this technology, there are limitations to its applications especially in the treatment of non-sulphidic minerals such as iron ore minerals. High levels of elements such as potassium (K) and phosphorus (P) in iron ore minerals are known to reduce the quality and price of these minerals. Hydrometallurgical methods that are non-biological involving the use of chemicals are usually used to deal with this problem. However, recent advances in mining technologies favour green technologies, known as biohydrometallurgy, with minimal impact on the environment. This technology can be divided into two, namely bioleaching and biobeneficiation. This review focuses on Biobeneficiation of iron ore minerals. Biobeneficiation of iron ore is very challenging due to the low price and chemical constitution of the ore. There are substantial interests in the exploration of this technology for improving the quality of iron ore minerals. In this review, current developments in the biobeneficiation of iron ore minerals are considered, and potential solutions to challenges faced in the wider adoption of this technology are proposed.

  16. Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

    Science.gov (United States)

    Mello, Juliana da Fonseca Rezende E; Gomes, Renan Augusto; Vital-Fujii, Drielli Gomes; Ferreira, Glaucio Monteiro; Trossini, Gustavo Henrique Goulart

    2017-12-01

    Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs. © 2017 John Wiley & Sons A/S.

  17. Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

    Science.gov (United States)

    Pulley, Jill M; Shirey-Rice, Jana K; Lavieri, Robert R; Jerome, Rebecca N; Zaleski, Nicole M; Aronoff, David M; Bastarache, Lisa; Niu, Xinnan; Holroyd, Kenneth J; Roden, Dan M; Skaar, Eric P; Niswender, Colleen M; Marnett, Lawrence J; Lindsley, Craig W; Ekstrom, Leeland B; Bentley, Alan R; Bernard, Gordon R; Hong, Charles C; Denny, Joshua C

    2017-04-01

    The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.

  18. Pharmacogenomics and its potential impact on drug and formulation development.

    Science.gov (United States)

    Regnstrom, Karin; Burgess, Diane J

    2005-01-01

    Recent advances in genomic research have provided the basis for new insights into the importance of genetic and genomic markers during the different stages of drug development. A new field of research, pharmacogenomics, which studies the relationship between drug effects and the genome, has emerged. Structural pharmacogenomics maps the complete DNA sequences of whole genomes (genotypes) including individual variations, and functional pharmacogenomics assesses the expression levels of thousands of genes in one single experiment. Together, these two areas of pharmacogenomics have generated massive databases, which have become a challenge for the research field of informatics and have fostered a new branch of research, bioinformatics. If skillfully used, the databases generated by pharmacogenomics together with data mining on the Web promise to improve the drug development process in a variety of areas: identification of drug targets, evaluation of toxicity, classification of diseases, evaluation of formulations, assessment of drug response and treatment, post-marketing applications, and development of personalized medicines.

  19. Otic drug delivery systems: formulation principles and recent developments.

    Science.gov (United States)

    Liu, Xu; Li, Mingshuang; Smyth, Hugh; Zhang, Feng

    2018-04-25

    Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an ongoing, but often overlooked challenge particularly in terms of formulation design and product development. The prevalence of ear disorders has spurred significant efforts to develop new therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, and current therapies used via the otic route of administration. The primary focuses are on the various administration routes and their formulation principles. The article also presents recent advances in otic drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next decade and more efficient or specific treatments for ear disease will arise from the development of less invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology targeting therapies.

  20. Recent developments in oral lipid-based drug delivery

    DEFF Research Database (Denmark)

    Thomas, N.; Rades, T.; Müllertz, A.

    2013-01-01

    The increasing number of poorly water-soluble drugs in development in the pharmaceutical industry has sparked interest in novel drug delivery options such as lipid-based drug delivery systems (LbDDS). Several LbDDS have been marketed successfully and have shown superior and more reliable...... bioavailability compared to conventional formulations. However, some reluctance in the broader application of LbDDS still appears, despite the growing commercial interest in lipids as a drug delivery platform. This reluctance might at least in part be related to the complexity associated with the development...... and characterization of LbDDS. In particular, the lack of standardized test protocols can be identified as the major obstacles for the broader application of LbDDS. This review seeks to summarize recent approaches in the field of lipid-based drug delivery that try to elucidate some critical steps in their development...

  1. Big Data: transforming drug development and health policy decision making.

    Science.gov (United States)

    Alemayehu, Demissie; Berger, Marc L

    The explosion of data sources, accompanied by the evolution of technology and analytical techniques, has created considerable challenges and opportunities for drug development and healthcare resource utilization. We present a systematic overview these phenomena, and suggest measures to be taken for effective integration of the new developments in the traditional medical research paradigm and health policy decision making. Special attention is paid to pertinent issues in emerging areas, including rare disease drug development, personalized medicine, Comparative Effectiveness Research, and privacy and confidentiality concerns.

  2. Design and Development of a Proniosomal Transdermal Drug ...

    African Journals Online (AJOL)

    Purpose: The aim of the study was to develop a proniosomal carrier system for captopril for the treatment of hypertension that is capable of efficiently delivering entrapped drug over an extended period of time. Method: The potential of proniosomes as a transdermal drug delivery system for captopril was investigated by ...

  3. Literature overview highlights lack of paediatric donation protocols but identifies common themes that could guide their development.

    Science.gov (United States)

    Vileito, A; Siebelink, M J; Verhagen, Aae

    2018-05-01

    Paediatric donation is a unique and extremely sensitive process that requires specific knowledge and competencies. Most countries use protocols for organ and tissue donation to ensure optimal care for the donor and family, but these mainly focus on adults. However, the donation process for children differs from adults in many ways. An overview of the literature was performed to identify protocols for the paediatric population. PubMed, Web of Science, EMBASE and the Internet were searched up to March 2016 for papers or other sources in English related to specific organ and tissue donation protocols for children and neonates. This comprised title, abstract and then full-text screening of relevant data. We included 12 papers and two electronic sources that were mainly from North America and Europe. Most discussed donations after cardiac death. The recurring themes included identifying potential donors, approaching parents, palliative care and collaboration with organ procurement organisations. Most papers called for paediatric donation policies to be standardised. Scientific publications in English on paediatric donation protocols are very scarce. No comprehensive paediatric donation protocol was found. We identified several recurring themes in the literature that could be used to develop such protocols. ©2018 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.

  4. Ethnically diverse pluripotent stem cells for drug development.

    Science.gov (United States)

    Fakunle, Eyitayo S; Loring, Jeanne F

    2012-12-01

    Genetic variation is an identified factor underlying drug efficacy and toxicity, and adverse drug reactions, such as liver toxicity, are the primary reasons for post-marketing drug failure. Genetic predisposition to toxicity might be detected early in the drug development pipeline by introducing cell-based assays that reflect the genetic and ethnic variation of the expected treatment population. One challenge for this approach is obtaining a collection of suitable cell lines derived from ethnically diverse populations. Induced pluripotent stem cells (iPSCs) seem ideal for this purpose. They can be obtained from any individual, can be differentiated into multiple relevant cell types, and their self-renewal capability makes it possible to generate large quantities of quality-controlled cell types. Here, we discuss the benefits and challenges of using iPSCs to introduce genetic diversity into the drug development process. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Tomioka, Haruaki; Namba, Kenji

    2006-12-01

    Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are

  6. Development of polymer-polysaccharide hydrogels for controlling drug delivery

    Science.gov (United States)

    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

  7. Benefit-Risk Assessment in Drug Development

    DEFF Research Database (Denmark)

    Sarac, Sinan

    developed, tested and used. Standardised diagrams for the visualisation of results from the assessment have been established, and different diagrams have been developed for different scenarios. For the visualisation of results from single and/or multiple similar trial assessments, tornado-like diagrams were...

  8. Investigational drugs in early development for treating dengue infection.

    Science.gov (United States)

    Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

    2016-09-01

    Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development. This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization's International Clinical Trials Registry Platform web portal using the search term 'dengue' on December 31(st), 2015. None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict 'high-risk' patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.

  9. A New Drug Release Method in Early Development of Transdermal Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    Bing Cai

    2012-01-01

    Full Text Available In vitro drug release tests are a widely used tool to measure the variance between transdermal product performances and required by many authorities. However, the result cannot provide a good estimation of the in vivo drug release. In the present work, a new method for measuring drug release from patches has been explored and compared with the conventional USP apparatus 2 and 5 methods. Durogesic patches, here used as a model patch, were placed on synthetic skin simulator and three moisture levels (29, 57, 198 μL cm−2 were evaluated. The synthetic skin simulators were collected after 1, 2, 3, 4, 6, and 24 hours and extracted with pH 1.0 hydrochloric acid solution. The drug concentrations in the extractions were measured by isocratic reverse phase high-pressure liquid chromatography. The results showed that, with the increasing moisture level on the synthetic skin simulator, the drug release rate increased. In comparison with the conventional USP method, the drug release results performed by the new method were in more correlation to the release rate claimed in the product label. This new method could help to differentiate the drug release rates among assorted formulations of transdermal drug delivery systems in the early stage of development.

  10. The Development of Drugs against Acanthamoeba Infections

    OpenAIRE

    Siddiqui, Ruqaiyyah; Aqeel, Yousuf; Khan, Naveed Ahmed

    2016-01-01

    For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. O...

  11. Breaking barriers to novel analgesic drug development.

    Science.gov (United States)

    Yekkirala, Ajay S; Roberson, David P; Bean, Bruce P; Woolf, Clifford J

    2017-08-01

    Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.

  12. The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development

    Science.gov (United States)

    Rehman, Waqas; Arfons, Lisa M.; Lazarus, Hillard M.

    2011-01-01

    Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses. PMID:23556097

  13. The teaching of drug development to medical students: collaboration between the pharmaceutical industry and medical school.

    Science.gov (United States)

    Stanley, A G; Jackson, D; Barnett, D B

    2005-04-01

    Collaboration between the medical school at Leicester and a local pharmaceutical company, AstraZeneca, led to the design and implementation of an optional third year special science skills module teaching medical students about drug discovery and development. The module includes didactic teaching about the complexities of the drug discovery process leading to development of candidate drugs for clinical investigation as well as practical experience of the processes involved in drug evaluation preclinically and clinically. It highlights the major ethical and regulatory issues concerned with the production and testing of novel therapies in industry and the NHS. In addition it helps to reinforce other areas of the medical school curriculum, particularly the understanding of clinical study design and critical appraisal. The module is assessed on the basis of a written dissertation and the critical appraisal of a drug advertisement. This paper describes the objectives of the module and its content. In addition we outline the results of an initial student evaluation of the module and an assessment of its impact on student knowledge and the opinion of the pharmaceutical industry partner. This module has proven to be popular with medical students, who acquire a greater understanding of the work required for drug development and therefore reflect more favourably on the role of pharmaceutical companies in the UK.

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

    Science.gov (United States)

    Zhang, Ping; Brusic, Vladimir

    2014-10-01

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

  15. Development of a gastroretentive pulsatile drug delivery platform.

    Science.gov (United States)

    Thitinan, Sumalee; McConville, Jason T

    2012-04-01

    To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag-time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag-time controlling layer. The lag-time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. By varying the composition of the lag-time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  16. Atmospheric Research 2011 Technical Highlights

    Science.gov (United States)

    2012-01-01

    The 2011 Technical Highlights describes the efforts of all members of Atmospheric Research. Their dedication to advancing Earth Science through conducting research, developing and running models, designing instruments, managing projects, running field campaigns, and numerous other activities, is highlighted in this report.

  17. PSI scientific highlights 2011

    International Nuclear Information System (INIS)

    Piwnicki, P.

    2012-04-01

    This comprehensive report for the Swiss Federal Office of Energy (SFOE) presents the major highlights of the work done at the Paul Scherrer Institute, Switzerland, in 2011. According to the institute's director, work was concerned with the design and analysis of advanced materials with new functionalities, for application in fields as diverse as communications and energy technology, transportation, construction and medicine. Of particular topical interest are research projects on materials for application in the field of energy, for example for improving batteries for future electrically powered vehicles. Another example is in the field of catalysts. Environmentally harmful compounds, such as nitrogen oxide and sulphur dioxide produced in an engine, are transformed into nontoxic gases through catalytic conversion. Work progress on the SwissFEL installation is noted, including a breakthrough for SwissFEL main Linac C-band accelerating systems. Further topics in relation to the SwissFEL system are noted. Planning of the initial set of experimental stations at the SwissFEL is discussed and close collaboration with growing number of user communities is noted. Cross-Correlation Scattering, and a theoretical framework for this method is being developed and experimentally verified, using artificial nanostructures and synchrotron radiation. Highlights of further research work are discussed, including topics such as Synchrotron light, work done on neutrons and muons, particle physics, micro and nanotechnology as well as on biomolecular research and radiopharmacy. Large research facilities are discussed as is the PSI proton therapy installation. General energy topics are looked at, as are nuclear energy and safety aspects and environmental and energy systems analysis. Various further work includes factors causing glacier retreat and aerosols. User facilities are listed, including accelerators, the SLS light source, the SINQ neutron source, the UCN ultra-cold neutron source

  18. [Development of new drugs: opportunities and benefits for Peru].

    Science.gov (United States)

    Bayona, Andrés; Fajardo, Natalia

    2012-01-01

    The development of innovative drugs allows coming up with new medicines to prevent and better treat illnesses. This improves people's quality of life and makes it more productive. Therefore, the mission of pharmaceutical research is to develop safe and effective drugs. Clinical trials allow the evaluation of the safety and efficacy profiles of new medicines, medical devices and diagnostic tests. Research and development (R&D) of new drugs is a long and costly process, where out of every 5000 to 10000 new components that enter preclinical testing, only one is approved. Compared to 2011, drug development has increased by 7.6%. According to ClinicalTrials.gov, 5% of the trials take place in Latin America, and Peru is in the fifth position. On the other hand, according to the Global Competitiveness Report issued by the World Economic Forum, Peru ranks 61st, its biggest challenges being the functioning of its public institutions, investment in R&D and technological capacity. The complexity of drug R&D results in a search for competitive places to develop clinical trials. Clinical Research is a humanized industry due to its ethical platform, stated in the guidelines of good clinical practices. This industry demands our country to develop a differentiating value that contributes to the development of knowledge and its competitiveness.

  19. Development of a brazilian nanoencapsulated drug for schistosomiasis treatment

    Directory of Open Access Journals (Sweden)

    Laís Bastos da Fonseca

    2013-11-01

    Full Text Available Schistosomiasis is a parasitic disease that, according to the World Health Organization, constitutes a major public health problem associated with severe morbidity, mostly children in preschool age. The administration of drugs in children always constitutes a difficult task, especially when formulations are not developed specifically for pediatric use, when high doses of drug are required and the drug has a bitter taste, as in the case of praziquantel. Polymer nanoparticles are promising systems for development of encapsulated drugs with low water solubility and bitter taste, due to the good physical and chemical stability, adequate biocompatibility and simple manufacturing processes. Moreover, they can enhance the bioavailabili-ty and reduce variability of treatment among patients. Poly (methyl methacrylate doped with praziquantel was produced through a miniemulsion polymerization pro-cess to compose a pediatric pharmaceutical suspension. Nanoparticles were cha-racterized in terms of physico-chemical properties, toxicological properties and biological activity in mice, being concluded that obtained results were satisfactory. The results were encapsulation rate around 90%, absence of chemical interaction drug - polymer and the presence of biological activity. A collaborative approach was used for this development, involving national partnerships and independent funding mechanisms, a powerful pathway for development of drugs for neglected diseases.

  20. Integration of Antibody Array Technology into Drug Discovery and Development.

    Science.gov (United States)

    Huang, Wei; Whittaker, Kelly; Zhang, Huihua; Wu, Jian; Zhu, Si-Wei; Huang, Ruo-Pan

    Antibody arrays represent a high-throughput technique that enables the parallel detection of multiple proteins with minimal sample volume requirements. In recent years, antibody arrays have been widely used to identify new biomarkers for disease diagnosis or prognosis. Moreover, many academic research laboratories and commercial biotechnology companies are starting to apply antibody arrays in the field of drug discovery. In this review, some technical aspects of antibody array development and the various platforms currently available will be addressed; however, the main focus will be on the discussion of antibody array technologies and their applications in drug discovery. Aspects of the drug discovery process, including target identification, mechanisms of drug resistance, molecular mechanisms of drug action, drug side effects, and the application in clinical trials and in managing patient care, which have been investigated using antibody arrays in recent literature will be examined and the relevance of this technology in progressing this process will be discussed. Protein profiling with antibody array technology, in addition to other applications, has emerged as a successful, novel approach for drug discovery because of the well-known importance of proteins in cell events and disease development.

  1. The intersection of stress, drug abuse and development.

    Science.gov (United States)

    Thadani, Pushpa V

    2002-01-01

    Use or abuse of licit and illicit substances is often associated with environmental stress. Current clinical evidence clearly demonstrates neurobehavioral, somatic growth and developmental deficits in children born to drug-using mothers. However, the effects of environmental stress and its interaction with prenatal drug exposure on a child's development is unknown. Studies in pregnant animals under controlled conditions show drug-induced long-term alterations in brain structures and functions of the offspring. These cytoarchitecture alterations in the brain are often associated with perturbations in neurotransmitter systems that are intimately involved in the regulation of the stress responses. Similar abnormalities have been observed in the brains of animals exposed to other adverse exogenous (e.g., environmental stress) and/or endogenous (e.g., glucocorticoids) experiences during early life. The goal of this article is to: (1) provide evidence and a perspective that common neural systems are influenced during development both by perinatal drug exposure and early stress exposure; and (2) identify gaps and encourage new research examining the effects of early stress and perinatal drug exposure, in animal models, that would elucidate how stress- and drug-induced perturbations in neural systems influence later vulnerability to abused drugs in adult offspring.

  2. Polymeric drugs: Advances in the development of pharmacologically active polymers

    Science.gov (United States)

    Li, Jing; Yu, Fei; Chen, Yi; Oupický, David

    2015-01-01

    Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

    Science.gov (United States)

    Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

    2018-05-22

    Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Mass spectrometry-driven drug discovery for development of herbal medicine.

    Science.gov (United States)

    Zhang, Aihua; Sun, Hui; Wang, Xijun

    2018-05-01

    Herbal medicine (HM) has made a major contribution to the drug discovery process with regard to identifying products compounds. Currently, more attention has been focused on drug discovery from natural compounds of HM. Despite the rapid advancement of modern analytical techniques, drug discovery is still a difficult and lengthy process. Fortunately, mass spectrometry (MS) can provide us with useful structural information for drug discovery, has been recognized as a sensitive, rapid, and high-throughput technology for advancing drug discovery from HM in the post-genomic era. It is essential to develop an efficient, high-quality, high-throughput screening method integrated with an MS platform for early screening of candidate drug molecules from natural products. We have developed a new chinmedomics strategy reliant on MS that is capable of capturing the candidate molecules, facilitating their identification of novel chemical structures in the early phase; chinmedomics-guided natural product discovery based on MS may provide an effective tool that addresses challenges in early screening of effective constituents of herbs against disease. This critical review covers the use of MS with related techniques and methodologies for natural product discovery, biomarker identification, and determination of mechanisms of action. It also highlights high-throughput chinmedomics screening methods suitable for lead compound discovery illustrated by recent successes. © 2016 Wiley Periodicals, Inc.

  6. The development of high-content screening (HCS) technology and its importance to drug discovery.

    Science.gov (United States)

    Fraietta, Ivan; Gasparri, Fabio

    2016-01-01

    High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.

  7. Actors of Columbian drug trade : development and transformation

    Directory of Open Access Journals (Sweden)

    Soňa Smolíková

    2011-06-01

    Full Text Available The aim of this article is to portray the main shifts which have been taking place in Colombian drug scene since the 70’s up to the present especially in relation to actors of this business and form of their activity. At first the development of Colombian drug trade till the 80’s when two big cartels centered in Medellín and Cali arose will be briefly outlined. These cartels were able to control a great part of domestic drug trade and due to their enormous power represented serious threat to Colombian state. Thus the cartels declared open warfare with the state in the 80’s. After the cartels’ elimination in the middle of 90’s new actors represented by small drug organizations arose in Colombian drug scene. These small groups were dependent upon cooperation with foreign partners, especially with Mexican cartels. Ever more important role in drug business is played by Colombian left-wing guerilla groups which will be described in the next part of the article. The problem of right-wing paramilitary groups and their participation in Colombian drug trade will be mentioned as well.

  8. Nano-formulations of drugs: Recent developments, impact and challenges.

    Science.gov (United States)

    Jeevanandam, Jaison; Chan, Yen San; Danquah, Michael K

    2016-01-01

    Nano-formulations of medicinal drugs have attracted the interest of many researchers for drug delivery applications. These nano-formulations enhance the properties of conventional drugs and are specific to the targeted delivery site. Dendrimers, polymeric nanoparticles, liposomes, nano-emulsions and micelles are some of the nano-formulations that are gaining prominence in pharmaceutical industry for enhanced drug formulation. Wide varieties of synthesis methods are available for the preparation of nano-formulations to deliver drugs in biological system. The choice of synthesis methods depend on the size and shape of particulate formulation, biochemical properties of drug, and the targeted site. This article discusses recent developments in nano-formulation and the progressive impact on pharmaceutical research and industries. Additionally, process challenges relating to consistent generation of nano-formulations for drug delivery are discussed. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

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

    Science.gov (United States)

    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.…

  10. Microdose clinical trial by use of radioisotope and perspective of its possible utilization in drug development

    International Nuclear Information System (INIS)

    Yano, Tsuneo; Watanabe, Yasuyoshi

    2009-01-01

    Many promising PET tracers have been developed by the progress of molecular imaging research, and new era could be opened by clinical trials using investigational products labeled by RI. Guidance for microdose clinical trial issued by MHLW in June, 2008, is the regulatory basis to develop PET tracer under clinical trial by the pharmaceutical affairs law. In this review, the discussion from the aspect of regulatory science is highlighted, particularly, on the topics of guidance for microdose and exploratory IND study including sub-therapeutic dose (type II) and therapeutic dose (type III), the revised GMP for investigational product including RI-labeled product, and to ward guidance for microdose clinical trial for biological product. Finally, the US FDA guidance developing medical imaging drug including biological product is introduced, and then perspective of possible utilization of in vivo radiopharmaceutical agents in drug development is discussed. (author)

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    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

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

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract 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

  14. Improving clinical drug development regulatory procedures for anticonvulsants

    Directory of Open Access Journals (Sweden)

    Janković Slobodan

    2015-01-01

    Full Text Available Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the noninferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

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

    Science.gov (United States)

    Velásquez, Germán

    2015-03-01

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

  16. The Use of Social Media in Orphan Drug Development.

    Science.gov (United States)

    Milne, Christopher-Paul; Ni, Wendi

    2017-11-01

    Social media has transformed how people interact with one another through the Internet, and it has the potential to do the same for orphan drug development. Currently, social media influences the orphan drug development process in the following three ways: assisting the study of orphan diseases, increasing the awareness of orphan disease, and playing a vital role in clinical trials. However, there are some caveats to the utilization of social media, such as the need to protect patient privacy by adequately de-identifying personal health information, assuring consistent quality and representativeness of the data, and preventing the unblinding of patient group assignments. Social media has both potential for improving orphan drug development and pitfalls, but with proper oversight on the part of companies, support and participation of patients and their advocacy groups, and timely guidance from regulatory authorities, the positives outweigh the negatives for this powerful and patient-centric tool. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  17. Low hanging fruit in infectious disease drug development.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Julius A Vaz

    2012-01-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  20. Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

    Science.gov (United States)

    Neri, Margherita; Bello, Stefania; Turillazzi, Emanuela; Riezzo, Irene

    2015-01-01

    The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

  1. Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy.

    Science.gov (United States)

    Naganawa, Mika; Gallezot, Jean-Dominique; Rossano, Samantha; Carson, Richard E

    2017-12-11

    Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

  2. Potential drug development candidates for human soil-transmitted helminthiases.

    Directory of Open Access Journals (Sweden)

    Piero Olliaro

    2011-06-01

    Full Text Available 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.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.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.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.

  3. Recent developments in drug eluting devices with tailored interfacial properties.

    Science.gov (United States)

    Sanchez-Rexach, Eva; Meaurio, Emilio; Sarasua, Jose-Ramon

    2017-11-01

    Drug eluting devices have greatly evolved during past years to become fundamental products of great marketing importance in the biomedical field. There is currently a large diversity of highly specialized devices for specific applications, making the development of these devices an exciting field of research. The replacement of the former bare metal devices by devices loaded with drugs allowed the sustained and controlled release of drugs, to achieve the desired local therapeutic concentration of drug. The newer devices have been "engineered" with surfaces containing micro- and nanoscale features in a well-controlled manner, that have shown to significantly affect cellular and subcellular function of various biological systems. For example, the topography can be structured to form an antifouling surface mimicking the defense mechanisms found in nature, like the skin of the shark. In the case of bone implants, well-controlled nanostructured interfaces can promote osteoblast differentiation and matrix production, and enhance short-term and long-term osteointegration. In any case, the goal of current research is to design implants that induce controlled, guided, and rapid healing. This article reviews recent trends in the development of drug eluting devices, as well as recent developments on the micro/nanotechnology scales, and their future challenges. For this purpose medical devices have been divided according to the different systems of the body they are focused to: orthopedic devices, breathing stents, gastrointestinal and urinary systems, devices for cardiovascular diseases, neuronal implants, and wound dressings. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Drugs' development in acute heart failure: what went wrong?

    Science.gov (United States)

    Teneggi, Vincenzo; Sivakumar, Nithy; Chen, Deborah; Matter, Alex

    2018-05-08

    Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

  5. Improvement of Pediatric Drug Development: Regulatory and Practical Frameworks.

    Science.gov (United States)

    Tsukamoto, Katusra; Carroll, Kelly A; Onishi, Taku; Matsumaru, Naoki; Brasseur, Daniel; Nakamura, Hidefumi

    2016-03-01

    A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status. We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union. Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 (P 15% after 2008. Recruitment and ethical obstacles make conducting pediatric clinical trials challenging. An improved operational framework for conducting clinical trials should mirror the ever-improving regulatory framework that incentivizes investment in pediatric clinical trials. Technological approaches, enhancements in electronic medical record systems, and community approaches that actively incorporate input from physicians, researchers, and patients could offer a sustainable solution to recruitment of pediatric study participants. The key therefore is to improve pediatric pharmacotherapy collaboration among industry, government, academia, and

  6. Use of radiopharmaceuticals in the development of drug delivery systems

    International Nuclear Information System (INIS)

    Frier, M.

