Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

Science.gov (United States)

Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul

2013-10-01

Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.

Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

Directory of Open Access Journals (Sweden)

Apurv Patel

2016-01-01

Full Text Available The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients.

Adolescents' future orientation and nonmedical use of prescription drugs.

Science.gov (United States)

Steiger, Rena M; Stoddard, Sarah A; Pierce, Jennifer

2017-02-01

How adolescents think about their future (i.e., future orientation) impacts their risk-taking behavior. The purpose of the present analysis was to explore whether future orientation (future planning, perceived risk to future goals, and positive future expectations) was associated with nonmedical use of stimulants and analgesics in a sample of high school students. Information on future orientation and nonmedical use of prescription drugs (NMUPD) were collected using a paper-and-pencil survey from a sample of 9th-12th grade students in a Midwestern school. Higher perceived risk to future goals and positive future expectations were associated with a lower likelihood of self-reported nonmedical use of stimulants (n=250; OR=0.46, 95% CI: 0.26, 0.83; OR=0.15, 95% CI: 0.05, 0.47, respectively). Only higher perceived risk to future goals was associated with a lower likelihood of self-reported nonmedical use of analgesics (n=250; OR=0.40, 95% CI: 0.24, 0.68). In a follow-up analysis limited to students who endorsed alcohol or marijuana use, perceived risk to future goals remained associated with a lower likelihood of nonmedical use of stimulants and analgesics. Results suggest that risk perception might be a salient protective factor against both nonmedical use of stimulants and analgesics. Overall, the differential impact of conceptualizations of future orientation might depend on the class of prescription drug used, demonstrating a need to consider prescription drugs individually in the development of future studies and interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

Science.gov (United States)

Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

2013-01-01

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

New High: A Future-Oriented Study of American Drug Policy

Science.gov (United States)

2017-12-01

physical health , leading to a decrease in morbidity and mortality from obesity. Nootropics on pharmacy shelves combat hunger, low energy, and...office of the future. 14. SUBJECT TERMS futures, megatrends, emerging technologies, drug policy, public health , war on drugs, forecasting, behavioral... health , scenarios, trends, innovation, regulation, policy, artificial intelligence, brain-computer interface, neural stimulation, nootropics

Metabolism of designer drugs of abuse.

Science.gov (United States)

Staack, Roland F; Maurer, Hans H

2005-06-01

Abuse of designer drugs is widespread among young people, especially in the so-called "dance club scene" or "rave scene", worldwide. Severe and even fatal poisonings have been attributed to the consumption of such drugs of abuse. However, in contrast to new medicaments, which are extensively studied in controlled clinical studies concerning metabolism, including cytochrome P450 isoenzyme differentiation, and further pharmacokinetics, designer drugs are consumed without any safety testing. This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA) and 4-methylthioamphetamine (4-MTA), were taken into consideration as new "classical" amphetamine-derived designer drugs. Furthermore, N-benzylpiperazine (BZP), 1-(3, 4-methylenedioxybenzyl)piperazine (MDBP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP) were taken into consideration as derivatives of the class of piperazine-derived designer drugs, as well as alpha-pyr-rolidinopropiophenone (PPP), 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), 3', 4'-methylenedioxy-alpha-pyrrolidino-propiophenone (MDPPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-methyl-alpha-pyrrolidinoexanophenone (MPHP) as derivatives of the class of alpha-pyrrolidinophenone-derived designer drugs. Papers describing identification of in vivo or in vitro human or animal metabolites and cytochrome P450 isoenzyme dependent metabolism have been considered and summarized.

Computer Aided Drug Design: Success and Limitations.

Science.gov (United States)

Baig, Mohammad Hassan; Ahmad, Khurshid; Roy, Sudeep; Ashraf, Jalaluddin Mohammad; Adil, Mohd; Siddiqui, Mohammad Haris; Khan, Saif; Kamal, Mohammad Amjad; Provazník, Ivo; Choi, Inho

2016-01-01

Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

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

Smarter Drugs: How Protein Crystallography Revolutionizes Drug Design

International Nuclear Information System (INIS)

Smith, Clyde

2005-01-01

According to Smith, protein crystallography allows scientists to design drugs in a much more efficient way than the standard methods traditionally used by large drug companies, which can cost close to a billion dollars and take 10 to 15 years. 'A lot of the work can be compressed down,' Smith said. Protein crystallography enables researchers to learn the structure of molecules involved in disease and health. Seeing the loops, folds and placement of atoms in anything from a virus to a healthy cell membrane gives important information about how these things work - and how to encourage, sidestep or stop their functions. Drug design can be much faster when the relationship between structure and function tells you what area of a molecule to target. Smith will use a timeline to illustrate the traditional methods of drug development and the new ways it can be done now. 'It is very exciting work. There have been some failures, but many successes too.' A new drug to combat the flu was developed in a year or so. Smith will tell us how. He will also highlight drugs developed to combat HIV, Tuberculosis, hypertension and Anthrax.

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

Science.gov (United States)

Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

2017-11-27

Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

Current situation and future usage of anticancer drug databases.

Science.gov (United States)

Wang, Hongzhi; Yin, Yuanyuan; Wang, Peiqi; Xiong, Chenyu; Huang, Lingyu; Li, Sijia; Li, Xinyi; Fu, Leilei

2016-07-01

Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug-target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug-drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes.

Antimalarial drug policy in India: past, present & future.

Science.gov (United States)

Anvikar, Anupkumar R; Arora, Usha; Sonal, G S; Mishra, Neelima; Shahi, Bharatendu; Savargaonkar, Deepali; Kumar, Navin; Shah, Naman K; Valecha, Neena

2014-02-01

The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17 th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions.

[Designer drugs in Jutland].

Science.gov (United States)

Simonsen, K W; Kaa, E

2001-04-16

The aim of this investigation was to examine illegal tablets and capsules seized in Jutland, the western part of Denmark, during the period 1995-