    1997-01-01

    Full text. Nuclear medicine imaging techniques have great potential in the study of the behaviour of drug formulations and drug delivery systems in human subjects. No other technique can locate so precisely the site of disintegration of a tablet in the Gl tract, the depth of penetration of a nebulized solution into the lung, or the residence time of a drug on the cornea. By using the gamma camera to image the in vivo distribution of pharmaceutical formulations radio labelled with a suitable gamma emitting radionuclide, images may be used to quantify the biodistribution, release and kinetics of drug formulations and delivery from novel carrier systems and devices. Radionuclide tracer techniques allow correlation between the observed pharmacological effects and the precise site of delivery. The strength of the technique lies in the quantitative nature of radionuclide images. Example will be shown of studies which examine the rate of transit of orally-administered formulations through the GI tract, as well as describing the development of devices for specific targeting of drugs to the colon. Data will also demonstrate the effectiveness of devices such as spacers in pulmonary drug delivery, in both normal volunteers, and in asthmatic subjects. Such studies not only provide data on the nature and characteristics of a product, such as reliability and reproducibility but, may also be used in submission to Regulatory Authorities in product registration dossiers

  7. Optimization and Simulation in Drug Development - Review and Analysis

    DEFF Research Database (Denmark)

    Schjødt-Eriksen, Jens; Clausen, Jens

    2003-01-01

    We give a review of pharmaceutical R&D and mathematical simulation and optimization methods used to support decision making within the pharmaceutical development process. The complex nature of drug development is pointed out through a description of the various phases of the pharmaceutical develo...... development process. A part of the paper is dedicated to the use of simulation techniques to support clinical trials. The paper ends with a section describing portfolio modelling methods in the context of the pharmaceutical industry....

  8. DEVELOPMENT OF DOMESTIC INFUSION DRUGS BASED ON PARACETAMOL

    Directory of Open Access Journals (Sweden)

    Almakaeva L.G.

    2016-06-01

    Full Text Available The intravenous form of paracetamol compared with oral more reliably supports effective drug concentration in blood plasma that promotes a higher therapeutic effect. Recent studies have confirmed that the use of the intravenous form of paracetamol to deal with postoperative pain multimodal analgesia modes results in reducing the frequency and quantity of opioids administered , and, as a consequence, its associated side effects. The drug Paracetamol , infusion solution 10 mg / ml to 100 ml glass bottles is a drug - generic . His qualitative and quantitative composition is developed from the study of literature data about the drug - similar to " Perfalhan , 10 mg / ml solution for infusion in 100 mL " company Bristol - Myers Squibb, France and experimental work. The aim of our study is development and support of the national composition of the infusion of the drug on the basis of paracetamol, selection of excipients that provide stability of the active substances. Materials and methods. The object of the study was the substance of paracetamol manufactured by Zhejiang Kangle Pharmaceutical Co. , Ltd, China. During the work conducted qualitative and quantitative monitoring sample preparation for indicators of stability: pH content of the active ingredient , transparency, color, impurities , contamination by the methods described in the SFU [and nor- ral documentation to the drug . One potential factor of instability is the effect of paracetamol oxygen, due to the presence in the molecule of paracetamol and -NH possibility of oxidation. Results and Discussion. Paracetamol is derived atsetamina . Substance acetylation are p - aminophenol with acetic anhydride . Saturated aqueous solution has a pH of paracetamol - ment about 6 . Paracetamol is a crystalline white powder , sparingly soluble in water, soluble in 96% alcohol, very slightly soluble in metilenhloride . . Active substance enters in comparison drug in the concentration of 10 mg/ml. Stable

  9. Recent Advances in Drug Development and Regulatory Science in China.

    Science.gov (United States)

    Chen, Jie; Zhao, Naiqing

    2018-01-01

    As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion.

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

    Science.gov (United States)

    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. 2010 Mount Sinai School of Medicine.

  11. [Does the public sector have an independent research role in the development of drugs?].

    Science.gov (United States)

    Poulsen, Henrik Enghusen; Grønlykke, Thor Buch

    2003-04-14

    Exclusively private companies do drug development. The State contributes with education of academics and basic research constituting the basis of half of the drugs developed by the private companies. The Danish private drug research amounts to six billion DKK per year, corresponding to the estimated price of the development of one new drug. The development shows a negative tendency. There are doubts about the scientific credibility, the number of new drugs is declining, drug development costs are rising, and the competitiveness in Europe is declining compared with the one of The United States. Continued improvement of Danish drug development can be achieved by stimulation of the public research related to drug development.

  12. From research on rare diseases to new orphan drug development

    NARCIS (Netherlands)

    Heemstra, H.E.

    2010-01-01

    Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of drugs

  13. ATLAS Outreach Highlights

    CERN Document Server

    Cheatham, Susan; The ATLAS collaboration

    2016-01-01

    The ATLAS outreach team is very active, promoting particle physics to a broad range of audiences including physicists, general public, policy makers, students and teachers, and media. A selection of current outreach activities and new projects will be presented. Recent highlights include the new ATLAS public website and ATLAS Open Data, the very recent public release of 1 fb-1 of ATLAS data.

  14. Studies Highlight Biodiesel's Benefits

    Science.gov (United States)

    , Colo., July 6, 1998 — Two new studies highlight the benefits of biodiesel in reducing overall air Energy's National Renewable Energy Laboratory (NREL) conducted both studies: An Overview of Biodiesel and Petroleum Diesel Life Cycles and Biodiesel Research Progress, 1992-1997. Biodiesel is a renewable diesel

  15. Developing drug formularies for the "National Medical Holding" JSC.

    Science.gov (United States)

    Akhmadyar, N S; Khairulin, B E; Amangeldy-Kyzy, S; Ospanov, M A

    2015-01-01

    One of the main problems of drug provision of multidisciplinary hospitals is the necessity to improve the efficiency of budget spending. Despite the efforts undertaken in Kazakhstan for improving the mechanism of drug distribution (creation of the Kazakhstan National Formulary, Unified National Health System, the handbook of medicines (drugs) costs in the electronic register of inpatients (ERI), having a single distributor), the number of unresolved issues still remain."National Medical Holding" JSC (NMH) was established in 2008 and unites 6 innovational healthcare facilities with up to 1431 beds (700 children and 731 adults), located in the medical cluster - which are "National Research Center for Maternal and Child Health" JSC (NRCMC), "Republic Children's Rehabilitation Center" JSC (RCRC), "Republican Diagnostic Center" JSC (RDC), "National Centre for Neurosurgery" JSC (NCN), "National Research Center for Oncology and Transplantation" JSC (NRCOT) and "National Research Cardiac Surgery Center" JSC (NRCSC). The main purpose of NMH is to create an internationally competitive "Hospital of the Future", which will provide the citizens of Kazakhstan and others with a wide range of medical services based on advanced medical technology, modern hospital management, international quality and safety standards. These services include emergency care, outpatient diagnostic services, obstetrics and gynecology, neonatal care, internal medicine, neurosurgery, cardiac surgery, transplantation, cancer care for children and adults, as well as rehabilitation treatment. To create a program of development of a drug formulary of NMH and its subsidiaries. In order to create drug formularies of NMH, analytical, software and statistical methods were used.AII subsidiary organizations of NMH (5 out of 6) except for the NRCOT have been accredited by Joint Commission International (JCI) standards, which ensure the safety of patients and clinical staff, by improving the technological

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  18. Drug development in Parkinson's disease: from emerging molecules to innovative drug delivery systems.

    Science.gov (United States)

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2013-11-01

    Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Microdosing and drug development: past, present and future

    Science.gov (United States)

    Lappin, Graham; Noveck, Robert; Burt, Tal

    2015-01-01

    Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date. PMID:23550938

  20. Progress and promise for the MDMA drug development program.

    Science.gov (United States)

    Feduccia, Allison A; Holland, Julie; Mithoefer, Michael C

    2018-02-01

    Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug "Ecstasy." MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself.

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

    Science.gov (United States)

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

    2013-02-01

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

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

    Science.gov (United States)

    Hanna, Debra; Romero, Klaus; Schito, Marco

    2017-03-01

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

  3. Core competencies for pharmaceutical physicians and drug development scientists

    Science.gov (United States)

    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

  4. Safe procedure development to manage hazardous drugs in the workplace

    Directory of Open Access Journals (Sweden)

    Marisa Gaspar Carreño

    2017-03-01

    Full Text Available Objective: To develop a safety working procedure for the employees in the Intermutual Hospital de Levante (HIL in those areas of activity that deal with the handling of hazardous drugs (MP. Methods: The procedure was developed in six phases: 1 hazard definition; 2 definition and identification of processes and development of general correct work practices about hazardous drugs’ selection and special handling; 3 detection, selection and set of specific recommendations to handle with hazardous drugs during the processes of preparation and administration included in the hospital GFT; 4 categorization of risk during the preparation/administration and development of an identification system; 5 information and training of professionals; 6 implementation of the identification measures and prevention guidelines. Results: Six processes were detected handling HD. During those processes, thirty HD were identified included in the hospital GFT and a safer alternative was found for 6 of them. The HD were classified into 4 risk categories based on those measures to be taken during the preparation and administration of each of them. Conclusions: The development and implementation of specific safety-work processes dealing with medication handling, allows hospital managers to accomplish effectively with their legal obligations about the area of prevention and provides healthcare professional staff with the adequate techniques and safety equipment to avoid possible dangers and risks of some drugs.

  5. Core Competencies for Pharmaceutical Physicians and Drug Development Scientists

    Directory of Open Access Journals (Sweden)

    Honorio eSilva

    2013-08-01

    Full Text Available 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 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 Learning Outcomes 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.

  6. Clinical highlights from Amsterdam

    Directory of Open Access Journals (Sweden)

    Jouke T. Annema

    2016-07-01

    Full Text Available This article contains highlights and a selection of the scientific advances from the Clinical Assembly that were presented at the 2015 European Respiratory Society International Congress in Amsterdam, the Netherlands. The most relevant topics for clinicians will be discussed, covering a wide range of areas including interventional pulmonology, rehabilitation and chronic care, thoracic imaging, diffuse and parenchymal lung diseases, and general practice and primary care. In this comprehensive review, exciting novel data will be discussed and put into perspective.

  7. FY 2016 Research Highlights

    Energy Technology Data Exchange (ETDEWEB)

    2017-03-23

    This fact sheet summarizes the research highlights for the Clean Energy Manufacturing Analysis Center (CEMAC) for Fiscal Year 2106. Topics covered include additive manufacturing for the wind industry, biomass-based chemicals substitutions, carbon fiber manufacturing facility siting, geothermal power plant turbines, hydrogen refueling stations, hydropower turbines, LEDs and lighting, light-duty automotive lithium-ion cells, magnetocaloric refrigeration, silicon carbide power electronics for variable frequency motor drives, solar photovoltaics, and wide bandgap semiconductor opportunities in power electronics.

  8. [Chapter 2. Transitions in drug-discovery technology and drug-development in Japan (1980-2010)].

    Science.gov (United States)

    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.

  9. A high efficiency, high quality and low cost internal regulated bioanalytical laboratory to support drug development needs.

    Science.gov (United States)

    Song, Yan; Dhodda, Raj; Zhang, Jun; Sydor, Jens

    2014-05-01

    In the recent past, we have seen an increase in the outsourcing of bioanalysis in pharmaceutical companies in support of their drug development pipeline. This trend is largely driven by the effort to reduce internal cost, especially in support of late-stage pipeline assets where established bioanalytical assays are used to analyze a large volume of samples. This article will highlight our perspective of how bioanalytical laboratories within pharmaceutical companies can be developed into the best partner in the advancement of drug development pipelines with high-quality support at competitive cost.

  10. Imaging mass spectrometry in drug development and toxicology.

    Science.gov (United States)

    Karlsson, Oskar; Hanrieder, Jörg

    2017-06-01

    During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

  11. Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

    Science.gov (United States)

    Long, Marcus John Curtis; Aye, Yimon

    2017-07-20

    This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Safe procedure development to manage hazardous drugs in the workplace.

    Science.gov (United States)

    Gaspar Carreño, Marisa; Achau Muñoz, Rubén; Torrico Martín, Fátima; Agún Gonzalez, Juan José; Sanchez Santos, Jose Cristobal; Cercos Lletí, Ana Cristina; Ramos Orozco, Pedro

    2017-03-01

    To develop a safety working procedure for the employees in the Intermutual Hospital de Levante (HIL) in those areas of activity that deal with the handling of hazardous drugs (MP). The procedure was developed in six phases: 1) hazard definition; 2) definition and identification of processes and development of general correct work practices about hazardous drugs' selection and special handling; 3) detection, selection and set of specific recommendations to handle with hazardous drugs during the processes of preparation and administration included in the hospital GFT; 4) categorization of risk during the preparation/administration and development of an identification system; 5) information and training of professionals; 6) implementation of the identification measures and prevention guidelines. Six processes were detected handling HD. During those processes, thirty HD were identified included in the hospital GFT and a safer alternative was found for 6 of them. The HD were classified into 4 risk categories based on those measures to be taken during the preparation and administration of each of them. The development and implementation of specific safety-work processes dealing with medication handling, allows hospital managers to accomplish effectively with their legal obligations about the area of prevention and provides healthcare professional staff with the adequate techniques and safety equipment to avoid possible dangers and risks of some drugs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  13. Development of Drugs and Technology for Radiation Theragnosis

    Directory of Open Access Journals (Sweden)

    Hwan-Jeong Jeong

    2016-06-01

    Full Text Available Personalized medicine is tailored medical treatment that targets the individual characteristics of each patient. Theragnosis, combining diagnosis and therapy, plays an important role in selecting appropriate patients. Noninvasive in vivo imaging can trace small molecules, antibodies, peptides, nanoparticles, and cells in the body. Recently, imaging methods have been able to reveal molecular events in cells and tissues. Molecular imaging is useful not only for clinical studies but also for developing new drugs and new treatment modalities. Preclinical and early clinical molecular imaging shows biodistribution, pharmacokinetics, mechanisms of action, and efficacy. When therapeutic materials are labeled using radioisotopes, nuclear imaging with positron emission tomography or gamma camera can be used to treat diseases and monitor therapy simultaneously. Such nuclear medicine technology is defined as radiation theragnosis. We review the current development of drugs and technology for radiation theragnosis using peptides, albumin, nanoparticles, and cells.

  14. Development of drugs and technology for radiation theragnosis

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Hwan Jeong [Dept. of Nuclear Medicine, Biomedical Research Institute, Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of); Lee, Byung Chul [Dept. of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Sungnam (Korea, Republic of); Ahn, Byeong Cheol [Dept. of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, Daegu (Korea, Republic of); Kang, Keon Wook [Dept. of Nuclear Medicine and Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

    2016-06-15

    Personalized medicine is tailored medical treatment that targets the individual characteristics of each patient. Theragnosis, combining diagnosis and therapy, plays an important role in selecting appropriate patients. Noninvasive in vivo imaging can trace small molecules, antibodies, peptides, nanoparticles, and cells in the body. Recently, imaging methods have been able to reveal molecular events in cells and tissues. Molecular imaging is useful not only for clinical studies but also for developing new drugs and new treatment modalities. Preclinical and early clinical molecular imaging shows biodistribution, pharmacokinetics, mechanisms of action, and efficacy. When therapeutic materials are labeled using radioisotopes, nuclear imaging with positron emission tomography or gamma camera can be used to treat diseases and monitor therapy simultaneously. Such nuclear medicine technology is defined as radiation theragnosis. We review the current development of drugs and technology for radiation theragnosis using peptides, albumin, nanoparticles, and cells.

  15. Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

    Science.gov (United States)

    Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

    2018-04-19

    Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

  16. Ethical challenges in developing drugs for psychiatric disorders.

    Science.gov (United States)

    Carrier, Felix; Banayan, David; Boley, Randy; Karnik, Niranjan

    2017-05-01

    As the classification of mental disorders advances towards a disease model as promoted by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC), there is hope that a more thorough neurobiological understanding of mental illness may allow clinicians and researchers to determine treatment efficacy with less diagnostic variability. This paradigm shift has presented a variety of ethical issues to be considered in the development of psychiatric drugs. These challenges are not limited to informed consent practices, industry funding, and placebo use. The consideration for alternative research models and quality of research design also present ethical challenges in the development of psychiatric drugs. The imperatives to create valid and sound research that justify the human time, cost, risk and use of limited resources must also be considered. Clinical innovation, and consideration for special populations are also important aspects to take into account. Based on the breadth of these ethical concerns, it is particularly important that scientific questions regarding the development of psychiatric drugs be answered collaboratively by a variety of stakeholders. As the field expands, new ethical considerations will be raised with increased focus on genetic markers, personalized medicine, patient-centered outcomes research, and tension over funding. We suggest that innovation in trial design is necessary to better reflect practices in clinical settings and that there must be an emphasized focus on expanding the transparency of consent processes, regard for suicidality, and care in working with special populations to support the goal of developing sound psychiatric drug therapies. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    Science.gov (United States)

    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. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  18. Non-profit Drug Research and Development at a Crossroads.

    Science.gov (United States)

    Jarosławski, Szymon; Toumi, Mondher; Auquier, Pascal; Dussart, Claude

    2018-02-07

    In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non-profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and "affordable" pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area.

  19. Nanomedicine highlights in atherosclerosis

    International Nuclear Information System (INIS)

    Karagkiozaki, Varvara

    2013-01-01

    Atherosclerosis is a multifactorial disease and many different approaches have been attempted for its accurate diagnosis and treatment. The disease is induced by a low-grade inflammatory process in the vascular wall, leading through a cascade of events to the eventual formation of atheromatous plaque and arterial stenosis. Different types of cells participate in the process making more difficult to recognize the potential cellular targets within the plaques for their effective treatment. The rise of nanomedicine over the last decade has provided new types of drug delivery nanosystems that are able to be delivered to a specific diseased site of the vessel for imaging while simultaneously act as therapeutic agents. In this paper, a review of the recent advances in nanomedicine that has provided novel insights to the disease diagnosis and treatment will be given in line with different nanotechnology-based approaches to advance the cardiovascular stents. The main complications of bare metal stents such as restenosis and of drug-eluting stents which is the late stent thrombosis are analyzed to comprehend the demand for emerging therapeutic strategies based on nanotechnology.

  20. Nanomedicine highlights in atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Karagkiozaki, Varvara, E-mail: vakaragk@physics.auth.gr [Aristotle University of Thessaloniki, Nanomedicine Group, Laboratory for Thin Films-Nanosystems and Nanometrology (LTFN), Physics Department (Greece)

    2013-04-15

    Atherosclerosis is a multifactorial disease and many different approaches have been attempted for its accurate diagnosis and treatment. The disease is induced by a low-grade inflammatory process in the vascular wall, leading through a cascade of events to the eventual formation of atheromatous plaque and arterial stenosis. Different types of cells participate in the process making more difficult to recognize the potential cellular targets within the plaques for their effective treatment. The rise of nanomedicine over the last decade has provided new types of drug delivery nanosystems that are able to be delivered to a specific diseased site of the vessel for imaging while simultaneously act as therapeutic agents. In this paper, a review of the recent advances in nanomedicine that has provided novel insights to the disease diagnosis and treatment will be given in line with different nanotechnology-based approaches to advance the cardiovascular stents. The main complications of bare metal stents such as restenosis and of drug-eluting stents which is the late stent thrombosis are analyzed to comprehend the demand for emerging therapeutic strategies based on nanotechnology.

  1. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    Science.gov (United States)

    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. © The Author(s) 2016. Published by Oxford University Press.

  2. Ion channels and transporters in the development of drug resistance in cancer cells

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay; Lambert, Ian Henry

    2014-01-01

    Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of i...

  3. 75 FR 65495 - Draft Guidance for Industry on Qualification Process for Drug Development Tools; Availability

    Science.gov (United States)

    2010-10-25

    ...] Draft Guidance for Industry on Qualification Process for Drug Development Tools; Availability AGENCY... Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm... Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 21, rm...

  4. Highlights from CMS

    CERN Document Server

    Autermann, Christian

    2018-01-01

    This article summarizes the latest highlights from the CMS experiment as presented at the Lepton Photon conference 2017 in Guangzhou, China. A selection of the latest physics results, the latest detector upgrades, and the current detector status are discussed. CMS has analyzed the full dataset of proton-proton collision data delivered by the LHC in 2016 at a center-of-mass energy of $13$\\,TeV corresponding to an integrated luminosity of $40$\\,fb$^{-1}$. The leap in center-of-mass energy and in luminosity with respect to the $7$ and $8$\\,TeV runs enabled interesting and relevant new physics results. A new silicon pixel tracking detector was installed during the LHC shutdown 2016/17 and has successfully started operation.

  5. PSI scientific highlights 2012

    International Nuclear Information System (INIS)

    Piwnicki, P.; Dury, T.

    2013-05-01

    This comprehensive report issued by the Paul Scherrer Institute (PSI) reviews research in various areas carried out by the institute in 2012. Also, the various facilities to be found at the institute are described. Research focus and highlights are discussed. These include work done using synchrotron light, neutrons and muons as well as work done in the particle physics, microtechnology and nanotechnology areas. Further areas of research include biomolecular research, radiopharmacy, radiochemistry and environmental chemistry. Other areas covered include general energy research and work done at the Competence Center for Energy and Mobility CCEM, work done on nuclear energy safety as well as systems analysis in the environmental and energy areas. The report is concluded with facts and figures on the PSI, its Advisory Board and its organisational structures

  6. [New drug developments of snake venom polypeptides and progress].

    Science.gov (United States)

    Fu, Sihai; Feng, Mei; Xiong, Yan

    2017-11-28

    The value of snake venom polypeptides in clinical application has drawn extensive attention, and the development of snake polypeptides into new drugs with anti-tumor, anti-inflammatory, antithrombotic, analgesic or antihypertensive properties has become the recent research hotspot. With the rapid development of molecular biology and biotechnology, the mechanisms of snake venom polypeptides are also gradually clarified. Numerous studies have demonstrated that snake venom polypeptides exert their pharmacological effects by regulating ion channels, cell proliferation, apoptosis, intracellular signaling pathway, and expression of cytokine as well as binding to relevant active sites or receptors.

  7. Discovery and development of new antibacterial drugs: learning from experience?

    Science.gov (United States)

    Jackson, Nicole; Czaplewski, Lloyd; Piddock, Laura J V

    2018-06-01

    Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.

  8. Bridging Adult Experience to Pediatrics in Oncology Drug Development.

    Science.gov (United States)

    Leong, Ruby; Zhao, Hong; Reaman, Gregory; Liu, Qi; Wang, Yaning; Stewart, Clinton F; Burckart, Gilbert

    2017-10-01

    Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers. © 2017, The American College of Clinical Pharmacology.

  9. Challenges and opportunities for the development of new antipsychotic drugs.

    Science.gov (United States)

    Forray, Carlos; Buller, Raimund

    2017-11-01

    In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a

  10. Which Benefits Are Mentioned Most Often in Drug Development Publications?

    Directory of Open Access Journals (Sweden)

    Vanessa Strüver, MSc

    2017-01-01

    Conclusions: Both theoretically expected and actually reported benefits in the majority of the included publications emphasized the importance of individual patient benefits from drug development rather than the collective benefits to society in general. The authors of these publications emphasized the right of each individual patient or subject to look for and expect some personal benefit from participating in a clinical trial rather than considering societal benefit as a top priority. From an ethical point of view, the benefits each individual patient receives from his or her participation in a clinical trial might also be seen as a societal benefit, especially when the drug or device tested, if approved for marketing, would eventually be made available for other similar patients from the country in which the clinical trial was conducted.

  11. Drug-diagnostics co-development in oncology

    Directory of Open Access Journals (Sweden)

    Richard eSimon

    2013-12-01

    Full Text Available Developments in genomics are providing a biological basis for the heterogeneity of clinical course and response to treatment that have long been apparent to clinicians The ability to molecularly characterize of human diseases presents new opportunities to develop more effective treatments and new challenges for the design and analysis of clinical trials.In oncology, treatment of broad populations with regimens that benefit a minority of patients is less economically sustainable with expensive molecularly targeted therapeutics. The established molecular heterogeneity of human diseases requires the development of new paradigms for the design and analysis of randomized clinical trials as a reliable basis for predictive medicine. We review prospective designs for the development of new therapeutics and predictive biomarkers to inform their use. We cover designs for a wide range of settings. At one extreme is the development of a new drug with a single candidate biomarker and strong biological evidence that marker negative patients are unlikely to benefit from the new drug. At the other extreme are phase III clinical trials involving both genome-wide discovery of a predictive classifier and internal validation of that classifier. We have outlined a prediction based approach to the analysis of randomized clinical trials that both preserves the type I error and provides a reliable internally validated basis for predicting which patients are most likely or unlikely to benefit from a new regimen.

  12. Biomarkers as drug development tools: discovery, validation, qualification and use.

    Science.gov (United States)

    Kraus, Virginia B

    2018-06-01

    The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

  13. Sex, gender, and pharmaceutical politics: From drug development to marketing.

    Science.gov (United States)

    Fisher, Jill A; Ronald, Lorna M

    2010-08-01

    Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing. This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials. The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals. The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome. Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and

  14. The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases

    Directory of Open Access Journals (Sweden)

    Peter Mubanga Cheuka

    2016-12-01

    Full Text Available Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness, leishmaniasis, schistosomiasis and lymphatic filariasis.

  15. Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

    Science.gov (United States)

    Maeda, Hideki; Kurokawa, Tatsuo

    2015-12-01

    This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

  16. Cancer Drug Development: New Targets for Cancer Treatment.

    Science.gov (United States)

    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

  17. Adolescent neurocognitive development, self-regulation, and school-based drug use prevention.

    Science.gov (United States)

    Pokhrel, Pallav; Herzog, Thaddeus A; Black, David S; Zaman, Adnin; Riggs, Nathaniel R; Sussman, Steve

    2013-06-01

    Adolescence is marked by several key development-related changes, including neurocognitive changes. Cognitive abilities associated with self-regulation are not fully developed until late adolescence or early adulthood whereas tendencies to take risks and seek thrilling and novel experience seem to increase significantly throughout this phase, resulting in a discrepancy between increased susceptibility to poor regulation and lower ability to exercise self-control. Increased vulnerability to drug use initiation, maintenance, and dependence during adolescence may be explained based on this imbalance in the self-regulation system. In this paper, we highlight the relevance of schools as a setting for delivering adolescent drug use prevention programs that are based on recent findings from neuroscience concerning adolescent brain development. We discuss evidence from school-based as well as laboratory research that suggests that suitable training may improve adolescents' executive brain functions that underlie self-regulation abilities and, as a result, help prevent drug use and abuse. We note that considerable further research is needed in order (1) to determine that self-regulation training has effects at the neurocognitive level and (2) to effectively incorporate self-regulation training based on neuropsychological models into school-based programming.

  18. RESEARCH HIGHLIGHTS IN IAS

    Directory of Open Access Journals (Sweden)

    Marko Kreft

    2017-03-01

    Full Text Available We are reviewing and commenting highlights of the research published in Image Analysis and Stereology journal (IAS, volume 35, where 16 original research papers on image analysis, computer vision, modelling, and other approaches were published. We have reported on the precision of curve length estimation in the plane. Further, a focus was on a robust estimation technique for 3D point cloud registration. Next contribution in computer vision was on the accuracy of stereo matching algorithm based on illumination control. An attempt was also made to automatically diagnose prenatal cleft lip with representative key points and identify the type of defect in three-dimensional ultrasonography. Similarly, a new report is presenting estimation of torsion of digital curves in 3D images and next, the nuchal translucency by ultrasound is being analyzed. Also in ophthalmology, image analysis may help physicians to establish a correct diagnosis, which is supported by a new approach to measure tortuosity of retinal vessel. Another report of medical significance analyzed correlation of the shape parameters for characterization of images of corneal endothelium cells. Shape analysis is also an important topic in material science, e.g. in analyzing fine aggregates in concrete. As in concrete, in fiber reinforced composites image analysis may aid in improved quality, where the direction of fibers have decisive impact on properties. Automatic defect detection using a computer vision system improves productivity quality in industrial production, hence we report of a new Haar wavelet-based approach.

  19. Synthesis and applications of radiolabelled drugs in pharmaceutical development

    International Nuclear Information System (INIS)

    Landvatter, S.W.; Heys, J.R.; Garner, K.T.; Mack, J.F.; Senderoff, S.G.; Shu, A.Y.; Villani, A.J.; Saunders, D.

    1994-01-01

    Radiolabelled drugs play a vital role in the development of new pharmaceuticals including application in drug discovery, pre-clinical development and clinical development. The synthesis of these pharmaceuticals in tritium or carbon-14 labelled form poses many challenges for the synthetic organic chemist. The actual choice of synthetic route must take into account the small scale, limited choice and high cost of labelled precursors, and the positioning of the label into a metabolically stable position. There are, however, a number of synthetic strategies available for overcoming these constraints. Although in some C-14 syntheses the requisite labelled raw material can be purchased and the existing synthesis adapted for labelling, frequently the synthetic challenge is the synthesis of a structurally simple, yet commercially unavailable, labelled precursor (e.g., γ-butyrolactone-[2- 14 C], cyclohexanone-[ 3 H], CuCN-[ 14 C], 2-furancarboxaldehyde-[ 14 C]). Another useful strategy in C-14 synthesis is the conversion of an advanced intermediate, or perhaps the unlabelled product itself, into a precursor which can then be reconverted into the labelled version of the intermediate. Occasionally, a new total synthesis must be developed. In addition to these strategies, tritium labelling can uniquely take advantage of exchange labelling techniques, synthesis and reduction of unsaturated precursors, or tritium-halogen replacement reactions. Examples of these strategies and use of the labelled products are discussed

  20. In silico machine learning methods in drug development.

    Science.gov (United States)

    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.

  1. Development of immunotoxicity testing strategies for immunomodulatory drugs.

    Science.gov (United States)

    Kawabata, Thomas T; Evans, Ellen W

    2012-01-01

    The ICH S8 immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional immunotoxicity testing should be considered. For most situations, immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed.

  2. Development of anti-inflammatory drugs - the research and development process.

    Science.gov (United States)

    Knowles, Richard Graham

    2014-01-01

    The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

  3. Drugs in development for toxoplasmosis: advances, challenges, and current status.

    Science.gov (United States)

    Alday, P Holland; Doggett, Joseph Stone

    2017-01-01

    Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

  4. Ethnobotany and ethnopharmacy--their role for anti-cancer drug development.

    Science.gov (United States)

    Heinrich, Michael; Bremner, Paul

    2006-03-01

    Local and traditional knowledge has been the starting point for many successful drug development projects over the last decades. Here we discuss some examples of anti-cancer drugs which have had enormous impact as anti-cancer agents (camptothecan, taxol and derivatives) and a few examples of drugs currently under various stages of preclinical development. Ethnobotanists investigate the relationship between humans and plants in all its complexity, and such research is generally based on a detailed observation and study of the use a society makes of plants. The requirements of modern research on natural products as, for example, outlined in the Convention on Biological Diversity (Rio Convention) and the overall approach in ethnobotanical research are also discussed. Selected phytochemical-pharmacological studies based on traditional plant use are used to highlight the potential of ethnobotany driven anti-cancer research. The link between traditionally used plants and targets of the NF-kappaB pathway is discussed using on an EU-funded, multidisciplinary project as an example. Lastly the potential of chemopreventive agents derived from traditional food plants is briefly addressed.

  5. Development and evaluation of an electronic drug and therapeutics bulletin.

    Science.gov (United States)

    Alderman, Christopher P

    2002-10-01

    To describe the development, implementation, and initial evaluation of a paperless drug and therapeutics bulletin that is distributed by electronic mail from the pharmacy department of an Australian teaching hospital. A standardized format for the bulletin was designed and approved in February 2001. The aim of the bulletin is to facilitate the timely dissemination of concise, factual information about issues of current interest in therapeutics, drug safety, and the cost-effective use of medicines. A simple and attractive graphic design was chosen, and the hospital's clinical pharmacists and drug information staff developed an initial bank of content during the period immediately preceding the launch. The bulletin is presented as a 1-page, read-only file in Word for Windows format and was initially distributed by electronic mail to all users of the hospital's computerized communication network. As the popularity of the bulletin increased, healthcare practitioners from outside of the hospital began to request permission for inclusion on the circulation list, and the content was frequently forwarded by E-mail to workers in other hospitals and community-based settings. The bulletin is now distributed to pharmacists around Australia via 2 separate moderated discussion lists, one of which provides an archive site for previous editions. Healthcare workers in Singapore, the US, Canada, and New Zealand also receive the bulletin, which is now also abstracted by a major Australian pharmacy journal. A readership survey (also electronically distributed) was used to seek feedback after the publication of the first 12 editions. Readers indicated a high level of satisfaction with the content, format, and frequency of distribution of the materials. Although the concept and execution of this project was relatively simple, an extensive literature review did not reveal any previously published reports describing this type of approach to the distribution of a pharmacy bulletin. The

  6. Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea.

    Science.gov (United States)

    Mash, Deborah C; Kovera, Craig A; Buck, Billy E; Norenberg, Michael D; Shapshak, Paul; Hearn, W Lee; Sanchez-Ramos, Juan

    1998-05-01

    The potential for deriving new psychotherapeutic medications from natural sources has led to renewed interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for the treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

  7. Medication development of ibogaine as a pharmacotherapy for drug dependence.

    Science.gov (United States)

    Mash, D C; Kovera, C A; Buck, B E; Norenberg, M D; Shapshak, P; Hearn, W L; Sanchez-Ramos, J

    1998-05-30

    The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

  8. What does systems biology mean for drug development?

    Science.gov (United States)

    Schrattenholz, André; Soskić, Vukić

    2008-01-01

    regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.

  9. Oil shale highlights

    International Nuclear Information System (INIS)

    1994-01-01

    The low prices of crude oil have continued to retard the commercial development of oil shale and other syn fuels. Although research funds are more difficult to find, some R and D work by industry, academia, and governmental agencies continues in the United States and in other parts of the world. Improvements in retorting technology, upgrading oil-shale feedstock, and developing high-value niche-market products from shale oil are three notable areas of research that have been prominent for the past several years. Although the future prices of conventional crude cannot be predicted, it seems evident that diminishing supplies and a burgeoning world population will force us to turn to alternate fossil fuels as well as to cleaner sources of non-fossil energy. (author)

  10. BARC highlights 1991

    International Nuclear Information System (INIS)

    1992-01-01

    Some of the important research and development (R and D) activities carried out at the Centre during the last two or three years are described in brief. The descriptions are arranged under the headings : Physical Sciences, Chemical Sciences, Material and Materials Science, Radioisotopes, Reactors, Fuel Cycle, Radiological Safety and Protection, Electronics and Instrumentation, Engineering Services, and Life Sciences. The text is illustrated with a number of photographs - some of them coloured. (M.G.B.)

  11. Interdisciplinary researches for potential developments of drugs and natural products

    Directory of Open Access Journals (Sweden)

    Arunrat Chaveerach

    2017-04-01

    Full Text Available Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs. The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas, such as foods, traditional medicine, fragrances and seasonings. Then those data will be associated with scientific researches, namely plant collection and identification, phytochemical screening by gas chromatography-mass spectrometry, pharmacological study/review for their functions, and finally safety and efficiency tests in human. For safety testing, in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed. When active chemicals and functions containing plants were chosen with safety and efficacy for human uses, then, the potential medicinal natural products will be produced. Based on these procedures, the producing cost will be cheaper and the products can be evaluated for their clinical properties. Thus, the best and lowest-priced medicines and natural products can be distributed worldwide.

  12. Drug discovery and development tomorrow -- changing the mindset.

    Science.gov (United States)

    Coleman, Robert A

    2009-09-01

    Today's drug discovery and development paradigm is not working, and something needs to be done about it. There is good reason to believe that a move away from reliance on animal surrogates for human subjects in the Pharma Industry's R&D programmes could provide an important step forward. However, no serious move will be made in that direction until there is some hard evidence that it will be rewarded with improved productivity outcomes. The Safer Medicines Trust are proposing that a study be undertaken, involving a range of drugs that have been approved for human use, but have subsequently proved to have limitations in terms of safety and/or efficacy. The aim is to determine the efficiency of a battery of human-based test methods to identify a compound's safety and efficacy profiles, and to compare this with that of the more traditional, largely animal-based methods that were employed in their original development. Should such an approach prove more reliable, the authorities will be faced with important decisions relating to the role of human biological test data in regulatory submissions, while the Pharma Industry will be faced with the key logistical issue of how to acquire the human biomaterials necessary to make possible the routine application of such test methods. 2009 FRAME.

  13. Interdisciplinary researches for potential developments of drugs and natural products

    Institute of Scientific and Technical Information of China (English)

    Arunrat Chaveerach; Runglawan Sudmoon; Tawatchai Tanee

    2017-01-01

    Developments of drugs or natural products from plants are possibly made,simple to use and lower cost than modern drugs.The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas,such as foods,traditional medicine,fragrances and seasonings.Then those data will be associated with scientific researches,namely plant collection and identification,phytochemical screening by gas chromatography-mass spectrometry,pharmacological study/review for their functions,and finally safety and efficiency tests in human.For safety testing,in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed.When active chemicals and functions containing plants were chosen with safety and efficacy for human uses,then,the potential medicinal natural products will be produced.Based on these procedures,the producing cost will be cheaper and the products can be evaluated for their clinical properties.Thus,the best and lowest-priced medicines and natural products can be distributed worldwide.

  14. Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids.

    Science.gov (United States)

    Hamilton, Gregory S

    2015-09-01

    Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that combine the targeting ability of monoclonal antibodies (mAbs) with small molecule drugs. The combination of a mAb targeting a cancer-specific antigen with a cytotoxin has tremendous promise as a new type of targeted cancer therapy. Two ADCs have been approved and many more are in clinical development, suggesting that this new class of drugs is coming to the forefront. Because of their unique nature as biologic-small drug hybrids, ADCs are challenging to develop, from both the scientific and regulatory perspectives. This review discusses both these aspects in current practice, and surveys the current state of the art of ADC drug development. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  15. BARC highlights 86

    International Nuclear Information System (INIS)

    1987-01-01

    The Bhabha Atomic Research Centre (BARC), Bombay, is the premier multidisciplinary research establishment of the Department of Atomic Energy (India). It provides Research and Development (R and D) support to the nuclear programmes of the country. Some of its important R and D activities and achievements during 1986 are described in brief in the chapters entitled: Physical Sciences, Chemical Sciences, Materials and Materials Sciences, Life Sciences, Reactors, Fuel Cycle, and Electronics and Instrumentation. The entire text is illustrated with a number of diagrams and photographs. (M.G.B.)

  16. Cytogenetic highlights and transitions.

    Science.gov (United States)

    Spinner, Nancy B

    2016-06-01

    Medical cytogenetics, genetic diagnostics, and medical genetics had their origins in the late 1950's, as evaluation of human chromosomes became possible, and it was recognized that chromosomal abnormalities could cause a variety of clinical phenotypes. Dr. Laird Jackson began his medical and scientific career just as this field was emerging and he was an early adopter and driver of several key trends in the development of these fields, notably in the area of prenatal diagnostics. Laird's greatest impact was in his work to demonstrate the clinical utility of amniocentesis, chorionic villous sampling, and chromosomal microarray analysis for prenatal diagnosis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Summary and highlights

    Directory of Open Access Journals (Sweden)

    Alimonti G.

    2013-06-01

    Full Text Available Energy means development, and access to energy and electricity should be possible for everyone. The energy challenge for the years to come is to have a sustainable energy supply and after the week spent in Varenna it is clear that “sustainable” cannot be identified with green gas emission reduction only: it has to be an energy supply system respectful of the environment and the humankind, able to provide reliable and affordable energy to the whole world population. This is definitely not an easy challenge: no single energy technology will suffice to safeguard our future and any possible solution has to be exploited at its best, from renewable to nuclear energy, from clean fossil fuels to biofuels. Last but not least, it is the energy efficiency that, given the actual technology, may give the most important and immediate contribution to this challenge. Meanwhile researchers must examine a broad range of options and develop different kinds of technologies: only new investments on R&D can allow to meet the growing demand for energy in a responsible, equitable, and sustainable way.

  18. Highlights of the Workshop

    Science.gov (United States)

    Noor, Ahmed K.

    1997-01-01

    Economic stresses are forcing many industries to reduce cost and time-to-market, and to insert emerging technologies into their products. Engineers are asked to design faster, ever more complex systems. Hence, there is a need for novel design paradigms and effective design tools to reduce the design and development times. Several computational tools and facilities have been developed to support the design process. Some of these are described in subsequent presentations. The focus of the workshop is on the computational tools and facilities which have high potential for use in future design environment for aerospace systems. The outline for the introductory remarks is given. First, the characteristics and design drivers for future aerospace systems are outlined; second, simulation-based design environment, and some of its key modules are described; third, the vision for the next-generation design environment being planned by NASA, the UVA ACT Center and JPL is presented. The anticipated major benefits of the planned environment are listed; fourth, some of the government-supported programs related to simulation-based design are listed; and fifth, the objectives and format of the workshop are presented.

  19. Energy Policy. Highlights. 2013 Edition

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-07-01

    Energy Policy Highlights showcases recent developments in energy policies among all 28 IEA member countries. Each contribution underscores the changing nature of both global and domestic energy challenges, as well as the commonality of energy concerns among member countries. The policies highlighted in this publication identify an urgent need to reduce greenhouse gas (GHG) emissions as a clear policy objective. Electricity, enhancing energy efficiency and increasing the share of renewables in the energy mix in a cost effective manner are likewise areas of common focus. On the end-user side, increasing public awareness of domestic energy policies through improved transparency and engagement is an important facet of policy support among IEA member countries. The successful implementation of policies and other initiatives benefitted from efforts to inform the public.

  20. Peripatetic Highlights in Bern

    Science.gov (United States)

    Hentschel, Ann M.

    The capital city of the Swiss Canton of Bern and of the Swiss Confederation is nestled in a narrow loop of the Aare river, at the foot of the Alps. The old town, founded around 1191, is well preserved despite a devastating fire in 1405.** Major industries of the region developed under the constraints of modest domestic markets, high transportation costs, and protectionist legislation across national borders. Switzerland thus found its niche in higher-end markets, such as chocolate making, engine building, instruments, fine textiles, and chemicals or pharmaceuticals. My tour past historically significant scientific sites in Bern will use the local legacy of its most illustrious residents, Albert Einstein (1879-1955), who lived there from 1902-1909, and Fritz Houtermans (1903-1966), who lived there from 1952-1966, as its guiding thread through the old town and the university district. Place names in italics mark stops along the tour.

  1. LISA system design highlights

    Energy Technology Data Exchange (ETDEWEB)

    Sallusti, M [European Space Agency, ESTEC, Keplerlaan 1, 2200 AG Noordwijk ZH (Netherlands); Gath, P; Weise, D; Berger, M; Schulte, H R, E-mail: marcello.sallusti@esa.in, E-mail: peter.gath@astrium.eads.ne, E-mail: dennis.weise@astrium.eads.ne, E-mail: marcel.berger@astrium.eads.ne, E-mail: Hans.Reiner.Schulte@astrium.eads.ne [Astrium GmbH Satellites, Claude-Dornier-Str., 88039 Friedrichshafen (Germany)

    2009-05-07

    A contract, started in January 2005, was awarded to a consortium of Astrium GmbH and Astrium Ltd for the LISA Mission Formulation. The scope of the contract was the development of a reference design for the mission architecture and for the mission elements (with particular focus on the payload) and a successive phase of derivation of requirements, to be concluded with a mission design review. The technical starting point was the output of the previous LISA study formalized in the Final Technical Report, issued in the year 2000. During the design phase, different architecture concepts were identified and traded off, including the LISA orbits, the measurement scheme and the opto-mechanical architecture. During the Mission Design Review (July 2008) the consolidated mission baseline design, and the specifications of the flight elements and of the payload subsystem and major components were presented. This paper gives a brief overview of the major design points of the latest design of the LISA system.

  2. LISA system design highlights

    International Nuclear Information System (INIS)

    Sallusti, M; Gath, P; Weise, D; Berger, M; Schulte, H R

    2009-01-01

    A contract, started in January 2005, was awarded to a consortium of Astrium GmbH and Astrium Ltd for the LISA Mission Formulation. The scope of the contract was the development of a reference design for the mission architecture and for the mission elements (with particular focus on the payload) and a successive phase of derivation of requirements, to be concluded with a mission design review. The technical starting point was the output of the previous LISA study formalized in the Final Technical Report, issued in the year 2000. During the design phase, different architecture concepts were identified and traded off, including the LISA orbits, the measurement scheme and the opto-mechanical architecture. During the Mission Design Review (July 2008) the consolidated mission baseline design, and the specifications of the flight elements and of the payload subsystem and major components were presented. This paper gives a brief overview of the major design points of the latest design of the LISA system.

  3. Brookhaven highlights 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-12-31

    Established in 1947 on Long Island, New York, on the site of the former army Camp Upton, BNL is a multidisciplinary laboratory that carries out basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is managed by Associated Universities, Inc., under contract to the US Department of Energy. BNL`s annual budget is about $400 million, and the Laboratory`s facilities are valued at replacements cost in excess of over $2.8 billion. Employees number around 3,300,and over 4,000 guests, collaborators and students come each year to use the Laboratory`s facilities and work with the staff. Scientific and technical achievements at BNL have made their way into daily life in areas as varied as health care, construction materials and video games. The backbone of these developments is fundamental research, which is and always will be an investment in the future.

  4. Highlights of CP 2000

    CERN Document Server

    Ellis, John R.

    2001-01-01

    Various developing topics in CP violation are reviewed. There are many theoretical reasons to hope that the CKM paradigm may be incomplete. It is surely too soon to be claiming new physics in \\epsilon^\\prime/\\epsilon or in D^0-\\bar D^0 mixing, but rare K decays offer interesting places to search for new physics. It is probably also premature to see a clash between global CKM fits and current estimates of sin \\beta and \\gamma, where much more precise data will soon be available. There are interesting possibilities to look for CP violation in neutrino oscillations and in Higgs physics. Rapid progress can be expected now that CP violation is moving to the top of the particle physics agenda.

  5. Highlights in subnuclear physics

    CERN Document Server

    Wolf, G

    2003-01-01

    An overview on new developments in experimental particle and astroparticle physics is presented. This includes observation of CP violation in the B-sector, detection of direct CP violation in the K /sup 0/-system, new measurements on solar neutrinos, cosmic microwave background radiation and properties of the universe, electroweak results from the large colliders and tests of the standard model, measurement of the anomalous magnetic moment of muons, structure of the proton at large energy transfers and virtualities, and heavy ion collisions at very high energies. Finally, the physics reach of TEVATRONII, LHC and TESLA, a linear e/sup +/e/sup -/ collider proposed for the 0.5 1 TeV regime, is briefly reviewed. (93 refs).

  6. Brookhaven highlights 1994

    International Nuclear Information System (INIS)

    1994-01-01

    Established in 1947 on Long Island, New York, on the site of the former army Camp Upton, BNL is a multidisciplinary laboratory that carries out basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is managed by Associated Universities, Inc., under contract to the US Department of Energy. BNL's annual budget is about $400 million, and the Laboratory's facilities are valued at replacements cost in excess of over $2.8 billion. Employees number around 3,300,and over 4,000 guests, collaborators and students come each year to use the Laboratory's facilities and work with the staff. Scientific and technical achievements at BNL have made their way into daily life in areas as varied as health care, construction materials and video games. The backbone of these developments is fundamental research, which is and always will be an investment in the future

  7. February 2017 - NIF Highlights

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, K. B. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2017-03-13

    February was a very productive month with only 20 shot days on the calendar. There were 41 target shots performed for the HED, ICF, and the Discovery Science (DS) program. The DS program had a week dedicated to their experiments that was extraordinarily fruitful: 14 target shots were performed for five independent teams, each of whom had a unique experimental platform to field. The teams and the facility worked extraordinarily well to pull off this feat! Additionally, the facility developed high-energy laser operations on a demonstration quad to investigate taking NIF to a new level of performance, and the ICF program demonstrated a 40% increase in the yield from a capsule that had a new, 5-μm-diameter fill tube that apparently mitigates some of the issues that have affected implosions to date. Details follow below.

  8. 2012 Ground Testing Highlights

    Science.gov (United States)

    Buchholz, Steven J.

    2012-01-01

    As part of the Fundamental Aeronautics Program and a collaborative effort with Boeing, and Lockheed Martin this past year a series of sonic boom test were completed in the NASA Ames Unitary Plan Wind Tunnel (UPWT). One of the goals was to develop new test techniques and hardware for measuring sonic boom signatures in the transonic and supersonic regimes. Data for various model designs and configurations were collected and will be used to validate CFD predictions of sonic boom signatures. Reactivation of the NASA Ames Mitsubishi compressor system was completed this past year. The compressor is intended to replace and augment the existing UPWT Clark Compressor as the primary Make Up Air (MUA) source. The MUA system provides air and vacuum pumping capability to the Ames UPWT. It will improve productivity and reliability of the UPWT as a vital testing and research facility for the U.S. aerospace industry and NASA. Funding for this task was provided from the American Recovery Investment Act (ARRA). Installation and validation of a Noncontact Stress Monitoring System (NSMS) for the 3-stage compressor was completed at the 11-foot Transonic Wind Tunnel. The system, originally developed at AEDC, consists of 36 pairs of LED light sources with optic beam send and receive probes along a 1-per rev signal. The new system allows for continuous monitoring and recording of compressor blade bending and torsion stress during normal test operations. A very unusual test was completed in the 11 FT TWT to acquire aerodynamic and flow field data for the Crew Exploration Vehicle (CEV) Parachute Assembly System (CPAS) to validate CFD methods and tools. Surface pressure distribution measurements and velocity measurements in the wake of the command module back to the drogues parachute location were acquired. Testing methods included Particle Image Velocimetry (PIV), Pressure Sensitive Paint (PSP), Schlieren Infrared Imaging (IR) and boundary layer survey and skin friction.

  9. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development.

    Science.gov (United States)

    Senese, S; Lo, Y C; Huang, D; Zangle, T A; Gholkar, A A; Robert, L; Homet, B; Ribas, A; Summers, M K; Teitell, M A; Damoiseaux, R; Torres, J Z

    2014-10-16

    Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAF(V600E) melanomas.

  10. Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

    Science.gov (United States)

    Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

    2017-05-01

    Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

  11. A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

    Science.gov (United States)

    Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U

    2011-08-01

    Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike. Copyright © 2011 Wiley-Liss, Inc.

  12. The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America.

    Science.gov (United States)

    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.

  13. 77 FR 11133 - Draft Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for...

    Science.gov (United States)

    2012-02-24

    ...] Draft Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for Treatment... Urinary Tract Infections: Developing Drugs for Treatment.'' The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of complicated urinary tract infections (c...

  14. HIGHLIGHTS OF MAGNETOELECTROPOLISHING

    Directory of Open Access Journals (Sweden)

    Tadeusz eHryniewicz

    2014-05-01

    Full Text Available The research work has been concerned on the studies and development of electrochemical polishing in the magnetic field (MEP in comparison with the standard electropolishing methods performed without stirring (EP and the process with the forced electrolyte mixing (MIX. Advanced techniques were used in the studies, to measure the effects of the surface treatment. They are as follows: scanning electron microscopy (SEM/EDS, X-ray Photoelectron Spectroscopy (XPS, Secondary Ion Mass Spectroscopy (SIMS, surface roughness, and nanoindentation measurements. For the corrosion studies, the electrochemical methods were used, such as: open circuit potential OCP, potentiodynamic curves PC, and electrochemical impedance spectroscopy EIS measurements. The MEP process is advised mainly due to the opportunity to enrich the surface layer with the chromium compounds (austenitic stainless steels, or titanium compounds (CP Ti Grade 2, Nitinol. The surface layers of biomaterials after MEP process contain much lower amount of carcinogenic compounds, like chromium VI oxidation stage (Cr6+ (austenitic stainless steels and nickel compounds (austenitic stainless steel & Nitinol versus those ones obtained after EP & MIX treatments. It is interesting that apart from the significant modification of the surface layer obtained after MEP, also mechanical properties, such as nanohardness, modulus of elasticity, and mechanical resistance to bending and torsion, undergo considerable advantageous changes. All they make the MEP process very promising for application in many clean industries, such as medical equipment and devices, electronics, food industry, etc.

  15. Developing a Molecular Roadmap of Drug-Food Interactions

    DEFF Research Database (Denmark)

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni

    2015-01-01

    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...... view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in Drug-Bank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing......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...

  16. Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

    Science.gov (United States)

    Jardim, Denis L; de Melo Gagliato, Débora; Giles, Francis J; Kurzrock, Razelle

    2018-04-15

    Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785-94. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. Origin and Development of Drug Addiction in South Asia with Special Reference to Pakistan

    Directory of Open Access Journals (Sweden)

    Syeda Farhana Sarfaraz

    2011-09-01

    Full Text Available During the course of this search man has extracted opium from poppy plant, cocaine from the leaves of coca bush, and cannabis from the hemp plant. Initially the use of these was only for the purpose of relieving the physical and mental capabilities, and for medicinaland surgical purpose. But the human spirit of innovation must have led to the use of these substances for mood-altering effects and offer an escape from the real and difficult world of existence to a more agreeable world of fantasy. These things are perhaps a few of the oldest natural substances a fewer of the oldest natural substances used by human race.The major purpose of the study is to highlight the origin and development of the drug addiction in the South Asian region, and discover its impacts on Pakistan. The problem of the drug addiction, which once could be learned as a by-product of drug traffickingthroughout Pakistan has become a major challenge for the governments, philanthropists and the social reformers of this age. The present extent of addiction depicts a bleak future for the generation to come, unless a revolutionary, well-coordinated and determined approach is envisaged and implemented.

  18. Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective.

    Science.gov (United States)

    Fornaro, Michele; Kardash, Lubna; Novello, Stefano; Fusco, Andrea; Anastasia, Annalisa; De Berardis, Domenico; Perna, Giampaolo; Carta, Mauro Giovanni

    2018-03-01

    Bipolar disorder (BD) is a considerable burden to the affected individual. The need for novel drug targets and improved drug design (DD) in BD is therefore clear. Areas covered: The following article provides a brief, narrative, clinician-oriented overview of the most promising novel pharmacological targets for BD along with a concise overview regarding the general DD process and the unmet needs relevant to BD. Expert opinion: A number of novel potential drug targets have been investigated. With the notable exception of the kynurenine pathway, available evidence is too scarce to highlight a definitive roadmap for forthcoming DD in BD. BD itself may present with different facets, as it is a polymorphic clinical spectrum. Therefore, promoting clinical-case stratification should be based on precision medicine, rather than on novel biological targets. Furthermore, the full release of raw study data to the scientific community and the development of uniform clinical trial standards (including more realistic outcomes) should be promoted to facilitate the DD process in BD.

  19. Approaches to modernize the combination drug development paradigm

    Directory of Open Access Journals (Sweden)

    Daphne Day

    2016-10-01

    Full Text Available Abstract Recent advances in genomic sequencing and omics-based capabilities are uncovering tremendous therapeutic opportunities and rapidly transforming the field of cancer medicine. Molecularly targeted agents aim to exploit key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality. Additionally, immunotherapies targeting the host immune system are proving to be another promising and complementary approach. Owing to substantial tumor genomic and immunologic complexities, combination strategies are likely to be required to adequately disrupt intricate molecular interactions and provide meaningful long-term benefit to patients. To optimize the therapeutic success and application of combination therapies, systematic scientific discovery will need to be coupled with novel and efficient clinical trial approaches. Indeed, a paradigm shift is required to drive precision medicine forward, from the traditional “drug-centric” model of clinical development in pursuit of small incremental benefits in large heterogeneous groups of patients, to a “strategy-centric” model to provide customized transformative treatments in molecularly stratified subsets of patients or even in individual patients. Crucially, to combat the numerous challenges facing combination drug development—including our growing but incomplete understanding of tumor biology, technical and informatics limitations, and escalating financial costs—aligned goals and multidisciplinary collaboration are imperative to collectively harness knowledge and fuel continual innovation.

  20. Developing a Dissociative Nanocontainer for Peptide Drug Delivery

    Directory of Open Access Journals (Sweden)

    Patrick Kelly

    2015-10-01

    Full Text Available 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.

  1. Developing drugs for the developing world: an economic, legal, moral, and political dilemma.

    Science.gov (United States)

    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

  2. Photon science 2012. Highlights and annual report

    International Nuclear Information System (INIS)

    Appel, Karen; Gehrke, Rainer; Gutt, Christian; Incoccia-Hermes, Lucia; Laarmann, Tim; Morgenroth, Wolfgang; Roehlsberger, Ralf; Schulte-Schrepping, Horst; Vainio, Ulla; Zimmermann, Martin von

    2012-12-01

    The synchrotron-radiation research at DESY is reviewed. The following topics are dealt with: Research highlights, research platforms and outstations, light sources, new technologies and developments. (HSI)

  3. Pitfalls in new artemisinin-containing antimalarial drug development.

    Science.gov (United States)

    Jambou, Ronan; Le Bras, Jacques; Randrianarivelojosia, Milijaona

    2011-02-01

    Artemisinin combination therapy (ACT) paves the way for new opportunities to eliminate malaria in the tropics. However, the huge increase of ACT consumption raises major concerns about their availability over the next few years. At the same time a decrease in their efficacy has already been reported. Alongside the deployment of multifocal control programs, the process ranging from artemisia crop production to accreditation of new ACT combinations urgently needs to be strengthened to supply sufficient quantities of high-quality drugs. New suppliers will have the opportunity to enter this market to develop new formulations, and bioequivalence studies are required to validate these new formulations. It is thus crucial for national malaria control teams to be able to better scrutinize the dossier of these new formulations. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. Multi-regional clinical trials and global drug development

    Directory of Open Access Journals (Sweden)

    Premnath Shenoy

    2016-01-01

    Full Text Available 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.

  5. Developing a coordinated response to drug abuse in Pakistan.

    LENUS (Irish Health Repository)

    Khalily, Muhammad Tahir

    2010-03-01

    This paper describes moves towards the coordination of efforts to respond to the worsening drug abuse situation in Pakistan which affects all segments of society. The efforts reported seek to rectify inconsistencies in treatment policy resulting in unsatisfactory outcomes. Examples of collaborative strategies with encouraging results need further underpinning and expansion. There is, however, a lack of realization at the policy level of the need to effect changes in treatment formulated on a consistent and evidence-based approach. Policy has therefore been reviewed and proposals made for a comprehensive treatment strategy in line with international best practices to deal with this problem effectively and efficiently. Establishment of an addiction study centre at university level to continue professional and academic development is suggested.

  6. 78 FR 68459 - Medical Device Development Tools; Draft Guidance for Industry, Tool Developers, and Food and Drug...

    Science.gov (United States)

    2013-11-14

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-D-1279] Medical Device Development Tools; Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food...

  7. A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

    Science.gov (United States)

    Allan, M C

    1992-01-01

    To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components

  8. Evaluation of transporters in drug development: Current status and contemporary issues.

    Science.gov (United States)

    Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

    2017-07-01

    Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

  9. Developing a molecular roadmap of drug-food interactions.

    Directory of Open Access Journals (Sweden)

    Kasper Jensen

    2015-02-01

    Full Text Available 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.

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

    Science.gov (United States)

    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, ptransdermal drug formulations with adjustable drug transport kinetics. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. When fragments link: a bibliometric perspective on the development of fragment-based drug discovery.

    Science.gov (United States)

    Romasanta, Angelo K S; van der Sijde, Peter; Hellsten, Iina; Hubbard, Roderick E; Keseru, Gyorgy M; van Muijlwijk-Koezen, Jacqueline; de Esch, Iwan J P

    2018-05-05

    Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university-industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields. Copyright © 2018. Published by Elsevier Ltd.

  12. Stable isotope-resolved metabolomics and applications for drug development

    Science.gov (United States)

    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

  13. Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections

    Science.gov (United States)

    O’Brien, Valerie P.; Hannan, Thomas J.; Nielsen, Hailyn V.; Hultgren, Scott J.

    2016-01-01

    Urinary tract infections (UTI) are among the most common bacterial infections in humans, affecting millions of people every year. UTI cause significant morbidity in women throughout their lifespan, in infant boys, in older men, in individuals with underlying urinary tract abnormalities, and in those that require long-term urethral catheterization, such as patients with spinal cord injuries or incapacitated individuals living in nursing homes. Serious sequelae include frequent recurrences, pyelonephritis with sepsis, renal damage in young children, pre-term birth, and complications of frequent antimicrobial use including high-level antibiotic resistance and Clostridium difficile colitis. Uropathogenic E. coli (UPEC) cause the vast majority of UTI, but less common pathogens such as Enterococcus faecalis and other enterococci frequently take advantage of an abnormal or catheterized urinary tract to cause opportunistic infections. While antibiotic therapy has historically been very successful in controlling UTI, the high rate of recurrence remains a major problem, and many individuals suffer from chronically recurring UTI, requiring long-term prophylactic antibiotic regimens to prevent recurrent UTI. Furthermore, the global emergence of multi-drug resistant UPEC in the past ten years spotlights the need for alternative therapeutic and preventative strategies to combat UTI, including anti-infective drug therapies and vaccines. In this chapter, we review recent advances in the field of UTI pathogenesis, with an emphasis on the identification of promising drug and vaccine targets. We then discuss the development of new UTI drugs and vaccines, highlighting the challenges these approaches face and the need for a greater understanding of urinary tract mucosal immunity. PMID:26999391

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

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

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

  15. Tailored approaches in drug development and diagnostics : from molecular design to biological model systems

    NARCIS (Netherlands)

    Sahlgren, C.M.; Meinander, A.; Zhang, H.; Cheng, F.; Preis, Maren; Xu, C.; Salminen, T.A.; Toivola, D.M.; Abankwa, D.; Rosling, A.; Karaman, D.Ş.; Salo-Ahen, O.M.H.; Österbacka, R.; Eriksson, J.E.; Willför, S.; Petre, I.; Peltonen, J.; Leino, R.; Johnson, M.; Rosenholm, J.; Sandler, N.

    2017-01-01

    Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic

  16. 78 FR 66744 - Draft Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment; Availability

    Science.gov (United States)

    2013-11-06

    ...] Draft Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment; Availability...) is announcing the availability of a draft guidance for industry entitled ``Pulmonary Tuberculosis... of antimycobacterial drugs for the treatment of pulmonary tuberculosis. This guidance applies to the...

  17. Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

    Science.gov (United States)

    El-Kattan, Ayman F; Varma, Manthena V; Steyn, Stefan J; Scott, Dennis O; Maurer, Tristan S; Bergman, Arthur

    2016-12-01

    To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

  18. Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis.

    Science.gov (United States)

    Döring, Jan Henje; Lampert, Anette; Hoffmann, Georg F; Ries, Markus

    2016-01-01

    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. Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. 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). 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.

  19. Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system

    International Nuclear Information System (INIS)

    Cao Quanliang; Han Xiaotao; Li Liang

    2011-01-01

    Deep magnetic capture and clinical application are the current trends for magnetic targeted drug delivery system. More promising and possible strategies are needed to overcome the current limitations and further improve the magnetic targeting technique. Recent advances in the development of targeting magnet system show promise in progressing this technology from the laboratory to the clinic. Starting from well-known basic concepts, current limitations of magnetic targeted drug delivery system are analyzed. Meanwhile, the design concepts and evaluations of some effective improvements in magnet system are discussed and reviewed with reference to (i) reasonable design of magnet system; (ii) control modes of magnet system used to generate dynamical magnetic fields; and (iii) magnetic field driving types. - Research Highlights: → The current limitations of MTDDS for deep capture and clinical application are analyzed. → The development of magnet system shows promise in progressing MTDDS to clinical application. → The design concepts and evaluations of improvements in magnet system are reviewed and discussed. → The key to improve magnet system lies in controllable magnets and different excitations.

  20. Genetic Interactions of STAT3 and Anticancer Drug Development

    International Nuclear Information System (INIS)

    Fang, Bingliang

    2014-01-01

    Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular insight into mechanisms of cancer resistance to pathway-targeted therapies and strategies for development of more effective anticancer agents and treatment regimens. This review focuses on functional regulation of STAT3 activity; possible interactions of the STAT3, RAS, epidermal growth factor receptor, and reduction-oxidation pathways; and molecular mechanisms that modulate therapeutic efficacies of STAT3 inhibitors

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

    Science.gov (United States)

    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. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  2. Paediatric Drug Development and Formulation Design-a European Perspective

    NARCIS (Netherlands)

    Nales, D.A.; Kozarewicz, Piotr; Aylward, Brian; de Vries, Rutger; Egberts, Toine C G; Rademaker, Carin M A; Schobben, Alfred F A M

    The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed

  3. Paediatric Drug Development and Formulation Design—a European Perspective

    NARCIS (Netherlands)

    van Riet-Nales, Diana A.; Kozarewicz, Piotr; Aylward, Brian; de Vries, Rutger; Egberts, Toine C G; Rademaker, Carin M A; Schobben, Alfred F A M

    The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed

  4. Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development

    Directory of Open Access Journals (Sweden)

    John W. Olney

    2013-07-01

    Full Text Available Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD, which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs and anti-epileptics (AEDs, mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which

  5. Homelessness and drug misuse in developing countries: A mathematical approach

    Science.gov (United States)

    Bhunu, C. P.

    2014-06-01

    Homelessness and drug-misuse are known to exist like siamese twins. We present a model to capture the dynamics in the growth in the number of homeless (street kids and street adults) and drug misusers. The reproduction numbers of the model are determined and analyzed. Results from this study suggests that adult peer pressure plays a more significant role in the growth of drug-misuse and the number of street kids. This result suggests that in resource constrained settings intervention strategies should be tailor made to target adults whose behaviour influence others to misuse drugs and abuse children. Furthermore, numerical simulations show that homelessness and drug-misuse positively enhances, the growth of each other. Thus, to effectively control these two social problems require strategies targeting both of them.

  6. HIV and AIDS among adolescents who use drugs: opportunities for drug policy reform within the sustainable development agenda.

    Science.gov (United States)

    Tinasti, Khalid

    2018-02-01

    The international community's commitment to halve by 2015 the HIV transmission among people who inject drugs has not only been largely missed, instead new HIV infections have increased by 30%. Moreover, drug injection remains one of the drivers of new HIV infections due to punitive responses and lack of harm reduction resourcing. In the midst of this situation, adolescents are a forgotten component of the global response to illegal drugs and their link with HIV infection. The Sustainable Development Goals (SDGs) present an opportunity to achieve the global objective of ending AIDS among adolescents who use drugs, by addressing the structural vulnerabilities they face be they economic, social, criminal, health-related or environmental. The implementation of the SDGs presents an opportunity to address the horizontal nature of drug policy and to efficiently address the drugs-adolescents-HIV risk nexus. Adolescent-focused drug policies are linked to goals 1, 3, 4, 10, 16 and 17. Goals 3 and 16 are the most relevant; the targets of the latter link to the criminalization of drug use and punitive policy environments and their impact on adolescents' health and HIV transmission risks. Moreover, it presents an opportunity to include adolescent needs that are missing in the three drug control conventions (1961, 1971 and 1988), and link them with the provisions of the Convention on the Rights of the Child (1989). Finally, the six principles to deliver on sustainable development are also an opportunity to divert adolescents who use drugs away from criminalization and punitive environments in which their vulnerability to HIV is greater. Addressing HIV among adolescents who use drugs is an extremely complex policy issue depending on different sets of binding and non-binding commitments, interventions and stakeholders. The complexity requires a horizontal response provided by the SDGs framework, starting with the collection of disaggregated data on this specific subgroup. Ending

  7. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

    International Nuclear Information System (INIS)

    Szebeni, Janos; Storm, Gert

    2015-01-01

    Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs. long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.

  8. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

    Energy Technology Data Exchange (ETDEWEB)

    Szebeni, Janos, E-mail: jszebeni2@gmail.com [Nanomedicine Research and Education Center, Semmelweis University, Budapest & SeroScience Ltd, Budapest (Hungary); Storm, Gert [Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht (Netherlands)

    2015-12-18

    Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs. long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.

  9. The impact of the written request process on drug development in childhood cancer.

    Science.gov (United States)

    Snyder, Kristen M; Reaman, Gregory; Avant, Debbie; Pazdur, Richard

    2013-04-01

    The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children. A search of the FDA document archiving, reporting, and regulatory tracking system was performed for January 1, 2000 to December 31, 2010. Drugs were identified and pediatric-specific labeling information was obtained from Drugs@fda.gov and FDA Pediatric Labeling Changes Table. Fifty WRs have been issued for oncology drugs. Pediatric studies have been submitted for 14 drugs. Thirteen received pediatric exclusivity. As of December 31, 2010, labeling changes have been made for 11 drugs. Three drugs were approved for pediatric use. WRs have provided a mechanism to promote the study of drugs in pediatric malignancies. Information from studies resulting from the WRs regarding safety, pharmacokinetics, and tolerability of oncology drugs has been incorporated into pediatric labeling for 11/14 of the drugs. Earlier communication and collaboration between the FDA, National Cancer Institute, clinical investigators, and commercial sponsors are envisioned to facilitate the identification and prioritization of emerging new drugs of interest for WR consideration. Since this is the only regulatory mechanism, resulting from specific legislative initiatives relevant to cancer drug development for children, efforts to enhance its impact on increasing drug approval for pediatric cancer indications are warranted. Copyright © 2013 Wiley Periodicals, Inc.

  10. Cdc7 kinase - a new target for drug development.

    Science.gov (United States)

    Swords, Ronan; Mahalingam, Devalingam; O'Dwyer, Michael; Santocanale, Corrado; Kelly, Kevin; Carew, Jennifer; Giles, Francis

    2010-01-01

    The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development.

  11. Development of Novel Drugs from Marine Surface Associated Microorganisms

    Directory of Open Access Journals (Sweden)

    Suhelen Egan

    2010-03-01

    Full Text Available While the oceans cover more than 70% of the Earth’s surface, marine derived microbial natural products have been largely unexplored. The marine environment is a habitat for many unique microorganisms, which produce biologically active compounds (“bioactives” to adapt to particular environmental conditions. For example, marine surface associated microorganisms have proven to be a rich source for novel bioactives because of the necessity to evolve allelochemicals capable of protecting the producer from the fierce competition that exists between microorganisms on the surfaces of marine eukaryotes. Chemically driven interactions are also important for the establishment of cross-relationships between microbes and their eukaryotic hosts, in which organisms producing antimicrobial compounds (“antimicrobials”, may protect the host surface against over colonisation in return for a nutrient rich environment. As is the case for bioactive discovery in general, progress in the detection and characterization of marine microbial bioactives has been limited by a number of obstacles, such as unsuitable culture conditions, laborious purification processes, and a lack of de-replication. However many of these limitations are now being overcome due to improved microbial cultivation techniques, microbial (meta- genomic analysis and novel sensitive analytical tools for structural elucidation. Here we discuss how these technical advances, together with a better understanding of microbial and chemical ecology, will inevitably translate into an increase in the discovery and development of novel drugs from marine microbial sources in the future.

  12. Overview of Biomarkers and Surrogate Endpoints in Drug Development

    Directory of Open Access Journals (Sweden)

    John A. Wagner

    2002-01-01

    Full Text Available There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin as a biomarker for in vivo activation of peroxisome proliferator-activated receptors (PPAR γ activity.

  13. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    Science.gov (United States)

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  14. Research synergy and drug development: Bright stars in neighboring constellations.

    Science.gov (United States)

    Keserci, Samet; Livingston, Eric; Wan, Lingtian; Pico, Alexander R; Chacko, George

    2017-11-01

    Drug discovery and subsequent availability of a new breakthrough therapeutic or 'cure' is a compelling example of societal benefit from research advances. These advances are invariably collaborative, involving the contributions of many scientists to a discovery network in which theory and experiment are built upon. To document and understand such scientific advances, data mining of public and commercial data sources coupled with network analysis can be used as a digital methodology to assemble and analyze component events in the history of a therapeutic. This methodology is extensible beyond the history of therapeutics and its use more generally supports (i) efficiency in exploring the scientific history of a research advance (ii) documenting and understanding collaboration (iii) portfolio analysis, planning and optimization (iv) communication of the societal value of research. Building upon prior art, we have conducted a case study of five anti-cancer therapeutics to identify the collaborations that resulted in the successful development of these therapeutics both within and across their respective networks. We have linked the work of over 235,000 authors in roughly 106,000 scientific publications that capture the research crucial for the development of these five therapeutics. Applying retrospective citation discovery, we have identified a core set of publications cited in the networks of all five therapeutics and additional intersections in combinations of networks. We have enriched the content of these networks by annotating them with information on research awards from the US National Institutes of Health (NIH). Lastly, we have mapped these awards to their cognate peer review panels, identifying another layer of collaborative scientific activity that influenced the research represented in these networks.

  15. Research synergy and drug development: Bright stars in neighboring constellations

    Directory of Open Access Journals (Sweden)

    Samet Keserci

    2017-11-01

    Full Text Available Drug discovery and subsequent availability of a new breakthrough therapeutic or ‘cure’ is a compelling example of societal benefit from research advances. These advances are invariably collaborative, involving the contributions of many scientists to a discovery network in which theory and experiment are built upon. To document and understand such scientific advances, data mining of public and commercial data sources coupled with network analysis can be used as a digital methodology to assemble and analyze component events in the history of a therapeutic. This methodology is extensible beyond the history of therapeutics and its use more generally supports (i efficiency in exploring the scientific history of a research advance (ii documenting and understanding collaboration (iii portfolio analysis, planning and optimization (iv communication of the societal value of research. Building upon prior art, we have conducted a case study of five anti-cancer therapeutics to identify the collaborations that resulted in the successful development of these therapeutics both within and across their respective networks. We have linked the work of over 235,000 authors in roughly 106,000 scientific publications that capture the research crucial for the development of these five therapeutics. Applying retrospective citation discovery, we have identified a core set of publications cited in the networks of all five therapeutics and additional intersections in combinations of networks. We have enriched the content of these networks by annotating them with information on research awards from the US National Institutes of Health (NIH. Lastly, we have mapped these awards to their cognate peer review panels, identifying another layer of collaborative scientific activity that influenced the research represented in these networks. Keywords: Information science, Cancer research

  16. 78 FR 29755 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...

    Science.gov (United States)

    2013-05-21

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure... an opportunity for public comment on human immunodeficiency virus (HIV) Patient-Focused Drug...

  17. 78 FR 46969 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...

    Science.gov (United States)

    2013-08-02

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure... for the notice of public meeting entitled ``Human Immunodeficiency Virus (HIV) Patient-Focused Drug...

  18. 78 FR 63223 - Fibromyalgia Public Meeting on Patient-Focused Drug Development; Correction

    Science.gov (United States)

    2013-10-23

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-N-2013-1041] Fibromyalgia Public Meeting on Patient-Focused Drug Development; Correction AGENCY: Food and Drug... 23, 2013 (78 FR 58313). The document announced a public meeting entitled ``Fibromyalgia Public...

  19. 78 FR 32667 - Draft Guidance for Industry on Rheumatoid Arthritis: Developing Drug Products for Treatment...

    Science.gov (United States)

    2013-05-31

    ... products. This guidance revises the guidance for industry entitled ``Clinical Development Programs for... Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave... (HFM-40), Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville...

  20. 78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

    Science.gov (United States)

    2013-05-31

    ... Management (HFA- 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. FOR... concern, we are seeking to explore new clinical development paradigms for antibacterial drugs. Areas of ongoing need are numerous and include new drugs for treatment of hospital-acquired bacterial pneumonia...

  1. Security, development and human rights: normative, legal and policy challenges for the international drug control system.

    Science.gov (United States)

    Barrett, Damon

    2010-03-01

    This commentary addresses some of the challenges posed by the broader normative, legal and policy framework of the United Nations for the international drug control system. The 'purposes and principles' of the United Nations are presented and set against the threat based rhetoric of the drug control system and the negative consequences of that system. Some of the challenges posed by human rights law and norms to the international drug control system are also described, and the need for an impact assessment of the current system alongside alternative policy options is highlighted as a necessary consequence of these analyses. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  2. Applying insights from biofilm biology to drug development - can a new approach be developed?

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Ciofu, Oana; Molin, Søren

    2013-01-01

    Most of the research on bacterial pathogenesis has focused on acute infections, but much less is known about the pathogenesis of infections caused by bacteria that grow as aggregates in biofilms. These infections tend to be chronic as they resist innate and adaptive immune defence mechanisms...... and pathology, and discuss how a deep insight into the physical and biological characteristics of biofilms can inform therapeutic strategies and molecular targets for the development of anti-biofilm drugs....

  3. The current status of orphan drug development in Europe and the US

    OpenAIRE

    Hall, Anthony K; Carlson, Marilyn R

    2014-01-01

    Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, e...

  4. Platelet-activating factor podoplanin: from discovery to drug development.

    Science.gov (United States)

    Takemoto, Ai; Miyata, Kenichi; Fujita, Naoya

    2017-06-01

    Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet-aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin-CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future.

  5. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the Stratum Corneum

    Directory of Open Access Journals (Sweden)

    Ahlam Zaid Alkilani

    2015-10-01

    Full Text Available The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies.

  6. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

    Science.gov (United States)

    Zaid Alkilani, Ahlam; McCrudden, Maelíosa T.C.; Donnelly, Ryan F.

    2015-01-01

    The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies. PMID:26506371

  7. Summary of highlights of the international conference of the United Nations on the environment and the development (CNUMAD) or summit of the earth

    International Nuclear Information System (INIS)

    Castano, Juanita

    1996-01-01

    In June of 1992, Rio de Janeiro became headquarters of the most impressive international summit that, from 1972, when it was carried out in Stockholm the first international meeting on environment, it had been carried out until the moment as regards environment and development: the Conference of the United Nations on environment and Development (CNUMAD). More than 100 state heads and 172 governments official representatives, thousands of members of non-governmental organizations, delegates of the UN and of other international organizations, and representatives of the media from all over the world participated. More than 18.000 participants of all the countries intervened in public forums, seminars and chats, parallel to the official conference. Their preparation lasted two years, from the moment in that the resolution was adopted 44/228 of the UN, in December of 1989 that approved its realization. This conference marked a true historical landmark in the analysis, reflection and agreement of agreements and programmatic bases, guided toward a new form of international cooperation as regards development and environment. If for some the summit was a success, for other it represented a failure. It should be pointed out, however that above all the conference must evaluate as a starting point, not necessarily simple, of an entire process of change in the treatment of the problem of the development. From the beginning of their preparation, the discussions on the conference polarized reflecting a debate of old it dates between the countries of the north and those of the south. Of a side, the developed countries were interested in only discussing the environment topics, while to the countries in development interested them the analysis of their development necessities. During many years, the countries of the south interpreted the controversy like an effort of the countries of the north to deviate the attention of the thematic of the trade and the development, and to escape

  8. Mechanisms Underlying the Risk to Develop Drug Addiction, Insights From Studies in Drosophila melanogaster.

    Science.gov (United States)

    Ryvkin, Julia; Bentzur, Assa; Zer-Krispil, Shir; Shohat-Ophir, Galit

    2018-01-01

    The ability to adapt to environmental changes is an essential feature of biological systems, achieved in animals by a coordinated crosstalk between neuronal and hormonal programs that allow rapid and integrated organismal responses. Reward systems play a key role in mediating this adaptation by reinforcing behaviors that enhance immediate survival, such as eating or drinking, or those that ensure long-term survival, such as sexual behavior or caring for offspring. Drugs of abuse co-opt neuronal and molecular pathways that mediate natural rewards, which under certain circumstances can lead to addiction. Many factors can contribute to the transition from drug use to drug addiction, highlighting the need to discover mechanisms underlying the progression from initial drug use to drug addiction. Since similar responses to natural and drug rewards are present in very different animals, it is likely that the central systems that process reward stimuli originated early in evolution, and that common ancient biological principles and genes are involved in these processes. Thus, the neurobiology of natural and drug rewards can be studied using simpler model organisms that have their systems stripped of some of the immense complexity that exists in mammalian brains. In this paper we review studies in Drosophila melanogaster that model different aspects of natural and drug rewards, with an emphasis on how motivational states shape the value of the rewarding experience, as an entry point to understanding the mechanisms that contribute to the vulnerability of drug addiction.

  9. Mechanisms Underlying the Risk to Develop Drug Addiction, Insights From Studies in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Julia Ryvkin

    2018-04-01

    Full Text Available The ability to adapt to environmental changes is an essential feature of biological systems, achieved in animals by a coordinated crosstalk between neuronal and hormonal programs that allow rapid and integrated organismal responses. Reward systems play a key role in mediating this adaptation by reinforcing behaviors that enhance immediate survival, such as eating or drinking, or those that ensure long-term survival, such as sexual behavior or caring for offspring. Drugs of abuse co-opt neuronal and molecular pathways that mediate natural rewards, which under certain circumstances can lead to addiction. Many factors can contribute to the transition from drug use to drug addiction, highlighting the need to discover mechanisms underlying the progression from initial drug use to drug addiction. Since similar responses to natural and drug rewards are present in very different animals, it is likely that the central systems that process reward stimuli originated early in evolution, and that common ancient biological principles and genes are involved in these processes. Thus, the neurobiology of natural and drug rewards can be studied using simpler model organisms that have their systems stripped of some of the immense complexity that exists in mammalian brains. In this paper we review studies in Drosophila melanogaster that model different aspects of natural and drug rewards, with an emphasis on how motivational states shape the value of the rewarding experience, as an entry point to understanding the mechanisms that contribute to the vulnerability of drug addiction.

  10. A pathway-specific microarray analysis highlights the complex and co-ordinated transcriptional networks of the developing grain of field-grown barley

    DEFF Research Database (Denmark)

    Hansen, Michael; Friis, Carsten; Bowra, Steve

    2009-01-01

    The aim of the study was to describe the molecular and biochemical interactions associated with amino acid biosynthesis and storage protein accumulation in the developing grains of field-grown barley. Our strategy was to analyse the transcription of genes associated with the biosynthesis of stora...

  11. Liposomes and nanotechnology in drug development: focus on oncotargets

    Directory of Open Access Journals (Sweden)

    Kozako T

    2012-09-01

    Full Text Available Tomohiro Kozako,1 Naomichi Arima,2 Makoto Yoshimitsu,3 Shin-Ichro Honda,1 Shinji Soeda11Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; 2Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; 3Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, JapanAbstract: Nanotechnology is the development of an engineered device at the atomic, molecular, and macromolecular level in the nanometer range. Advances in nanotechnology have proven beneficial in therapeutic fields such as drug-delivery and gene/protein delivery. Antigen delivery systems are important for inducing and modifying immune responses. In cellular immunity, cytotoxic T lymphocytes (CTLs are important in the host defense against tumors. Key to the development of CTL-inducible vaccines is the ability to deliver antigens to antigen-presenting cells efficiently and to induce the subsequent activation of T cell-mediated immunity without adjuvants, as they can induce excessive inflammation leading to systemic febrile disease. Since expression and cloning methods for tumor-associated antigens have been reported, cancer vaccines that induce effective cell immunity may be promising therapeutic candidates, but Th2 cells are undesirable for use in cancer immunotherapy. Peptide vaccines have immunological and economic advantages as cancer vaccines because CTL epitope peptides from tumor-associated antigens have high antigen-specificity. However, cancer vaccines have had limited effectiveness in clinical responses due to the ability of cancer cells to “escape” from cancer immunity and a low efficiency of antigen-specific CTL induction due to immunogenic-free synthetic peptides. In contrast, carbohydrate-decorated particles such as carbohydrate-coated liposomes with encapsulated antigens might be more suitable as

  12. Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

    Science.gov (United States)

    Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

    2017-12-01

    Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

  13. Development of magnetic drug delivery system using HTS bulk magnet

    International Nuclear Information System (INIS)

    Terada, T.; Fukui, S.; Mishima, F.; Akiyama, Y.; Izumi, Y.; Nishijima, S.

    2008-01-01

    Magnetic drug delivery system (MDDS) is the method which the magnetic seeded drug is injected into a blood vessel and then controlled and accumulated by a magnet located outside of the human body. A high accumulation efficiency of the drug to a local diseased part and reduction in side-effects to normal organs are expected by using MDDS. The most important element in MDDS is a magnetic field generator. The high temperature superconducting (HTS) bulk magnet which can generate high magnetic field and magnetic field gradient extending to a point distant from the magnet in several ten millimeters is necessary to achieve the MDDS. In this study, the computer simulation and model experiment were conducted in order to confirm the applicability of MDDS to ovary of the cow body

  14. Drugs of abuse and increased risk of psychosis development.

    Science.gov (United States)

    Gururajan, Anand; Manning, Elizabeth E; Klug, Maren; van den Buuse, Maarten

    2012-12-01

    There is considerable evidence to suggest that the abuse of illicit drugs, particularly cannabis and methamphetamine, has aetiological roles in the pathogenesis of psychosis and schizophrenia. Factors that may increase susceptibility to the propsychotic effects of these drugs include the age at which the abuse starts as well as family history of genetic polymorphisms relevant to the pathophysiology of this disorder. However, the neurobiological mechanisms involved in drug abuse-associated psychosis remain largely unclear. This paper presents an overview of the available evidence, including clinical, animal model, and molecular studies, with a focus on brain regions and neurotransmitters systems, such as dopamine and glutamate, previously implicated in psychosis. It is clear that further studies are urgently needed to provide a greater insight into the mechanisms that mediate the long-term and neurodevelopmental effects of cannabis and methamphetamine. A dialogue between basic science and clinical research may help to identify at-risk individuals and novel pathways for treatment and prevention.

  15. Developing framework to analyze world-class maintenance (wcm) indicators: gap analysis to highlight challenges and opportunities for the Norwegian petroleum industry

    OpenAIRE

    Imam, Syeda Fahmida

    2012-01-01

    Master's thesis in Offshore Technology World-class Maintenance (WCM) is a unique business process which actually does not cost, rather pays back. This study was an initial attempt to understand the extent of WCM concept being utilized in the Norwegian industry. The aim of the study was to develop a framework for analyzing the WCM indicators. For this purpose, the study was focused to: identify measurable WCM indicators, find the trends of WCM in the Norwegian sector, and find gap betwee...

  16. [Significance of re-evaluation and development of Chinese herbal drugs].

    Science.gov (United States)

    Gao, Yue; Ma, Zengchun; Zhang, Boli

    2012-01-01

    The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.

  17. Preparative Scale Resolution of Enantiomers Enables Accelerated Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Hanna Leek

    2017-01-01

    Full Text Available The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca. The combination of chromatography and racemization as well as strategies on when to apply preparative chiral chromatography of enantiomers in a multi-step synthesis of a drug compound can further facilitate accelerated drug discovery and the early clinical evaluation of the drug candidates.

  18. The Impact of Breakthrough Therapy Designation on Development Strategies and Timelines for Nononcology Drugs and Vaccines.

    Science.gov (United States)

    Poirier, A F; Murphy, W R

    2016-12-01

    The US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA, 2012) introduced the Breakthrough Therapy Designation (BTD), a new tool to expedite development of medicines to treat serious or life-threatening diseases. The majority of BTDs have gone to oncology drugs, and a recent publication by Shea et al. 1 reviewed the impact of BTD on oncology drug development. This article reviews the impact of BTD on development strategies and timelines for nononcology drugs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

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

    Directory of Open Access Journals (Sweden)

    R Pignatello

    2011-01-01

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

  20. Therapeutic Targets for Influenza - Perspectives in Drug Development

    Czech Academy of Sciences Publication Activity Database

    Majerová, Taťána; Hoffman, H.; Majer, F.

    2010-01-01

    Roč. 75, č. 1 (2010), s. 81-103 ISSN 0010-0765 R&D Projects: GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : influenza * drug research * protein structure * oligonucleotides Subject RIV: CE - Biochemistry Impact factor: 0.853, year: 2010

  1. Drugs in development and dietary approach for Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Angelini C

    2015-08-01

    Full Text Available Corrado Angelini, Elisabetta Tasca Neuromuscular Laboratory, Fondazione San Camillo Hospital IRCCS, Venice, Italy Abstract: Therapeutic trials studying Duchenne muscular dystrophy (DMD in Europe and the USA have been done using a protocol that includes manual muscle testing and functional testing, and have shown the efficacy of steroid drugs in various doses and regimens. Further, drisapersen and eteplirsen (exon skipping drugs and ataluren (a drug to overcome stop codon mutations have achieved some clinical improvement. Cardioprotective drugs are efficacious in DMD, and eplerenone, an aldosterone inhibitor and diuretic, is now being used to treat the disease. The dietary approach should be used in wheelchair-bound DMD children in combination with respiratory assistance. The importance of some of the treatments proposed is that they might also be useful in other genetic disorders where stop codon mutations are present; moreover, it is possible that these new treatments will improve quality of life for many patients. Keywords: Duchenne muscular dystrophy, steroids, ataluren, drisapersen, eplerenone, eteplirsen

  2. Development of a Gastroretentive Drug Delivery System based on ...

    African Journals Online (AJOL)

    Erah

    Purpose: The aim of this work was to synthesize superporous hydrogels of rosiglitazone using chitosan and to study its swelling behaviour for application as a gastroretentive drug delivery system. Methods: Chitosan superporous hydrogels were synthesized using glyoxal as a crosslinking agent by gas blowing method.

  3. Challenges in the clinical development of orphan drugs

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, A.R.

    2015-01-01

    Rare diseases are characterised by a low prevalence. There are so many different rare diseases, that millions of people are affected.The vast majority of these diseases suffer from a lack of approved treatment options and orphan drugs (ODs) therefore represent a huge unmet medical need. ODs face

  4. Dietary intake among adults in Trinidad and Tobago and development of a quantitative food frequency questionnaire to highlight nutritional needs for lifestyle interventions.

    Science.gov (United States)

    Ramdath, D Dan; Hilaire, Debbie G; Cheong, Kimlyn D; Sharma, Sangita

    2011-09-01

    To create a food list and develop a draft quantitative food frequency questionnaire (QFFQ) for Trinidad and Tobago. A mixed sampling method was used to obtain a representative sample and trained interviewers administered 24-h dietary recalls. Portion sizes were assessed and the most frequently reported foods were tabulated. Results are from 155 men and 169 women aged 21-64 years. The most frequently reported food items were: full-cream milk (64%), rice (61%), and sweetened fruit drinks (50%). Carbonated drinks were consumed by 28%. The most frequently consumed fruits were banana (23%) and citrus (22%); pastas/noodles; 12 dairy; 26 meats/poultry/fish/soy products; 15 fruits; 34 vegetables; six legumes; 11 other; 12 drinks; four alcoholic drinks. A list of commonly consumed foods in Trinidad and Tobago was obtained and a draft QFFQ was prepared.

  5. Highlights of DAMA/LIBRA

    Directory of Open Access Journals (Sweden)

    Bernabei R.

    2016-01-01

    Full Text Available The DAMA project develops and uses new/improved low background scintillation detectors to investigate the Dark Matter (DM particle component(s in the galactic halo and rare processes deep underground at the Gran Sasso National Laboratory (LNGS of the I.N.F.N.. Here some highlights of DAMA/LIBRA (Large sodium Iodide Bulk for Rare processes as a unique apparatus in direct DM investigation for its full sensitive mass, target material, intrinsic radio-purity, methodological approach and all the controls performed on the experimental parameters are outlined. The DAMA/LIBRA–phase1 and the former DAMA/NaI data (cumulative exposure 1.33 ton × yr, corresponding to 14 annual cycles have reached a model-independent evidence at 9.3 σ C.L. for the presence of DM particles in the galactic halo exploiting the DM annual modulation signature with highly radio-pure NaI(Tl target. Some of the perspectives of the presently running DAMA/LIBRA–phase2 are summarised and the powerful tools offered by a model independent strategy of DM investigation are pointed out.

  6. ESO PR Highlights in 2000

    Science.gov (United States)

    2001-01-01

    At the beginning of the new millennium, ESO and its staff are facing the future with confidence. The four 8.2-m Unit Telescopes of the Very Large Telescope (VLT) are in great shape and the VLT Interferometer (VLTI) will soon have "first fringes". The intercontinental ALMA project is progressing well and concepts for extremely large optical/infrared telescopes are being studied. They can also look back at a fruitful and rewarding past year. Perhaps the most important, single development has been the rapid transition of the Very Large Telescope (VLT). From being a "high-tech project under construction" it has now become a highly proficient, world-class astronomical observatory. This trend is clearly reflected in ESO's Press Releases , as more and more front-line scientific results emerge from rich data obtained at this very efficient facility. There were also exciting news from several of the instruments at La Silla. At the same time, the ESO community may soon grow, as steps towards membership are being taken by various European countries. Throughout 2000, a total of 54 PR communications were made, with a large number of Press Photos and Video Clips, cf. the 2000 PR Index. Some of the ESO PR highlights may be accessed directly via the clickable image on the present page. ESO PR Photo 01/01 is also available in a larger (non-clickable) version [ JPEG: 566 x 566 pix - 112k]. It may be reproduced, if credit is given to the European Southern Observatory.

  7. Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag.

    Science.gov (United States)

    Kogure, Seiji; Koyama, Nobuyuki; Hidaka, Shinji

    2017-11-01

    Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early-initiation BG strategy were significantly shorter than that in the late-initiation BG strategy. The findings in our study suggest that the late-initiation BG strategy may not contribute to shortening drug lag. Because the number of late-initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non-Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign-capital companies. © 2017, The American College of Clinical Pharmacology.

  8. Biomarkers in early phase development of central nervous system drugs : a conceptual framework

    NARCIS (Netherlands)

    Post, Jeroen-Paul van der

    2006-01-01

    The main objective of this thesis is to provide a conceptual framework for the use of Central Nervous System (CNS) biomarkers in early phase clinical drug development. In the Introduction the current use of biomarkers in early CNS drug development is discussed. A conceptual framework for the

  9. 77 FR 69634 - International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug...

    Science.gov (United States)

    2012-11-20

    ...] International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug Substances... Administration (FDA) is announcing the availability of a guidance entitled ``Q11 Development and Manufacture of... guidance is intended to apply only to the manufacture of drug substance, not the manufacture of finished...

  10. Development of PLGA–PEG encapsulated miltefosine based drug delivery system against visceral leishmaniasis

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Rishikesh; Sahoo, Ganesh Chandra [Biomedical and Nanomedicine Department, Rajendra Memorial Research Institute Medical Science (ICMR) (India); Pandey, Krishna; Das, V.N.R.; Topno, Roshan K. [Clinical Medicine Department, Rajendra Memorial Research Institute Medical Science (ICMR) (India); Ansari, Md Yousuf [Pharmacoinformatics Department, National Institute Pharmaceutica Research and Education Industrial Area, Hajipur (India); Rana, Sindhuprava [Biomedical and Nanomedicine Department, Rajendra Memorial Research Institute Medical Science (ICMR) (India); Das, Pradeep [Molecular Biology Department, Rajendra Memorial Research Institute Medical Science (ICMR) (India)

    2016-02-01

    Targeted drug delivery systems are ideal technology to increase the maximum mechanism of action with smaller dose, we have developed miltefosine encapsulated PLGA–PEG nanoparticles (PPEM) to target macrophage of infected tissues against Leishmania donovani. The structural characterization of PLGA–PEG by transmission electron microscopy (TEM) has shown a size range of 10 to 15 nm. Synthesis and drug encapsulation confirmed by dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR) and confirmed NP encapsulation. The dose of nano encapsulated miltefosine decreased by fifty percent as compared to that of a conventional miltefosine and Amphoterecin B. The inhibition of amastigotes in the splenic tissue with nano encapsulated miltefosine (23.21 ± 23) was significantly more than the conventional miltefosine (89.22 ± 52.7) and Amphoterecin B (94.12 ± 55.1). This study signifies that there is an increased contact surface area of the nano encapsulated drug and significant reduction in size, improved the efficacy in both in vitro and in vivo study than that of the conventional miltefosine, Amphoterecin B. - Graphical abstract: The analyses of detailed structure characterized by TEM and DLS confirmed the nano-size of the particle 10–20 nm and FTIR confirmed for antileishmanial drug encapsulation in to PLGA–PEG. The dose of miltefosine is decreased by fifty percent as the IC50 value is decreased from 0.2 to 0.1 μg. Further inhibitions of amastigotes in the splenic tissue with these nanoparticles are significantly more than the conventional miltefosine and PLGA–PEG encapsulated Amphoterecin B (23.21 ± 23/89.09 ± 52.7/92.12 ± 55.1). - Highlights: • Synthesis of PLGA-PEG encapsulated miltefosine nanoparticles has been done. • An IC50 value of PPEM (0.1 ug/ml), miltefosine (0.2 μg/ml) and AmpB (1 μg/ml) were observed two fold better efficacies. • Inhibition of amastigotes of PPEM (23.21 ± 23) was significantly more than

  11. Drug delivery system design and development for boron neutron capture therapy on cancer treatment

    International Nuclear Information System (INIS)

    Sherlock Huang, Lin-Chiang; Hsieh, Wen-Yuan; Chen, Jiun-Yu; Huang, Su-Chin; Chen, Jen-Kun; Hsu, Ming-Hua

    2014-01-01

    We have already synthesized a boron-containing polymeric micellar drug delivery system for boron neutron capture therapy (BNCT). The synthesized diblock copolymer, boron-terminated copolymers (Bpin-PLA-PEOz), consisted of biodegradable poly(D,L-lactide) (PLA) block and water-soluble polyelectrolyte poly(2-ethyl-2-oxazoline) (PEOz) block, and a cap of pinacol boronate ester (Bpin). In this study, we have demonstrated that synthesized Bpin-PLA-PEOz micelle has great potential to be boron drug delivery system with preliminary evaluation of biocompatibility and boron content. - Highlights: • Herein, we have synthesized boron-modified diblock copolymer. • Bpin-PLA-PEOz, which will be served as new boron containing vehicle for transporting the boron drug. • This boron containing Bpin-PLA-PEOz micelle was low toxicity can be applied to drug delivery

  12. Stem cell technology for drug discovery and development.

    Science.gov (United States)

    Hook, Lilian A

    2012-04-01

    Stem cells have enormous potential to revolutionise the drug discovery process at all stages, from target identification through to toxicology studies. Their ability to generate physiologically relevant cells in limitless supply makes them an attractive alternative to currently used recombinant cell lines or primary cells. However, realisation of the full potential of stem cells is currently hampered by the difficulty in routinely directing stem cell differentiation to reproducibly and cost effectively generate pure populations of specific cell types. In this article we discuss how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Probing suitable therapeutic nanoparticles for controlled drug delivery and diagnostic reproductive health biomarker development

    Energy Technology Data Exchange (ETDEWEB)

    Jha, Rakhi [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721 302 (India); National Institute of Animal Welfare, Ministry of Environment, Forest and Climate Change, Faridabad, Haryana 121 004 (India); Jha, Pradeep K., E-mail: jha.rk.pk@gmail.com [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721 302 (India); Gupta, Santosh; Bhuvaneshwaran, S.P. [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721 302 (India); Hossain, Maidul [Department of Chemistry & Chemical Technology, Vidyasagar University, Midnapore 721102 (India); Guha, Sujoy K. [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721 302 (India)

    2016-04-01

    Nanomaterial mediated drug delivery represents a highly promising technique while its selectivity for reproductive healthcare application still remains a challenge. Since the delicate structure and functional role of reproductive tissue and gametes require the use of biocompatible nanomedicine/devices that do not affect fertility or the development of resulting offspring, this paper reports an intercomparative study of human spermatozoa interaction with three different nanoparticles (NPs) namely; iron oxide (Fe{sub 3}O{sub 4)}, multiwalled carbon nanotubes (MWCNT) and graphene platelet nanopowder (GPN) to probe their suitability for drug delivery carrier and biomarker development purposes. ATR–FTIR results revealed that the sperm cell interaction with GPN had maximum amide I absorption for cell proteins and C=O stretching of the peptide backbone at the band around 1657 cm{sup −1} followed by iron oxide NPs whereas MWCNT had no absorption. These results showed that GPN followed by iron oxide NPs got maximally entrapped by cell membrane protein with maximum disruption but MWCNT exhibited less entrapment but significantly higher internalization which was further validated by morphological analysis of these cell NP interaction by SEM, HRTEM and fluorescence microscopy. The uptake kinetics and penetration mechanism of NPs were examined with isothermal titration calorimetry (ITC). Interestingly, ITC results confirmed ATR–FTIR and morphological observations that the binding of GPN and Fe{sub 3}O{sub 4} NPs with cell was exothermic and their bindings were favored by both negative enthalpy and positive entropy whereas in the case of MWCNT it was endothermic supported by unfavorable positive enthalpy and a favorable entropy change. Hence, it was evident that MWCNT had better internalization efficiency without disrupting the sperm lipid membrane compared to Fe{sub 3}O{sub 4} and GPN NPs. Therefore, this work proposes CNT as promising means. - Highlights: • Biophysical

  14. Highlights of nuclear chemistry 1995

    International Nuclear Information System (INIS)

    1996-07-01

    In this report 9 topics of the work of the Nuclear Chemistry Group in 1995 are highlighted. A list of publications and an overview of the international cooperation is given. (orig.). 19 refs., 19 figs., 2 tabs., 2 app

  15. Highlights of nuclear chemistry 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-07-01

    In this report 9 topics of the work of the Nuclear Chemistry Group in 1995 are highlighted. A list of publications and an overview of the international cooperation is given. (orig.). 19 refs., 19 figs., 2 tabs., 2 app.

  16. LAMA Preconference and Program Highlights.

    Science.gov (United States)

    Library Administration & Management, 1988

    1988-01-01

    Highlights events of the Library Administration and Management Association 1988 conference, including presentation of awards and programs on: (1) transfer of training; (2) hiring; (3) mentoring; (4) acquisitions automation; (5) library building consultation; and (6) managing shared systems. (MES)

  17. Development of controlled drug release systems based on thiolated polymers.

    Science.gov (United States)

    Bernkop-Schnürch, A; Scholler, S; Biebel, R G

    2000-05-03

    The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, L-cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100+/-8 and 1280+/-84 micromol thiol groups per gram, respectively (means+/-S.D.; n=6-8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.

  18. Research and technology highlights, 1993

    Science.gov (United States)

    1994-01-01

    This report contains highlights of the major accomplishments and applications that have been made by Langley researchers and by our university and industry colleagues during the past year. The highlights illustrate both the broad range of the research and technology activities supported by NASA Langley Research Center and the contributions of this work toward maintaining United States leadership in aeronautics and space research. This report also describes some of the Center's most important research and testing facilities.

  19. Development of Bioadhesive Chitosan Superporous Hydrogel Composite Particles Based Intestinal Drug Delivery System

    Directory of Open Access Journals (Sweden)

    Hitesh Chavda

    2013-01-01

    Full Text Available Bioadhesive superporous hydrogel composite (SPHC particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 32 full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery.

  20. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

    2014-01-01

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  1. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

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

    Science.gov (United States)

    Kiyosawa, Naoki; Manabe, Sunao

    2016-01-01

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

  3. Prescription Drugs

    Science.gov (United States)

    ... different competition is going on: the National Football League (NFL) vs. drug use. Read More » 92 Comments ... Future survey highlights drug use trends among the Nation’s youth for marijuana, alcohol, cigarettes, e-cigarettes (e- ...

  4. Biotransformation and bioactivation reactions - 2015 literature highlights.

    Science.gov (United States)

    Baillie, Thomas A; Dalvie, Deepak; Rietjens, Ivonne M C M; Cyrus Khojasteh, S

    2016-05-01

    Since 1972, Drug Metabolism Reviews has been recognized as one of the principal resources for researchers in pharmacological, pharmaceutical and toxicological fields to keep abreast of advances in drug metabolism science in academia and the pharmaceutical industry. With a distinguished list of authors and editors, the journal covers topics ranging from relatively mature fields, such as cytochrome P450 enzymes, to a variety of emerging fields. We hope to continue this tradition with the current compendium of mini-reviews that highlight novel biotransformation processes that were published during the past year. Each review begins with a summary of the article followed by our comments on novel aspects of the research and their biological implications. This collection of highlights is not intended to be exhaustive, but rather to be illustrative of recent research that provides new insights or approaches that advance the field of drug metabolism. Abbreviations NAPQI N-acetyl-p-benzoquinoneimine ALDH aldehyde dehydrogenase AO aldehyde oxidase AKR aldo-keto reductase CES carboxylesterase CSB cystathionine β-synthase CSE cystathionine γ-lyase P450 cytochrome P450 DHPO 2,3-dihydropyridin-4-one ESI electrospray FMO flavin monooxygenase GSH glutathione GSSG glutathione disulfide ICPMS inductively coupled plasma mass spectrometry i.p. intraperitoneal MDR multidrug-resistant NNAL 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol NNK 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone oaTOF orthogonal acceleration time-of-flight PBK physiologically based kinetic PCP pentachlorophenol SDR short-chain dehydrogenase/reductase SULT sulfotransferase TB tuberculosis.

  5. DOE Research and Development Accomplishments Previous Highlights

    Science.gov (United States)

    through his Nobel Lecture in 1961, about unraveling the secrets of photosynthesis -- the process by which . March 10, 2015 Twenty years ago, the top quark was first observed in experiments at the Tevatron proton sophisticated detectors, the top was hard to find. After a top is made from a proton-antiproton collision, a

  6. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Wenhu, E-mail: wenhu.huang@pfizer.com; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-12-15

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  7. Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

    International Nuclear Information System (INIS)

    Huang, Wenhu; Collette, Walter; Twamley, Michelle; Aguirre, Shirley A.; Sacaan, Aida

    2015-01-01

    Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.

  8. The development of a value based pricing index for new drugs in metastatic colorectal cancer

    OpenAIRE

    Lubbe, Martha Susanna; Dranitsaris, George; Truter, Ilse

    2011-01-01

    Background Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country’s ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. Methods ...

  9. Application of in situ polymerization for design and development of oral drug delivery systems.

    Science.gov (United States)

    Ngwuluka, Ndidi

    2010-12-01

    Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.

  10. Application of In Situ Polymerization for Design and Development of Oral Drug Delivery Systems

    OpenAIRE

    Ngwuluka, Ndidi

    2010-01-01

    Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.

  11. Atmospheric Research 2014 Technical Highlights

    Science.gov (United States)

    Platnick, Steven

    2015-01-01

    Earth Sciences Division in atmospheric science research. Figure 1.1 shows the 20-year record of peer-reviewed publications and proposals among the various Laboratories. This data shows that the scientific work being conducted in the Laboratories is competitive with the work being done elsewhere in universities and other government agencies. The office of Deputy Director for Atmospheric Research will strive to maintain this record by rigorously monitoring and promoting quality while emphasizing coordination and integration among atmospheric disciplines. Also, an appropriate balance will be maintained between the scientists' responsibility for large collaborative projects and missions and their need to carry out active science research as a principal investigator. This balance allows members of the Laboratories to improve their scientific credentials, and develop leadership potentials. Interdisciplinary research is carried out in collaboration with other laboratories and research groups within the Earth Sciences Division, across the Sciences and Exploration Directorate, and with partners in universities and other government agencies. Members of the Laboratories interact with the general public to support a wide range of interests in the atmospheric sciences. Among other activities, the Laboratories raise the public's awareness of atmospheric science by presenting public lectures and demonstrations, by making scientific data available to wide audiences, by teaching, and by mentoring students and teachers. The Atmosphere Laboratories make substantial efforts to attract and recruit new scientists to the various areas of atmospheric research. We strongly encourage the establishment of partnerships with Federal and state agencies that have operational responsibilities to promote the societal application of our science products. This report describes our role in NASA's mission, provides highlights of our research scope and activities, and summarizes our scientists' major

  12. Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens.

    Science.gov (United States)

    Ito, Yusuke; Sadar, Marianne D

    2018-01-01

    Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information. Steady-state concentration minimums (C min or trough) in the range of ~1-13 μg/mL are measured in patients at therapeutic doses. Interestingly, enzalutamide which is considered to have strong affinity for the androgen receptor (AR) requires C min levels >10 μg/mL. The sequence of antiandrogens and the clinical order of application in regard to other drugs that target the androgen axis remain of high interest. One novel first-in-class drug, called ralaniten, which binds to a unique region in the N-terminus domain of both the full-length and the truncated constitutively active splice variants of the AR, is currently in clinical trials for patients who previously received abiraterone, enzalutamide, or both. This highlights the trend to develop drugs with novel mechanisms of action and potentially differing mechanisms of resistance compared with antiandrogens. Better and more complete inhibition of the transcriptional activity of the AR appears to continue to provide improvements in the clinical management of mCRPC.

  13. Considerations for a business model for the effective integration of novel biomarkers into drug development.

    Science.gov (United States)

    Frueh, Felix W

    2008-11-01

    It is 10 years since the introduction of trastuzumab into the US market, and we are still waiting for a validation of the business case for biomarker-driven drug development. While many reasons for the lack of duplication of this model may exist, the need for accelerated innovation in drug development paired with the opportunity of integrating biomarker-driven research into drug development programs may lead to new and creative ways of fostering the cooperation between drug developers and test manufacturers. The rapid increase in knowledge about biomarkers and our understanding of disease and disease mechanisms open unprecedented prospects to make not only better, more informed decisions regarding patient care, but also strategic decisions during drug development. This requires that a biomarker strategy becomes an integral part of (early) drug development and that new, innovative paths are tried towards a model that combines the scientific approach with an economically feasible implementation strategy. Collaborative research, the use of new communication tools, the exploration of alternative ways to position a product in the market, and other considerations are part of such a strategy. This perspective article illustrates the current landscape and takes a look at some of these new ways for more effectively integrating biomarkers into drug development.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-07-26

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

  15. Site-specific antibody-drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development.

    Science.gov (United States)

    Agarwal, Paresh; Bertozzi, Carolyn R

    2015-02-18

    Antibody-drug conjugates (ADCs) combine the specificity of antibodies with the potency of small molecules to create targeted drugs. Despite the simplicity of this concept, generation of clinically successful ADCs has been very difficult. Over the past several decades, scientists have learned a great deal about the constraints on antibodies, linkers, and drugs as they relate to successful construction of ADCs. Once these components are in hand, most ADCs are prepared by nonspecific modification of antibody lysine or cysteine residues with drug-linker reagents, which results in heterogeneous product mixtures that cannot be further purified. With advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in producing ADCs by site-specific conjugation to the antibody, yielding more homogeneous products that have demonstrated benefits over their heterogeneous counterparts in vivo. Here, we chronicle the development of a multitude of site-specific conjugation strategies for assembly of ADCs and provide a comprehensive account of key advances and their roots in the fields of bioorthogonal chemistry and protein engineering.

  16. [The trend of developing new disease-modifying drugs in Alzheimer's disease].

    Science.gov (United States)

    Arai, Hiroyuki; Furukawa, Katsutoshi; Tomita, Naoki; Ishiki, Aiko; Okamura, Nobuyuki; Kudo, Yukitsuka

    2016-03-01

    Development of symptomatic treatment of Alzheimer s disease by cholinesterase inhibitors like donepezil was successful. However, it is a disappointment that development of disease-modifying drugs such as anti-amyloid drug based on amyloid-cascade theory has been interrupted or unsuccessful. Therefore, we have to be more cautious regarding inclusion criteria for clinical trials of new drugs. We agree that potentially curative drugs should be started before symptoms begin as a preemptive therapy or prevention trial. The concept of personalized medicine also is important when ApoE4-related amyloid reducing therapy is considered. Unfortunately, Japanese-ADNI has suffered a setback since 2014. However, Ministry of Health, Labour and Welfare gave a final remark that there was nothing wrong in the data managing process in the J-ADNI data center. We should pay more attention to worldwide challenges of speeding up new drug development.

  17. Site-selective protein-modification chemistry for basic biology and drug development.

    Science.gov (United States)

    Krall, Nikolaus; da Cruz, Filipa P; Boutureira, Omar; Bernardes, Gonçalo J L

    2016-02-01

    Nature has produced intricate machinery to covalently diversify the structure of proteins after their synthesis in the ribosome. In an attempt to mimic nature, chemists have developed a large set of reactions that enable post-expression modification of proteins at pre-determined sites. These reactions are now used to selectively install particular modifications on proteins for many biological and therapeutic applications. For example, they provide an opportunity to install post-translational modifications on proteins to determine their exact biological roles. Labelling of proteins in live cells with fluorescent dyes allows protein uptake and intracellular trafficking to be tracked and also enables physiological parameters to be measured optically. Through the conjugation of potent cytotoxicants to antibodies, novel anti-cancer drugs with improved efficacy and reduced side effects may be obtained. In this Perspective, we highlight the most exciting current and future applications of chemical site-selective protein modification and consider which hurdles still need to be overcome for more widespread use.

  18. From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis.

    Science.gov (United States)

    Aly, Lilian; Hemmer, Bernhard; Korn, Thomas

    2017-01-01

    Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide. Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy. Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Exploring Professional Identity Development in Alcohol and Drug Counselors in the 21st Century

    Science.gov (United States)

    Simmons, Lori; Haas, Deborah; Massella, John; Young, Jared; Toth, Paul

    2017-01-01

    Professional identity development is an emerging area for alcohol and drug counselors. Few studies have investigated professional identity in alcohol and drug counselors (Ogborne, Braun, & Schmidt, 2001; Massella, Simons, Young, Haas, & Toth 2013). The goal of the current study is to add to this area of research. A total of 1,333 certified…

  20. The Development of Videos in Culturally Grounded Drug Prevention for Rural Native Hawaiian Youth

    Science.gov (United States)

    Okamoto, Scott K.; Helm, Susana; McClain, Latoya L.; Dinson, Ay-Laina

    2012-01-01

    The purpose of this study was to adapt and validate narrative scripts to be used for the video components of a culturally grounded drug prevention program for rural Native Hawaiian youth. Scripts to be used to film short video vignettes of drug-related problem situations were developed based on a foundation of pre-prevention research funded by the…

  1. 78 FR 15371 - Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Public Workshop

    Science.gov (United States)

    2013-03-11

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0962] Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Public Workshop AGENCY... therapies to treat signs and symptoms related to chronic fatigue syndrome (CFS) and myalgic...

  2. Sirtuins: Novel targets for metabolic disease in drug development

    International Nuclear Information System (INIS)

    Jiang Weijian

    2008-01-01

    Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases such as type 2 diabetes. SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity. Activation of SIRT1 leads to enhanced activity of multiple proteins, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and FOXO which helps to mediate some of the in vitro and in vivo effects of sirtuins. Resveratrol, a polyphenolic SIRT1 activator, mimics the effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance. In this review, we summarize recent research advances in unveiling the molecular mechanisms that underpin sirtuin as therapeutic candidates and discuss the possibility of using resveratrol as potential drug for treatment of diabetes

  3. Brookhaven highlights, 1986-1987

    International Nuclear Information System (INIS)

    Rowe, M.S.

    1988-01-01

    The highlights of research conducted between October 1985 and September 1987 at Brookhaven National Laboratory are reviewed in this publication. Also covered are the administrative and financial status of the laboratory and a brief mention of meetings held and honors received. (FI)

  4. Orphan drugs in development for urea cycle disorders: current perspectives

    Directory of Open Access Journals (Sweden)

    Häberle J

    2014-09-01

    Full Text Available Johannes Häberle,1 Shawn E McCandless2 1Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; 2Center for Human Genetics, University Hospitals Case Medical Center, and Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA Abstract: The urea cycle disorders are caused by deficiency of one of the six hepatic enzymes or two transporters involved in detoxification of ammonia. The resulting hyperammonemia causes severe brain injury unless aggressive steps are taken to reduce the accumulation of ammonia, which is thought to be the most toxic metabolite. This review describes the current state of chronic management of urea cycle disorders, focusing on new and emerging therapies. Management strategies include the mainstay of treatment, namely dietary protein restriction and supplementation with l-arginine or l-citrulline. Several currently approved medications utilize and enhance alternative pathways of waste nitrogen excretion (sodium benzoate, sodium phenylacetate, sodium phenylbutyrate in several formulations, and glycerol phenylbutyrate, working through conjugation of the drug to either glycine (in the case of benzoate or glutamine, the products of which are excreted in the urine. Carglumic acid activates the first committed step of conversion of ammonia to urea, carbamoylphosphate synthetase, and thus effectively treats defective synthesis of the endogenous activator, N-acetylglutamate, whether due to genetic defects or biochemical inhibition of the N-acetylglutamate synthase enzyme. Approaches to neuroprotection during episodes of hyperammonemia are discussed, including the use of controlled hypothermia (brain cooling, as well as proposed, but as yet untested, pharmacologic therapies. Finally, cell-based therapies, including liver transplantation, infusion of fresh or cryopreserved hepatocytes, use of stem cells, and new approaches to gene

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

    Directory of Open Access Journals (Sweden)

    Regina Au

    2014-12-01

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

  6. The current status of orphan drug development in Europe and the US.

    Science.gov (United States)

    Hall, Anthony K; Carlson, Marilyn R

    2014-02-01

    Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, explain the incentives and procedures, and touch on the role of patient organisations in the process.

  7. Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development.

    Science.gov (United States)

    Khan, Masood U; Bowsher, Ronald R; Cameron, Mark; Devanarayan, Viswanath; Keller, Steve; King, Lindsay; Lee, Jean; Morimoto, Alyssa; Rhyne, Paul; Stephen, Laurie; Wu, Yuling; Wyant, Timothy; Lachno, D Richard

    2015-01-01

    Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality. This paper offers a systematic approach to assessment, method adaptation and validation of commercial immunoassay kits for quantification of biomarkers in drug development, expanding upon previous publications and guidance. These recommendations aim to standardize and harmonize user practices, contributing to reliable biomarker data from commercial immunoassays, thus, enabling properly informed decisions during drug development.

  8. GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

    Science.gov (United States)

    Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

    2009-11-01

    G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.

  9. PRELIMINARILY DEVELOPMENT OF A MOISTURE-ACTIVATED BIORESORBABLE POLYMERIC PLATFORM FOR DRUG DELIVERY

    Directory of Open Access Journals (Sweden)

    Renê O. do Couto

    2015-08-01

    Full Text Available Bioresorbable polymeric films were prepared by solvent casting using a tyrosine-derived polycarbonate and metronidazole (MDZ as the model drug at 2.5%, 5% and 10% (w/w. Drug loading did not affect the water uptake, drug release, polymer degradation or erosion profiles. All devices released approximately 85% (w/w of the drug within a 1.5 h period. This may be attributed to the rapid water uptake of the polymer. An increase in the water uptake correlated with a linear rate increase of the polymer degradation (0.968 ≤ R2 ≤ 0.999. Moreover, MDZ presented a remarkable plasticizing effect for the polymer and drug loading exerted a significant impact on the mechanical properties of the obtained films. The results obtained can be used to further the development of novel biocompatible and biodegradable polymeric platforms for the delivery of metronidazole and other drugs in a broad range of pharmaceutical applications.

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

    Science.gov (United States)

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

    2018-01-01

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

  11. Prevention of cardiovascular disease guided by total risk estimations - challenges and opportunities for practical implementation: highlights of a CardioVascular Clinical Trialists (CVCT) Workshop of the ESC Working Group on CardioVascular Pharmacology and Drug Therapy.

    LENUS (Irish Health Repository)

    Zannad, Faiez

    2011-11-03

    This paper presents a summary of the potential practical and economic barriers to implementation of primary prevention of cardiovascular disease guided by total cardiovascular risk estimations in the general population. It also reviews various possible solutions to overcome these barriers. The report is based on discussion among experts in the area at a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy that took place in September 2009. It includes a review of the evidence in favour of the \\'treat-to-target\\' paradigm, as well as potential difficulties with this approach, including the multiple pathological processes present in high-risk patients that may not be adequately addressed by this strategy. The risk-guided therapy approach requires careful definitions of cardiovascular risk and consideration of clinical endpoints as well as the differences between trial and \\'real-world\\' populations. Cost-effectiveness presents another issue in scenarios of finite healthcare resources, as does the difficulty of documenting guideline uptake and effectiveness in the primary care setting, where early modification of risk factors may be more beneficial than later attempts to manage established disease. The key to guideline implementation is to improve the quality of risk assessment and demonstrate the association between risk factors, intervention, and reduced event rates. In the future, this may be made possible by means of automated data entry and various other measures. In conclusion, opportunities exist to increase guideline implementation in the primary care setting, with potential benefits for both the general population and healthcare resources.

  12. The Expected Net Present Value of Developing Weight Management Drugs in the Context of Drug Safety Litigation.

    Science.gov (United States)

    Chawla, Anita; Carls, Ginger; Deng, Edmund; Tuttle, Edward

    2015-07-01

    Following withdrawals, failures, and significant litigation settlements, drug product launches in the anti-obesity category slowed despite a large and growing unmet need. Litigation concerns, a more risk-averse regulatory policy, and the difficulty of developing a product with a compelling risk-benefit profile in this category may have limited innovators' expected return on investment and restricted investment in this therapeutic area. The objective of the study was to estimate perceived manufacturer risk associated with product safety litigation and increased development costs vs. revenue expectations on anticipated return on investment and to determine which scenarios might change a manufacturer's investment decision. Expected net present value of a weight-management drug entering pre-clinical trials was calculated for a range of scenarios representing evolving expectations of development costs, revenue, and litigation risk over the past 25 years. These three factors were based on published estimates, historical data, and analogs from other therapeutic areas. The main driver in expected net present value calculations is expected revenue, particularly if one assumes that litigation risk and demand are positively correlated. Changes in development costs associated with increased regulatory concern with potential safety issues for the past 25 years likely did not impact investment decisions. Regulatory policy and litigation risk both played a role in anti-obesity drug development; however, product revenue-reflecting efficacy at acceptable levels of safety-was by far the most important factor. To date, relatively modest sales associated with recent product introductions suggest that developing a product that is sufficiently efficacious with an acceptable level of safety continues to be the primary challenge in this market.

  13. Development, implementation and management of a drug testing program in the workplace

    Energy Technology Data Exchange (ETDEWEB)

    Burtis, C.A.

    1990-01-01

    To combat the rising use of drugs in the workplace many American companies have implemented drug testing programs and are testing employees and job applicants for use of illegal drugs. In addition, on September 15, 1986, Executive Order No.12564 was issued by President Reagan, which requires all federal agencies to develop programs and policies, one of the goals of which is to achieve a drug-free federal workplace. Included in this Executive Order is the requirement that federal agencies implement drug testing has become a prevalent practice as a means to detect and deter drug use in the workplace. Before a drug testing program is implemented, it is imperative that policies and procedures are developed that (1) ensure the accuracy of test results, (2) protect the validity and integrity of the specimen, (3) guarantee due process, and (4) maintain confidentiality. To make certain that these prerequisites were met in the government drug testing programs, the US Department of Health and Human Services (HHS) was directed to develop technical and scientific guidelines for conducting such programs. 15 refs., 1 fig., 2 tabs.

  14. Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration.

    Science.gov (United States)

    Green, Dionna J; Liu, Xiaomei I; Hua, Tianyi; Burnham, Janelle M; Schuck, Robert; Pacanowski, Michael; Yao, Lynne; McCune, Susan K; Burckart, Gilbert J; Zineh, Issam

    2017-12-08

    Clinical trial enrichment involves prospectively incorporating trial design elements that increase the probability of detecting a treatment effect. The use of enrichment strategies in pediatric drug development has not been systematically assessed. We analyzed the use of enrichment strategies in pediatric trials submitted to the US Food and Drug Administration from 2012-2016. In all, 112 efficacy studies associated with 76 drug development programs were assessed and their overall success rates were 78% and 75%, respectively. Eighty-eight trials (76.8%) employed at least one enrichment strategy; of these, 66.3% employed multiple enrichment strategies. The highest trial success rates were achieved when all three enrichment strategies (practical, predictive, and prognostic) were used together within a single trial (87.5%), while the lowest success rate was observed when no enrichment strategy was used (65.4%). The use of enrichment strategies in pediatric trials was found to be associated with trial and program success in our analysis. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  15. Cost-effectiveness analysis of microdose clinical trials in drug development.

    Science.gov (United States)

    Yamane, Naoe; Igarashi, Ataru; Kusama, Makiko; Maeda, Kazuya; Ikeda, Toshihiko; Sugiyama, Yuichi

    2013-01-01

    Microdose (MD) clinical trials have been introduced to obtain human pharmacokinetic data early in drug development. Here we assessed the cost-effectiveness of microdose integrated drug development in a hypothetical model, as there was no such quantitative research that weighed the additional effectiveness against the additional time and/or cost. First, we calculated the cost and effectiveness (i.e., success rate) of 3 types of MD integrated drug development strategies: liquid chromatography-tandem mass spectrometry, accelerator mass spectrometry, and positron emission tomography. Then, we analyzed the cost-effectiveness of 9 hypothetical scenarios where 100 drug candidates entering into a non-clinical toxicity study were selected by different methods as the conventional scenario without MD. In the base-case, where 70 drug candidates were selected without MD and 30 selected evenly by one of the three MD methods, incremental cost-effectiveness ratio per one additional drug approved was JPY 12.7 billion (US$ 0.159 billion), whereas the average cost-effectiveness ratio of the conventional strategy was JPY 24.4 billion, which we set as a threshold. Integrating MD in the conventional drug development was cost-effective in this model. This quantitative analytical model which allows various modifications according to each company's conditions, would be helpful for guiding decisions early in clinical development.

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

    Science.gov (United States)

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

    2015-01-26

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

  17. Moonlighting adenosine deaminase: a target protein for drug development.

    Science.gov (United States)

    Cortés, Antoni; Gracia, Eduard; Moreno, Estefania; Mallol, Josefa; Lluís, Carme; Canela, Enric I; Casadó, Vicent

    2015-01-01

    Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest. © 2014 Wiley Periodicals, Inc.

  18. Highlights of nuclear chemistry 1994

    International Nuclear Information System (INIS)

    1994-12-01

    Highlights were: 1. Fission product release: benchmark calculations for severe nuclear accidents; 2. Thermochemical data for reactor materials and fission products; 3. thermochemical calculations on fuel of the high-temperature gas-cooled reactor; 4. Formation of organic tellurides during nuclear accidents?; 5. Reaction of tellurium with Zircaloy-4; 6. Transmutation of fission products; 7. The thermal conductivity of high-burnup UO 2 fuel; 8. Tritium retention in graphite. (orig./HP)

  19. Tourette syndrome research highlights 2015

    Science.gov (United States)

    Richards, Cheryl A.; Black, Kevin J.

    2016-01-01

    We present selected highlights from research that appeared during 2015 on Tourette syndrome and other tic disorders. Topics include phenomenology, comorbidities, developmental course, genetics, animal models, neuroimaging, electrophysiology, pharmacology, and treatment. We briefly summarize articles whose results we believe may lead to new treatments, additional research or modifications in current models of TS. PMID:27429744

  20. LHC Results Highlights (CLASHEP 2013)

    CERN Document Server

    Gonzalez, O.

    2015-05-22

    The good performance of the LHC provided enough data at 7 TeV and 8 TeV to allow the experiments to perform very competitive measurements and to expand the knowledge about the fundamental interaction far beyond that from previous colliders. This report summarizes the highlights of the results obtained with these data samples by the four large experiments, covering all the topics of the physics program and focusing on those exploiting the possibilities of the LHC.

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

    Science.gov (United States)

    Lynch, Wendy J

    2018-01-01

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

  2. Bird Flu Fears: Is There a Better Way to Develop Drugs?

    OpenAIRE

    Dean Baker

    2005-01-01

    Government-granted patent monopolies have limited the ability to produce and stockpile large quantities of the drugs deemed most effective in treating the Avian Flu. This report examines alternative mechanisms for financing the development of pharmaceutical products.

  3. Collaboration with Pharma Will Introduce Nanotechnologies in Early Stage Drug Development | Poster

    Science.gov (United States)

    The Frederick National Lab has begun to assist several major pharmaceutical companies in adopting nanotechnologies in early stage drug development, when the approach is most efficient and cost-effective.

  4. Collaboration with Pharma Will Introduce Nanotechnologies in Early Stage Drug Development | FNLCR Staging

    Science.gov (United States)

    The Frederick National Lab has begun to assist several major pharmaceutical companies in adopting nanotechnologies in early stage drug development, when the approach is most efficient and cost-effective. For some time, the national lab’s Nanotechno

  5. TERATOGENIC EFFECTS OF DRUGS ON THE ORGANISM OF A FUTURE CHILD DURING FETAL STAGE OF DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    S.A. Sher

    2011-01-01

    Full Text Available Article assesses the impact of adverse factors on intrauterine development of the child, first of all, drugs. The author stresses that the importance of drug safety (D is due to the large number of unintended pregnancies worldwide. A list of the D, providing proven teratogenic effects on a child organism is presenting. It is shown that the D teratogenic effect in humans can not be assessed on the basis of experimental data obtained in animals due to the difference between metabolic and detoxification processes in a different mammals and individuals. Key words: drugs, safety, teratogenic effects, fetal development, the unborn child. (Pediatric pharmacology. — 2011; 8 (6: 57–60.

  6. Guidelines to PET measurements of the target occupancy in the brain for drug development

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

    2016-11-15

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

  7. Common characteristics of open source software development and applicability for drug discovery: a systematic review.

    Science.gov (United States)

    Ardal, Christine; Alstadsæter, Annette; Røttingen, John-Arne

    2011-09-28

    Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.

  8. Mutagenicity in drug development: interpretation and significance of test results.

    Science.gov (United States)

    Clive, D

    1985-03-01

    , methapyrilene). In vivo mutagenicity assays are more physiological but appear to be relatively insensitive due to the inability to achieve sufficiently high acute plasma levels to mimic cumulative long-term effects. Examination of the mutagenicity of naturally occurring analogs may indicate the irrelevance of a test compound's mutagenicity (e.g., deoxyguanosine and the structurally related antiviral drug, acyclovir, have identical mutagenicity patterns). Life-threatening or severe debilitating diseases (e.g., cancer, severe psychoses, severe crippling arthritis, sight-threatening diseases) may justify treatment with mutagenic or even carcinogenic therapeutic agents (benefit/risk considerations).(ABSTRACT TRUNCATED AT 400 WORDS)

  9. Recent developments in our understanding of the implications of traditional African medicine on drug metabolism.

    Science.gov (United States)

    Gouws, Chrisna; Hamman, Josias H

    2018-02-01

    The use of traditional herbal medicines has become increasingly popular globally, but in some countries, it is the main or sometimes even the only healthcare service available in the most rural areas. This is especially true for Africa where herbal medicines form a key component of traditional medicinal practices and there is access to a diversity of medicinal plants. Although many benefits have been derived from the use of traditional herbal medicines, many concerns are associated with their use of which herb-drug interactions have been identified to have a rising impact on patient treatment outcome. One type of pharmacokinetic interaction involves the modulation of drug metabolizing enzymes, which may result in enhanced or reduced bioavailability of co-administered drugs. Areas covered: This review highlights the current information available on drug metabolism-associated information with regards to traditional African medicines related to some of the most prevalent diseases burdening the African continent. Expert opinion: It is clear from previous studies that enzyme modulation by traditional African medicines plays a significant role in the pharmacokinetics of some co-administered drugs, but more research is needed to provide detailed information on these interactions, specifically for treatment of prevalent diseases such as tuberculosis and hypertension.

  10. Strategic R&D transactions in personalized drug development.

    Science.gov (United States)

    Makino, Tomohiro; Lim, Yeongjoo; Kodama, Kota

    2018-03-21

    Although external collaboration capability influences the development of personalized medicine, key transactions in the pharmaceutical industry have not been addressed. To explore specific trends in interorganizational transactions and key players, we longitudinally surveyed strategic transactions, comparing them with other advanced medical developments, such as antibody therapy, as controls. We found that the financing deals of start-ups have surged over the past decade, accelerating intellectual property (IP) creation. Our correlation and regression analyses identified determinants of financing deals among alliance deals, acquisition deals, patents, research and development (R&D) licenses, market licenses, and scientific papers. They showed that patents positively correlated with transactions, and that the number of R&D licenses significantly predicted financing deals. This indicates, for the first time, that start-ups and investors lead progress in personalized medicine. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Technological advances in precision medicine and drug development.

    Science.gov (United States)

    Maggi, Elaine; Patterson, Nicole E; Montagna, Cristina

    New technologies are rapidly becoming available to expand the arsenal of tools accessible for precision medicine and to support the development of new therapeutics. Advances in liquid biopsies, which analyze cells, DNA, RNA, proteins, or vesicles isolated from the blood, have gained particular interest for their uses in acquiring information reflecting the biology of tumors and metastatic tissues. Through advancements in DNA sequencing that have merged unprecedented accuracy with affordable cost, personalized treatments based on genetic variations are becoming a real possibility. Extraordinary progress has been achieved in the development of biological therapies aimed to even further advance personalized treatments. We provide a summary of current and future applications of blood based liquid biopsies and how new technologies are utilized for the development of biological therapeutic treatments. We discuss current and future sequencing methods with an emphasis on how technological advances will support the progress in the field of precision medicine.

  12. Antiviral Information Management System (AIMS): a prototype for operational innovation in drug development.

    Science.gov (United States)

    Jadhav, Pravin R; Neal, Lauren; Florian, Jeff; Chen, Ying; Naeger, Lisa; Robertson, Sarah; Soon, Guoxing; Birnkrant, Debra

    2010-09-01

    This article presents a prototype for an operational innovation in knowledge management (KM). These operational innovations are geared toward managing knowledge efficiently and accessing all available information by embracing advances in bioinformatics and allied fields. The specific components of the proposed KM system are (1) a database to archive hepatitis C virus (HCV) treatment data in a structured format and retrieve information in a query-capable manner and (2) an automated analysis tool to inform trial design elements for HCV drug development. The proposed framework is intended to benefit drug development by increasing efficiency of dose selection and improving the consistency of advice from US Food and Drug Administration (FDA). It is also hoped that the framework will encourage collaboration among FDA, industry, and academic scientists to guide the HCV drug development process using model-based quantitative analysis techniques.

  13. The role of radio pharmacological imaging in streamlining the drug development process

    International Nuclear Information System (INIS)

    Campbell, D. B.

    1997-01-01

    Radio imaging techniques have found a place in clinical diagnosis, but there has been a hesitancy to use this approach in drug development. This reluctance may have been due to the availability of ligands, the time and cost of synthesis and the number of centres and for many the benefits are not evident. The use in drug development is potentially large since tomography can measure drug levels, specific binding, blood flow and activity within the human body. In drug discovery, the synthesis of candidate drugs with specific binding properties are dependent on understanding the disease and using appropriate in vitro or animal models. Using small animal tomographs, these can be validated using radio imaging. Pharmacokinetics and metabolic problems, such as the distribution of inhaled gases, drug targeting into tumours of the brain or specific gastrointestinal absorption sites can be investigated within the human rather than relying on animals. The high specific activity allows low doses to be administered to man with limited safety studies permitting kinetic and metabolic studies to be undertaken early in development. Safety studies and ensuing toxicological endpoints in animals rely on histopathology for gross degenerative in physiological function. Where concern exists, radio imaging could detect early in situ changes in humans, for example hepatic toxicity, before they become hazardous. In clinical studies, the action of drugs can be measured directly at the effector site prior to undertaking longer studies, which is important for many diseases, but particularly for those such as Alzheimer's disease, where improvements may be slow or subtle

  14. Application of radiations to development of controlled release drugs and diagnostic drugs

    International Nuclear Information System (INIS)

    Yoshida, Masaru

    1990-01-01

    The report briefly outlines various biological materials developed by the author by means of chemical reactions and processing techniques using radiations. They include testosterone release materials for artificial spermary, controlled anticancer medicine release materials, in vivo degrading materials (parabolic, linear or S-shape degradation-time curve), functional particles with activated functional groups, targeting materials, substances for immunity diagnosis, and other 'intelligent' materials. Intelligent materials, like human organs, respond to specific stimuli from the external environment. Some components such as amino acids and nucleic acids are converted into acryloyl or methacryloyl derivatives to allow the material to show various functions. Methacryloyl-L-proline polymer in an aqueous system, for example, shows an reversible thermal response to changes in the water temperature, that is, swelling and shrinking at low and high temperature, respectively. The mechanism of the thermal response of its copolymer wiht hydroxypropylmethacrylate can be interpreted as resulting from the formation of a surface regulating layer. (N.K.)

  15. STS-95 Day 02 Highlights

    Science.gov (United States)

    1998-01-01

    On this second day of the STS-95 mission, the flight crew, Cmdr. Curtis L. Brown, Pilot Steven W. Lindsey, Mission Specialists Scott E. Parazynski, Stephen K. Robinson, and Pedro Duque, and Payload Specialists Chiaki Mukai and John H. Glenn, are seen preparing a glovebox device in the middeck area of Discovery, an enclosed research facility that will support numerous science investigations throughout the mission. Payload Specialist John Glenn, activates the Microgravity Encapsulation Process experiment (MEPS). This experiment will study the formation of capsules containing two kinds of anti-tumor drugs that could be delivered directly to solid tumors with applications for future chemotherapy treatments and the pharmaceutical industry.

  16. Turning theory into practice: the development of modern transdermal drug delivery systems and future trends.

    Science.gov (United States)

    Perumal, O; Murthy, S N; Kalia, Y N

    2013-01-01

    Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. © 2013 S. Karger AG, Basel.

  17. Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Clive Ballard

    2013-10-01

    Full Text Available Alzheimer’s Disease (AD is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.

  18. A drug target that stimulates development of healthy stem cells

    Science.gov (United States)

    Scientists have overcome a major impediment to the development of effective stem cell therapies by studying mice that lack CD47, a protein found on the surface of both healthy and cancer cells. They discovered that cells obtained from the lungs of CD47-de

  19. The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A; Schouw, Marieke L J; Klomp, Anne; Tamminga, Hyke G H; Schrantee, Anouk G M; Bouziane, Cheima; de Ruiter, Michiel B; Boer, Frits; Ruhé, Henricus G; Denys, D.; Rijsman, Roselyne; Lindauer, Ramon J L; Reitsma, Hans B; Geurts, Hilde M; Reneman, Liesbeth

    2014-01-01

    BACKGROUND: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  20. The effects of psychotropic drugs on developing brain (ePOD) study: methods and design

    NARCIS (Netherlands)

    Bottelier, M.A.; Schouw, M.L.J.; Klomp, A.; Tamminga, G.H.; Schrantee, A.G.M.; Bouziane, C.; de Ruiter, M.B.; Boer, F.; Ruhé, H.G.; Denys, D.; Rijsman, R.; Lindauer, R.J.L.; Reitsma, H.B.; Geurts, H.M.; Reneman, L.

    2014-01-01

    Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  1. The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhe, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

    2014-01-01

    Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  2. The effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhé, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

    2014-01-01

    Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different

  3. The impact of nanobiotechnology on the development of new drug delivery systems

    NARCIS (Netherlands)

    Kayser, Oliver; Lemke, A.; Hernandez-Trejo, N.

    2005-01-01

    Nanotechnology, or systems/devices manufactured at the molecular level, is a multidisciplinary scientific field undergoing explosive development. A part of this field is the development of nanoscaled drug delivery devices. Nanoparticles have been developed as an important strategy to deliver

  4. Organized crime impact study highlights

    Energy Technology Data Exchange (ETDEWEB)

    Porteous, S D

    1998-10-01

    A study was conducted to address the issue of how organized crime impacts on Canadians and their communities both socially and economically. As far as environmental crime is concerned, three main areas of concern have been identified: (1) illicit trade in ozone depleting substances, (2) illicit hazardous waste treatment, and (3) disposal of illicit trade in endangered species. To gauge the magnitude of organized crime activity, the market value of worldwide illegal trafficking in illicit drugs was estimated to be as high as $100 billion worldwide (between $1.4 to 4 billion in Canada). It is suspected that Canada supplies a substantial portion of the U.S. black market in chlorofluorocarbons with most of the rest being supplied from Mexico. Another area of concern involves the disposal of hazardous wastes. Canada produces approximately 5.9 million tonnes of hazardous waste annually. Of these, 3.2 million tonnes are sent to off-site disposal facilities for specialized treatment and recycling. The treatment of hazardous waste is a very profitable business, hence vulnerable to fraudulent practices engaged in by organized crime groups. Environmental implications of this and other environmental crimes, as well as their economic, commercial, health and safety impact were examined. Other areas of organized crime activity in Canada (drugs, economic crimes, migrant trafficking, counterfeit products, motor vehicle theft, money laundering) were also part of the study.

  5. Development of a rational scale to assess the harm of drugs of potential misuse.

    Science.gov (United States)

    Nutt, David; King, Leslie A; Saulsbury, William; Blakemore, Colin

    2007-03-24

    Drug misuse and abuse are major health problems. Harmful drugs are regulated according to classification systems that purport to relate to the harms and risks of each drug. However, the methodology and processes underlying classification systems are generally neither specified nor transparent, which reduces confidence in their accuracy and undermines health education messages. We developed and explored the feasibility of the use of a nine-category matrix of harm, with an expert delphic procedure, to assess the harms of a range of illicit drugs in an evidence-based fashion. We also included five legal drugs of misuse (alcohol, khat, solvents, alkyl nitrites, and tobacco) and one that has since been classified (ketamine) for reference. The process proved practicable, and yielded roughly similar scores and rankings of drug harm when used by two separate groups of experts. The ranking of drugs produced by our assessment of harm differed from those used by current regulatory systems. Our methodology offers a systematic framework and process that could be used by national and international regulatory bodies to assess the harm of current and future drugs of abuse.

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

    Science.gov (United States)

    Lötsch, Jörn; Ultsch, Alfred

    2016-04-01

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

  7. The development of multiple drug use among anabolic-androgenic steroid users: six subjective case reports

    Directory of Open Access Journals (Sweden)

    Nyberg Fred

    2008-11-01

    Full Text Available Abstract Background The inappropriate use of anabolic androgenic steroids (AAS was originally a problem among athletes but AAS are now often used in nonsport situations and by patients attending regular addiction clinics. The aim of this study was to improve understanding of the development of multiple drug use in patients seeking treatment at an addiction clinic for AAS-related problems. Methods We interviewed six patients (four men and two women with experience of AAS use who were attending an addiction clinic for what they believed were AAS-related problems. The patients were interviewed in-depth about their life stories, with special emphasis on social background, substance use, the development of total drug use and subjective experienced psychological and physical side effects. Results There was significant variation in the development of drug use in relation to social background, onset of drug use, relationship to AAS use and experience of AAS effects. All patients had initially experienced positive effects from AAS but, over time, the negative experiences had outweighed the positive effects. All patients were dedicated to excess training and took AAS in combination with gym training, indicating that the use of these drugs is closely related to this form of training. Use of multiple drugs was common either in parallel with AAS use or serially. Conclusion The study shows the importance of understanding how AAS use can develop either with or without the concomitant use of other drugs of abuse. The use of AAS can, however, progress to the use of other drugs. The study also indicates the importance of obtaining accurate, comprehensive information about the development of AAS use in designing treatment programmes and prevention strategies in this area.

  8. Studies on novel drug development using developing chick embryo and its future aspect

    International Nuclear Information System (INIS)

    Abe, Chiaki; Uto, Yoshihiro; Hori, Hitoshi; Endo, Yoshio

    2011-01-01

    Described is the use of developing chick embryo (DCE), an advantageous alternative experimental animal, in studies on development of novel drugs like radio-sensitizer and on toxicological evaluation. Authors have established DCE transplanted with mouse mammary gland tumor EMT6/KU cells and have found that etanidazole, a radio-sensitizing nitroimidazole derivative, exerts the significant tumor shrinking activity in this tumor-bearing DCE when irradiated by 8 Gy X-ray. They are to test the sensitizing activity of their synthetic nitroimidazole derivatives and other structure-related sensitizers like clinically used (in Denmark) nimorazole. In addition, as the antioxidant activity in vivo can be hardly tested, authors are trying to make DCE system for it since they have studied the activity of derivatives of artepillin C, an active principle of propolis. They are also using DCE chorioallantoic membrane (CAM) for testing the anti-angiogenic activity aiming to develop an antitumor agent from compounds related to fingolimod (FTY-720). For the test of anti-tumor activity in various cell types, their observation is that some of tumor cell types cannot take in DCE. Recently DCE has been used in toxicology for prediction of cardiovascular system like bradycardia and QT elongation, and for lethality test. Hen's egg test-CAM (HET-CAM) and cultured cell system to test irritation are reported to be more valid than other standard methods. DCE system is simple, inexpensive, and unnecessary for particular equipment and facility and desirably becomes an alternative experimental animal next to those like zebra-fish, rat and mouse. (author)

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

    Science.gov (United States)

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

    2012-01-01

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

  10. Public and private sector contributions to the discovery and development of "impact" drugs.

    Science.gov (United States)

    Reichert, Janice M; Milne, Christopher-Paul

    2002-01-01

    Recently, well-publicized reports by Public Citizen and the Joint Economic Committee (JEC) of the US Congress questioned the role of the drug industry in the discovery and development of therapeutically important drugs. To gain a better understanding of the relative roles of the public and private sectors in pharmaceutic innovation, the Tufts Center for the Study of Drug Development evaluated the underlying National Institutes of Health (NIH) and academic research cited in the Public Citizen and JEC reports and performed its own assessment of the relationship between the private and public sectors in drug discovery and development of 21 "impact" drugs. We found that, ultimately, any attempt to measure the relative contribution of the public and private sectors to the research and development (R&D) of therapeutically important drugs by output alone, such as counting publications or even product approvals, is flawed. Several key factors (eg, degree of uncertainty, expected market value, potential social benefit) affect investment decisions and determine whether public or private sector funds, or both, are most appropriate. Because of the competitiveness and complexity of today's R&D environment, both sectors are increasingly challenged to show returns on their investment and the traditional boundaries separating the roles of the private and public research spheres have become increasingly blurred. What remains clear, however, is that the process still starts with good science and ends with good medicine.

  11. Adhesive Pili in UTI Pathogenesis and Drug Development.

    Science.gov (United States)

    Spaulding, Caitlin N; Hultgren, Scott J

    2016-03-15

    Urinary tract infections (UTIs) are one of the most common bacterial infections, affecting 150 million people each year worldwide. High recurrence rates and increasing antimicrobial resistance among uropathogens are making it imperative to develop alternative strategies for the treatment and prevention of this common infection. In this Review, we discuss how understanding the: (i) molecular and biophysical basis of host-pathogen interactions; (ii) consequences of the molecular cross-talk at the host pathogen interface in terms of disease progression; and (iii) pathophysiology of UTIs is leading to efforts to translate this knowledge into novel therapeutics to treat and prevent these infections.

  12. Atmospheric Research 2012 Technical Highlights

    Science.gov (United States)

    Lau, William K -M.

    2013-01-01

    This annual report, as before, is intended for a broad audience. Our readers include colleagues within NASA, scientists outside the Agency, science graduate students, and members of the general public. Inside are descriptions of atmospheric research science highlights and summaries of our education and outreach accomplishments for calendar year 2012.The report covers research activities from the Mesoscale Atmospheric Processes Laboratory, the Climate and Radiation Laboratory, the Atmospheric Chemistry and Dynamics Laboratory, and the Wallops Field Support Office under the Office of Deputy Director for Atmospheres, Earth Sciences Division in the Sciences and Exploration Directorate of NASAs Goddard Space Flight Center. The overall mission of the office is advancing knowledge and understanding of the Earths atmosphere. Satellite missions, field campaigns, peer-reviewed publications, and successful proposals are essential to our continuing research.

  13. Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2006-05-01

    The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select

  14. Status of drug development for the prevention and treatment of osteoporosis

    DEFF Research Database (Denmark)

    Schwarz, Peter; Jørgensen, Niklas Rye; Abrahamsen, Bo

    2014-01-01

    supplementation. Several new medications for the treatment of postmenopausal osteoporosis are in the pipeline. AREAS COVERED: The authors present the most recent studies on new and current antiresorptive as well as anabolic drugs. Specifically, the authors present the current knowledge on drugs directed against...... cathepsin K and sclerostin as well as the new pathways of interest from preclinical studies. EXPERT OPINION: New scientific results have identified novel signaling pathways as potential targets for future development of anti-osteoporotic drugs. The treatments close to marketing at the moment are odanacatib...

  15. STS-95 Day 04 Highlights

    Science.gov (United States)

    1998-01-01

    On this forth day of the STS-95 mission, the flight crew, Cmdr. Curtis L. Brown, Pilot Steven W. Lindsey, Mission Specialists Scott E. Parazynski, Stephen K. Robinson, and Pedro Duque, and Payload Specialists Chiaki Mukai and John H. Glenn, are seen performing an evaluation of bone cell activity under microgravity conditions. Glenn then provides blood samples as part of the Protein Turnover Experiment, which is looking at the balance between the building and breakdown of muscle. He also works with the Advanced Organic Separations (ADSEP) experiment, to provides the capability to separate and purify biological materials in microgravity; and with the Microencapsulation Electrostatic Processing System (MEPS), that studies the formation of anti-tumor capsules containing two kinds of drugs.

  16. The Nicotinic Acetylcholine Receptor as a Target for Antidepressant Drug Development

    Directory of Open Access Journals (Sweden)

    Noah S. Philip

    2012-01-01

    Full Text Available An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR. This receptor, which is distributed widely in regions of the brain associated with depression, is also implicated in other important processes that are relevant to depression, such as stress and inflammation. The two classes of drugs that target nAChRs can be broadly divided into mecamylamine- and cytisine-based compounds. These drugs probably exert their effects via antagonism at α4β2 nAChRs, and strong preclinical data support the antidepressant efficacy of both classes when used in conjunction with other primary antidepressants (e.g., monoamine reuptake inhibitors. Although clinical data remain limited, preliminary results in this area constitute a compelling argument for further evaluation of the nAChR as a target for future antidepressant drug development.

  17. Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

    Science.gov (United States)

    Otsubo, Yasuto; Ishiguro, Akihiro; Uyama, Yoshiaki

    2013-01-01

    Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

  18. The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

    Science.gov (United States)

    Denny, Joshua C; Van Driest, Sara L; Wei, Wei-Qi; Roden, Dan M

    2018-03-01

    Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  19. Orphan drugs in development for Huntington's disease: challenges and progress

    Directory of Open Access Journals (Sweden)

    Burgunder JM

    2015-02-01

    Full Text Available Jean-Marc Burgunder1–4 1Swiss Huntington’s Disease Centre, Department of Neurology, University of Bern, Bern, Switzerland; 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, 4Department of Neurology, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Huntington’s disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine repeat in the huntingtin (HTT gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and

  20. Beyond America's War on Drugs: Developing Public Policy to Navigate the Prevailing Pharmacological Revolution.

    Science.gov (United States)

    Golub, Andrew; Bennett, Alex S; Elliott, Luther

    2015-03-30

    This paper places America's "war on drugs" in perspective in order to develop a new metaphor for control of drug misuse. A brief and focused history of America's experience with substance use and substance use policy over the past several hundred years provides background and a framework to compare the current Pharmacological Revolution with America's Nineteenth Century Industrial Revolution. The paper concludes with cautions about growing challenges and provides suggestions for navigating this revolution and reducing its negative impact on individuals and society.

  1. The Pim kinases: new targets for drug development.

    Science.gov (United States)

    Swords, Ronan; Kelly, Kevin; Carew, Jennifer; Nawrocki, Stefan; Mahalingam, Devalingam; Sarantopoulos, John; Bearss, David; Giles, Francis

    2011-12-01

    The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

  2. Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs.

    Science.gov (United States)

    Molchanova, Natalia; Hansen, Paul R; Franzyk, Henrik

    2017-08-29

    The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids ( N -alkylated glycine oligomers), β-peptoids ( N -alkylated β-alanine oligomers), β³-peptides, α/β³-peptides, α-peptide/β-peptoid hybrids, α/γ N -acylated N -aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

  3. Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

    Science.gov (United States)

    Externbrink, Anna; Eggenreich, Karin; Eder, Simone; Mohr, Stefan; Nickisch, Klaus; Klein, Sandra

    2017-01-01

    Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

    Science.gov (United States)

    Marugán, Carlos; Torres, Raquel; Lallena, María José

    2015-01-01

    Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  5. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  6. Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

    Directory of Open Access Journals (Sweden)

    Carlos eMarugán

    2016-01-01

    Full Text Available Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins such as Aurora A and B. Current drugs which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules, have several side effects (neutropenia, alopecia, emesis. Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype.We will briefly describe two multiplexing technologies (high-content imaging, microarrays and flow cytometry and two key processes for drug discovery research (assay development and validation following our own published industry quality standards. We will further focus on high-content imaging as a useful tool for phenotypic screening and will provide a concrete example of high-content imaging assay to detect Aurora A or B selective inhibitors discriminating the off-target effects related to inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  7. Exosomes in Cancer Development, Metastasis and Drug Resistance: A Comprehensive Review

    Science.gov (United States)

    Azmi, Asfar S.; Bao, Bin; Sarkar, Fazlul H.

    2013-01-01

    Trafficking of biological material across membranes is an evolutionary conserved mechanism and is part of any normal cell homeostasis. Such transport is comprised of active, passive, export through microparticles and vesicular transport (exosomes) that collectively maintain proper compartmentalization of important micro and macromolecules. In pathological states, such as cancer, aberrant activity of export machinery results in expulsion of a number of key proteins and microRNAs resulting in their misexpression. Exosome mediated expulsion of intracellular drugs could be another barrier in the proper action of most of the commonly used therapeutics, targeted agents and their intracellular metabolites. Over the last decade, a number of studies have revealed that exosomes cross-talk and/or influence major tumor related pathways such as hypoxia driven EMT, cancer stemness, angiogenesis and metastasis involving many cell types within the tumor microenvironment. Emerging evidence suggest that exosome secreted proteins can also propel fibroblast growth, resulting in Desmoplastic reaction (DR); a major barrier in effective cancer drug delivery. This comprehensive review highlights the advancements in the understanding of the biology of exosomes secretions and the consequence on cancer drug resistance. We propose that the successful combination of cancer treatments to tackle exosome mediated drug resistance requires an interdisciplinary understanding of these cellular exclusion mechanisms, and how secreted biomolecules are involved in cellular cross-talk within the tumor microenvironment. PMID:23709120

  8. NF-κB-IKKβ pathway as a target for drug development: realities, challenges and perspectives.

    Science.gov (United States)

    Freitas, Rosana H C N; Fraga, Carlos A M

    2018-02-19

    Nuclear factor κB (NF-κB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-κB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF-κB-IKKβ pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells. Inhibition of the NF-κB-IKKβ cascade can be considered an attractive therapeutic method for the genesis of new prototypes to combat these chronic multifactorial diseases. This review describes some prototypes and drugs that act to inhibit the NF-κB-IKKβ pathway, highlighting the realities, challenges and perspectives for therapeutic use. Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-κB-IKKβ pathway, some other prototypes described as IKKβ inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-κB pathway modulators as IKKβ inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Incentives for orphan drug research and development in the United States.

    Science.gov (United States)

    Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Szeinbach, Sheryl L; Visaria, Jay

    2008-12-16

    The Orphan Drug Act (1983) established several incentives to encourage the development of orphan drugs (ODs) to treat rare diseases and conditions. This study analyzed the characteristics of OD designations, approvals, sponsors, and evaluated the effective patent and market exclusivity life of orphan new molecular entities (NMEs) approved in the US between 1983 and 2007. Primary data sources were the FDA Orange Book, the FDA Office of Orphan Drugs Development, and the US Patent and Trademark Office. Data included all orphan designations and approvals listed by the FDA and all NMEs approved by the FDA during the study period. The FDA listed 1,793 orphan designations and 322 approvals between 1983 and 2007. Cancer was the main group of diseases targeted for orphan approvals. Eighty-three companies concentrated 67.7% of the total orphan NMEs approvals. The average time from orphan designation to FDA approval was 4.0 +/- 3.3 years (mean +/- standard deviation). The average maximum effective patent and market exclusivity life was 11.7 +/- 5.0 years for orphan NME. OD market exclusivity increased the average maximum effective patent and market exclusivity life of ODs by 0.8 years. Public programs, federal regulations, and policies support orphan drugs R&D. Grants, research design support, FDA fee waivers, tax incentives, and orphan drug market exclusivity are the main incentives for orphan drug R&D. Although the 7-year orphan drug market exclusivity provision had a positive yet relatively modest overall effect on effective patent and market exclusivity life, economic incentives and public support mechanisms provide a platform for continued orphan drug development for a highly specialized market.

  10. Biotransformation and bioactivation reactions - 2016 literature highlights.

    Science.gov (United States)

    Khojasteh, S Cyrus; Rietjens, Ivonne M C M; Dalvie, Deepak; Miller, Grover

    2017-08-01

    We are pleased to present a second annual issue highlighting a previous year's literature on biotransformation and bioactivation. Each contributor to this issue worked independently to review the articles published in 2016 and proposed three to four articles, which he or she believed would be of interest to the broader research community. In each synopsis, the contributing author summarized the procedures, analyses and conclusions as described in the original manuscripts. In the commentary sections, our authors offer feedback and highlight aspects of the work that may not be apparent from an initial reading of the article. To be fair, one should still read the original article to gain a more complete understanding of the work conducted. Most of the articles included in this review were published in Drug Metabolism and Disposition or Chemical Research in Toxicology, but attempts were made to seek articles in 25 other journals. Importantly, these articles are not intended to represent a consensus of the best papers of the year, as we did not want to make any arbitrary standards for this purpose, but rather they were chosen by each author for their notable findings and descriptions of novel metabolic pathways or biotransformations. I am pleased that Drs. Rietjens and Dalvie have again contributed to this annual review. We would like to welcome Grover P Miller as an author for this year's issue, and we thank Tom Baillie for his contributions to last year's edition. We have intentionally maintained a balance of authors such that two come from an academic setting and two come from industry. Finally, please drop us a note if you find this review helpful. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. This article is dedicated to Professor Thomas Baillie for his exceptional contributions to the field of drug metabolism.

  11. MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.

    Science.gov (United States)

    Bonnel, David; Legouffe, Raphaël; Eriksson, André H; Mortensen, Rasmus W; Pamelard, Fabien; Stauber, Jonathan; Nielsen, Kim T

    2018-04-01

    Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.

  12. Study on Mixed Solvency Concept in Formulation Development of Aqueous Injection of Poorly Water Soluble Drug

    Directory of Open Access Journals (Sweden)

    Shailendra Singh Solanki

    2013-01-01

    Full Text Available In the present investigation, mixed-solvency approach has been applied for the enhancement of aqueous solubility of a poorly water- soluble drug, zaltoprofen (selected as a model drug, by making blends (keeping total concentrations 40% w/v, constant of selected water-soluble substances from among the hydrotropes (urea, sodium benzoate, sodium citrate, nicotinamide; water-soluble solids (PEG-4000, PEG-6000; and co-solvents (propylene glycol, glycerine, PEG-200, PEG-400, PEG-600. Aqueous solubility of drug in case of selected blends (12 blends ranged from 9.091 ± 0.011 mg/ml–43.055 ± 0.14 mg/ml (as compared to the solubility in distilled water 0.072 ± 0.012 mg/ml. The enhancement in the solubility of drug in a mixed solvent containing 10% sodium citrate, 5% sodium benzoate and 25 % S cosolvent (25% S cosolvent contains PEG200, PEG 400, PEG600, Glycerine and Propylene glycol was more than 600 fold. This proved a synergistic enhancement in solubility of a poorly water-soluble drug due to mixed cosolvent effect. Each solubilized product was characterized by ultraviolet and infrared techniques. Various properties of solution such as pH, viscosity, specific gravity and surface tension were studied. The developed formulation was studied for physical and chemical stability. This mixed solvency shall prove definitely a boon for pharmaceutical industries for the development of dosage form of poorly water soluble drugs.

  13. Pharmacogenetics in diverse ethnic populations--implications for drug discovery and development.

    Science.gov (United States)

    McCarthy, Linda C; Davies, Kirstie J; Campbell, David A

    2002-07-01

    It is widely acknowledged that the vast quantities of data now publicly available as a result of the human genome initiative have the potential to revolutionize the pharmaceutical industry. More tangibly to the drug development business, the dawn of the pharmacogenetics era has the potential to impact not only the discovery of new medicines but also the safety and efficacy of pharmaceutical agents. Coincident with these scientific advances is the emergence of new markets for pharmaceutical agents. Japan, which represents the world's second biggest market, is a good example. With the ICH E5 agreement in 1998 and a rapid change in the drug registration process in Japan, there are increasing opportunities to improve access to more medicines in all parts of the world. However, it is increasingly clear that significant genetic variation still exists between populations, with a host of data on interethnic variation in drug metabolizing enzyme and drug transporter activity. Evidence suggesting that this genetic variation may play an important role in defining some of the interethnic variation in drug response to currently marketed compounds is reviewed here, and future possibilities of using such information to better streamline the drug development process are discussed.

  14. Stem cells: a model for screening, discovery and development of drugs.

    Science.gov (United States)

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.

  15. [Development of anti-Alzheimer's disease drug based on beta-amyloid hypothesis].

    Science.gov (United States)

    Sugimoto, Hachiro

    2010-04-01

    Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.

  16. Emerging technologies, recent developments, and novel applications for drug metabolite identification.

    Science.gov (United States)

    Lu, Wenjie; Xu, Youzhi; Zhao, Yinglan; Cen, Xiaobo

    2014-01-01

    Drug metabolite identification and metabolic characteristics analysis play a crucial role in new drug research and development, because they can lead to varied efficacy, severe adverse reactions, and even toxicity. Classical methodologies for metabolite identification have mainly been based on mass spectrometry (MS) coupled with gas chromatography (GC) or liquid chromatography (LC), and some other techniques are used as complementary approaches, such as nuclear magnetic resonance (NMR). Over the past decade, more and more newly emerging techniques or technologies have been applied to metabolite identification, and are making the procedure easier and more robust, such as LC-NMR-MS, ion mobility MS, ambient ionization techniques, and imaging MS. A novel application of drug metabolite identification based on "omics" known as pharmacometabonomics is discussed, which is an interdisciplinary field that combines pre-dose metabolite profiling and chemometrics methods for data analysis and modeling, aiming to predict the responses of individuals to drugs.

  17. Cassini's Grand Finale Science Highlights

    Science.gov (United States)

    Spilker, Linda

    2017-10-01

    After 13 years in orbit, the Cassini-Huygens Mission to Saturn ended in a science-rich blaze of glory. Cassini returned its final bits of unique science data on September 15, 2017, as it plunged into Saturn's atmosphere satisfying planetary protection requirements. Cassini's Grand Finale covered a period of roughly five months and ended with the first time exploration of the region between the rings and planet.The final close flyby of Titan in late April 2017 propelled Cassini across Saturn’s main rings and into its Grand Finale orbits; 22 orbits that repeatedly dove between Saturn’s innermost rings and upper atmosphere making Cassini the first spacecraft to explore this region. The last orbit turned the spacecraft into the first Saturn upper atmospheric probe.The Grand Finale orbits provided highest resolution observations of both the rings and Saturn, and in-situ sampling of the ring particle composition, Saturn's atmosphere, plasma, and innermost radiation belts. The gravitational field was measured to unprecedented accuracy, providing information on the interior structure of the planet, winds in the deeper atmosphere, and mass of the rings. The magnetic field provided insight into the physical nature of the magnetic dynamo and structure of the internal magnetic field. The ion and neutral mass spectrometer sampled the upper atmosphere for molecules that escape the atmosphere in addition to molecules originating from the rings. The cosmic dust analyzer directly sampled the composition from different parts of the main rings for the first time. Fields and particles instruments directly measured the plasma environment between the rings and planet.Science highlights and new mysteries gleaned to date from the Grand Finale orbits will be discussed.The research described in this paper was carried out in part at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. Copyright 2017

  18. Bioanalysis-related highlights from the 2011 AAPS National Biotechnology Conference.

    Science.gov (United States)

    Crisino, Rebecca M; Dulanto, Beatriz

    2011-08-01

    The American Association of Pharmaceutical Scientists is a dynamic international forum for the exchange of knowledge among scientists to enhance their contributions to drug development. The annual National Biotechnology Conference, conducted and organized by the American Association of Pharmaceutical Scientists, is a forum dedicated to advancements in science and technology related to discovery, development and manufacture of medical biotechnology products. The 2011 National Biotechnology Conference meeting convened in San Francisco, CA, USA on 16-18 May. Over 300 abstracts were submitted and approximately 50 sessions examined topics pertaining to advances in drug development, emerging analytical technologies, bioanalysis-related issues, biosimilar therapies, updates on global regulatory documents and expectations, and other topics. The focus of this article is to highlight key developments relevant to immunogenicity and pharmacokinetic drug concentration bioanalysis.

  19. A peek into the drug development scenario of endometriosis - A systematic review.

    Science.gov (United States)

    Goenka, Luxitaa; George, Melvin; Sen, Maitrayee

    2017-06-01

    Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis. A systematic review was done and all the RCTs were selected from the identified hits. We included studies that explored the usage of therapeutic drugs on endometriosis patients from inception till November 2016. The search term used was 'Endometriosis' using PubMed and Clinicaltrials.gov. For the final analysis, 60 articles were analyzed and we identified the newly emerging drug therapies for endometriosis treatment and have briefed their current status and challenges in drug development for endometriosis. The quality of the selected studies was assessed based on the degree of bias. The current classes of drugs that have shown promising therapeutic results include Gonadotropin- releasing hormone (GnRH) antagonists, aromatase inhibitors (AI), and selective progesterone and estrogen receptor modulators, dopamine receptor-2-agonists and statins. The drugs that failed midway during development include tanezumab, rosiglitazone, infliximab, pentoxifylline, telapristone acetate, asoprisnil and raloxifene. From the literature review, it appears that the most promising molecules for the treatment of endometriosis in the near future include elagolix, mifepristone, TAK-385, KLH-2109 and ASP1707 and cabergoline. It remains to be seen if these molecules would succeed large phase 3 clinical trials and overcome the regulatory hurdles to become an essential tool in the gynaecologist's armamentarium against endometriosis

  20. Ask the experts: the challenges and benefits of flow chemistry to optimize drug development.

    Science.gov (United States)

    Anderson, Neal; Gernaey, Krist V; Jamison, Timothy F; Kircher, Manfred; Wiles, Charlotte; Leadbeater, Nicholas E; Sandford, Graham; Richardson, Paul

    2012-09-01

    Against a backdrop of a struggling economic and regulatory climate, pharmaceutical companies have recently been forced to develop new ways to provide more efficient technology to meet the demands of a competitive drug industry. This issue, coupled with an increase in patent legislation and a rising generics market, makes these themes common issues in the growth of drug development. As a consequence, the importance of process chemistry and scale-up has never been more under the spotlight. Future Medicinal Chemistry wishes to share the thoughts and opinions of a variety of experts from this field, discussing issues concerning the use of flow chemistry to optimize drug development, the potential regulatory and environmental challenges faced with this, and whether the academic and industrial sectors could benefit from a more harmonized system relevant to process chemistry.

  1. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    Energy Technology Data Exchange (ETDEWEB)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N. [Stony Brook University Health Science Center, Department of Psychiatry, Stony Brook, NY (United States)

    2016-06-15

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  2. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    International Nuclear Information System (INIS)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N.

    2016-01-01

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  3. Development and characterization of multifunctional nanoparticles for drug delivery to cancer cells

    Science.gov (United States)

    Nahire, Rahul Rajaram

    Lipid and polymeric nanoparticles, although proven to be effective drug delivery systems compared to free drugs, have shown considerable limitations pertaining to their uptake and release at tumor sites. Spatial and temporal control over the delivery of anticancer drugs has always been challenge to drug delivery scientists. Here, we have developed and characterized multifunctional nanoparticles (liposomes and polymersomes) which are targeted specifically to cancer cells, and release their contents with tumor specific internal triggers. To enable these nanoparticles to be tracked in blood circulation, we have imparted them with echogenic characteristic. Echogenicity of nanoparticles is evaluated using ultrasound scattering and imaging experiments. Nanoparticles demonstrated effective release with internal triggers such as elevated levels of MMP-9 enzyme found in the extracellular matrix of tumor cells, decreased pH of lysosome, and differential concentration of reducing agents in cytosol of cancer cells. We have also successfully demonstrated the sensitivity of these particles towards ultrasound to further enhance the release with internal triggers. To ensure the selective uptake by folate receptor- overexpressing cancer cells, we decorated these nanoparticles with folic acid on their surface. Fluorescence microscopic images showed significantly higher uptake of folate-targeted nanoparticles by MCF-7 (breast cancer) and PANC-1 (pancreatic cancer) cells compared to particles without any targeting ligand on their surface. To demonstrate the effectiveness of these nanoparticles to carry the drugs inside and kill cancer cells, we encapsulated doxorubicin and/or gemcitabine employing the pH gradient method. Drug loaded nanoparticles showed significantly higher killing of the cancer cells compared to their non-targeted counterparts and free drugs. With further development, these nanoparticles certainly have potential to be used as a multifunctional nanocarriers for image

  4. Development and evaluation of 'Pure Rush': An online serious game for drug education.

    Science.gov (United States)

    Stapinski, Lexine A; Reda, Bill; Newton, Nicola C; Lawler, Siobhan; Rodriguez, Daniel; Chapman, Catherine; Teesson, Maree

    2018-04-01

    Learning is most effective when it is active, enjoyable and incorporates feedback. Past research demonstrates that serious games are prime candidates to utilise these principles, however the potential benefits of this approach for delivering drug education are yet to be examined in Australia, a country where drug education in schools is mandatory. The serious game 'Pure Rush' was developed across three stages. First, formative consultation was conducted with 115 students (67% male, aged 15-17 years), followed by feasibility and acceptability testing of a prototype of the game (n = 25, 68% male). In the final stage, 281 students (62% female, aged 13-16 years) were randomly allocated to receive a lesson involving Pure Rush or an active control lesson. The lessons were compared in terms of learning outcomes, lesson engagement and future intentions to use illicit drugs. Students enjoyed playing Pure Rush, found the game age-appropriate and the information useful to them. Both the Pure Rush and the active control were associated with significant knowledge increase from pre to post-test. Among females, multi-level mixed-effects regression showed knowledge gain was greater in the Pure Rush condition compared to control (β = 2.36, 95% confidence interval 0.36-4.38). There was no evidence of between condition differences in lesson engagement or future intentions to use illicit drugs. Pure Rush is an innovative online drug education game that is well received by students and feasible to implement in schools. [Stapinski LA, Reda B, Newton NC, Lawler S, Rodriguez D, Chapman C, Teesson M. Development and evaluation of 'Pure Rush': An online serious game for drug education. Drug Alcohol Rev 2017]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  5. Development of Bilayer Tablets with Modified Release of Selected Incompatible Drugs.

    Science.gov (United States)

    Dhiman, Neha; Awasthi, Rajendra; Jindal, Shammy; Khatri, Smriti; Dua, Kamal

    2016-01-01

    The oral route is considered to be the most convenient and commonly-employed route for drug delivery. When two incompatible drugs need to be administered at the same time and in a single formulation, bilayer tablets are the most appropriate dosage form to administer such incompatible drugs in a single dose. The aim of the present investigation was to develop bilayered tablets of two incompatible drugs; telmisartan and simvastatin. The bilayer tablets were prepared containing telmisartan in a conventional release layer using croscarmellose sodium as a super disintegrant and simvastatin in a slow-release layer using HPMC K15M, Carbopol 934P and PVP K 30 as matrix forming polymers. The tablets were evaluated for various physical properties, drug-excipient interactions using FTIR spectroscopy and in vitro drug release using 0.1M HCl (pH 1.2) for the first hour and phosphate buffer (pH 6.8) for the remaining period of time. The release kinetics of simvastatin from the slow release layer were evaluated using the zero order, first order, Higuchi equation and Peppas equation. All the physical parameters (such as hardness, thickness, disintegration, friability and layer separation tests) were found to be satisfactory. The FTIR studies indicated the absence of interactions between the components within the individual layers, suggesting drug-excipient compatibility in all the formulations. No drug release from the slow-release layer was observed during the first hour of the dissolution study in 0.1M HCl. The release-controlling polymers had a significant effect on the release of simvastatin from the slow-release layer. Thus, the formulated bilayer tablets avoided incompatibility issues and proved the conventional release of telmisartan (85% in 45 min) and slow release of simvastatin (80% in 8 h). Stable and compatible bilayer tablets containing telmisartan and simvastatin were developed with better patient compliance as an alternative to existing conventional dosage forms.

  6. A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

    Science.gov (United States)

    Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

    2018-06-01

    Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

    Science.gov (United States)

    Moreno, Lucas; Caron, Hubert; Geoerger, Birgit; Eggert, Angelika; Schleiermacher, Gudrun; Brock, Penelope; Valteau-Couanet, Dominique; Chesler, Louis; Schulte, Johannes H; De Preter, Katleen; Molenaar, Jan; Schramm, Alexander; Eilers, Martin; Van Maerken, Tom; Johnsen, John Inge; Garrett, Michelle; George, Sally L; Tweddle, Deborah A; Kogner, Per; Berthold, Frank; Koster, Jan; Barone, Giuseppe; Tucker, Elizabeth R; Marshall, Lynley; Herold, Ralf; Sterba, Jaroslav; Norga, Koen; Vassal, Gilles; Pearson, Andrew Dj

    2017-08-01

    Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

  8. How modeling and simulation have enhanced decision making in new drug development.

    Science.gov (United States)

    Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

    2005-04-01

    The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug

  9. Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

    Science.gov (United States)

    Ioset, Jean-Robert; Chang, Shing

    2011-09-01

    The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

  10. Discovery and Development of Therapeutic Drugs against Lethal Human RNA Viruses: a Multidisciplinary Assault.

    Science.gov (United States)

    1991-07-16

    AD-A239 742 AD GRANT NO: DAMD17-89-Z-9021 TITLE: DISCOVERY AND DEVELOPMENT OF THERAPEUTIC DRUGS AGAINST LETHAL HUMAN RNA VIRUSES: A MULTIDISCIPLINARY...62787A871 AB WrJDA317987 11. TITLE (Include Securty Classification) DISCOVERY AND DEVELOPMENT OF THERAPEUTIC DRUGS AGAINST LETHAL HUMAN RNA VIRUSES: A...G. R. Pettit, III, D.-S. Huang, and G. R. Pettit, 23rd Int’l. Horticulture Congress, Italy, 8/27 - 9/1/90. "Bryostatins Define the Role of Protein

  11. [The trend of new drug development for the treatment of diabetes mellitus].

    Science.gov (United States)

    Kaku, Kohei

    2015-12-01

    The trend of new drug development in the field of diabetes mellitus is overviewed. The hypoglycemic drugs such as glucagon receptor antagonists, glucokinase activators, and GPR agonists and oral medication of GLP-1 receptor agonist are under phase 2 trial in Japan. As for therapeutic medicines for diabetic nephropathy, atrasentan as an endothelin A receptor antagonist is in phase 3 trial, and bardoxolone methyl as Nrf2 activator in phase 2 in Japan. Canagliflozin, a SGLT2 inhibitor, is in phase 3 study to obtain new indication of diabetic nephropathy. An environment surrounding development of therapeutic medicines for diabetes has been tough since FDA guidance in 2008.

  12. Developing new drugs for ovarian cancer: a challenging task in a changing reality.

    Science.gov (United States)

    Canetta, R M; Carter, S K

    1984-01-01

    Recent therapeutic and technological advances have profoundly modified the parameters of new drug testing in ovarian cancer. The potential of compounds tested today in this disease therefore needs to be assessed according to this changing reality. Previous treatment with or without cisplatin is the criterion we have applied in our review of the single agent clinical data. Results obtained with older compounds have also been, when possible, reassessed in order to facilitate a comparative interpretation of recent trials. A brief overview of the most recently developed laboratory screening models has been conducted in order to stress their close relationship and their crucial role in future new drug development.

  13. The development of a value based pricing index for new drugs in metastatic colorectal cancer.

    Science.gov (United States)

    Dranitsaris, George; Truter, Ilse; Lubbe, Martie S

    2011-06-01

    Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country's ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. A pharmacoeconomic model was developed to simulate mCRC patients receiving chemotherapy plus a 'new drug' that improves survival by 1.4, 3 and 6months, respectively. Cost and utility data were obtained from cancer centres and oncology nurses (n=112) in Canada, Spain, India, South Africa and Malaysia. Multivariable analysis was then used to develop the pricing index, which considers survival benefit, per capita GDP and income dispersion (as measured by the Gini coefficient) as predictor variables. Higher survival benefits were associated with elevated drug prices, especially in higher income countries such as Canada. For Argentina with a per capita GDP of $15,000 and a Gini coefficient of 51, the index estimated that for a drug which provides a 4month survival benefit in mCRC, the value based price would be $US 630 per dose. In contrast, the same drug in a wealthier country like Norway (per capita GDP=$50,000) could command a price of $US 2,775 per dose. The application of this index to estimate a price based on cost effectiveness and the wealth of a nation would be important for opening dialogue between the key stakeholders and a better alternative to government mandated price cuts. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Incorporation of in silico biodegradability screening in early drug development--a feasible approach?

    Science.gov (United States)

    Steger-Hartmann, Thomas; Länge, Reinhard; Heuck, Klaus

    2011-05-01

    The concentration of a pharmaceutical found in the environment is determined by the amount used by the patient, the excretion and metabolism pattern, and eventually by its persistence. Biological degradation or persistence of a pharmaceutical is experimentally tested rather late in the development of a pharmaceutical, often shortly before submission of the dossier to regulatory authorities. To investigate whether the aspect of persistence of a compound could be assessed early during drug development, we investigated whether biodegradation of pharmaceuticals could be predicted with the help of in silico tools. To assess the value of in silico prediction, we collected results for the OECD 301 degradation test ("ready biodegradability") of 42 drugs or drug synthesis intermediates and compared them to the prediction of the in silico tool BIOWIN. Of these compounds, 38 were predictable with BIOWIN, which is a module of the Estimation Programs Interface (EPI) Suite™ provided by the US EPA. The program failed to predict the two drugs which proved to be readily biodegradable in the degradation tests. On the other hand, BIOWIN predicted two compounds to be readily biodegradable which, however, proved to be persistent in the test setting. The comparison of experimental data with the predicted one resulted in a specificity of 94% and a sensitivity of 0%. The results of this study do not indicate that application of the biodegradation prediction tool BIOWIN is a feasible approach to assess the ready biodegradability during early drug development.

  15. Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Shweta Sinha

    2017-10-01

    Full Text Available The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000–2,000,000 compounds per screening campaign, before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug–drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells.

  16. Development and evaluation of diclofenac sodium thermorevesible subcutaneous drug delivery system.

    Science.gov (United States)

    Nasir, Fazli; Iqbal, Zafar; Khan, Jamshaid A; Khan, Abad; Khuda, Fazli; Ahmad, Lateef; Khan, Amirzada; Khan, Abbas; Dayoo, Abdullah; Roohullah

    2012-12-15

    The objective of current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for diclofenac sodium. The poloxamer 407, methyl cellulose, hydroxypropyl methyl cellulose and polyethylene glycol were used alone and in combination in different ratios to design the delivery system. The physical properties like Tsol-gel, viscosity, clarity of solution and gel were evaluated. The in vitro release of the drug delivery system was evaluated using membrane less method and the drug release kinetics and mechanism was predicted by applying various mathematical models to the in vitro dissolution data. Rabbits were used as in vivo model following subcutaneous injection to predict various pharmacokinetics parameters by applying Pk-Summit software. The in vitro and in vivo data revealed that the system consisting of the poloxamer 407 in concentration of 20% (DP20) was the most capable formulation for extending the drug release and maintaining therapeutic blood level of DS for longer duration (144 h). The data obtained for drug content after autoclaving the solutions indicate that autoclaving results in 6% degradation of DS. The data also suggested that the studied polymers poloxamer, MC and PG are good candidate to extend the drug release possessing a unique thermoreversible property. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Development of Drug Loaded Nanoparticles Binding to Hydroxyapatite Based on a Bisphosphonate Modified Nonionic Surfactant

    Directory of Open Access Journals (Sweden)

    Jiabin Zhang

    2015-01-01

    Full Text Available This study aimed at development of drug loaded nanoparticles which could bind to hydroxyapatite (HA to construct drug or growth factor releasing bone graft substitutes. To this end, the terminal hydroxyl group of a nonionic surfactant Brij 78 (polyoxyethylene (20 stearyl ether was first modified with pamidronate (Pa. Using Pa-Brij 78 as both a surfactant and an affinity ligand to HA, three different Pa surface functionalized nanoparticles were prepared, named as solid lipid nanoparticles (Pa-SNPs, nanoemulsions (Pa-NEMs, and PLGA nanoparticles (Pa-PNPs. A model drug curcumin was successfully encapsulated in the three nanoparticles. The sizes of Pa-NEM and Pa-PNP were around 150 nm and the size of Pa-SNP was around 90 nm with polydispersity indexes (PDIs less than 0.20. Drug encapsulation efficiencies of the three nanoparticles were all greater than 85%. Furthermore, the order of binding affinity of the nanoparticles to HA was Pa-PNP>Pa-NEM=Pa-SNP. After lyophilization, the sizes of the three nanoparticles were increased about 0.5–2.0-fold but their binding affinities to HA were almost the same as the fresh prepared nanoparticles. In conclusion, a Pa-modified Brij 78 was synthesized and used for fabrication of a series of drug loaded nanoparticles to construct drug-eluting HA-based bone graft substitutes.

  18. Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan

    Directory of Open Access Journals (Sweden)

    Jaydeep Patel

    2011-01-01

    Full Text Available Irbesartan (IRB is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg, Cremophor® EL (43.33%, Carbitol® (21.67% and Capryol® 90 (32%. SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB.

  19. Atmospheric Research 2016 Technical Highlights

    Science.gov (United States)

    Platnick, Steven

    2017-01-01

    Atmospheric research in the Earth Sciences Division (610) consists of research and technology development programs dedicated to advancing knowledge and understanding of the atmosphere and its interaction with the climate of Earth. The Divisions goals are to improve understanding of the dynamics and physical properties of precipitation, clouds, and aerosols; atmospheric chemistry, including the role of natural and anthropogenic trace species on the ozone balance in the stratosphere and the troposphere; and radiative properties of Earth's atmosphere and the influence of solar variability on the Earth's climate. Major research activities are carried out in the Mesoscale Atmospheric Processes Laboratory, the Climate and Radiation Laboratory, the Atmospheric Chemistry and Dynamics Laboratory, and the Wallops Field Support Office. The overall scope of the research covers an end-to-end process, starting with the identification of scientific problems, leading to observation requirements for remote-sensing platforms, technology and retrieval algorithm development; followed by flight projects and satellite missions; and eventually, resulting in data processing, analyses of measurements, and dissemination from flight projects and missions. Instrument scientists conceive, design, develop, and implement ultraviolet, infrared, optical, radar, laser, and lidar technology to remotely sense the atmosphere. Members of the various laboratories conduct field measurements for satellite sensor calibration and data validation, and carry out numerous modeling activities. These modeling activities include climate model simulations, modeling the chemistry and transport of trace species on regional-to-global scales, cloud resolving models, and developing the next-generation Earth system models. Satellite missions, field campaigns, peer-reviewed publications, and successful proposals are essential at every stage of the research process to meeting our goals and maintaining leadership of the

  20. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353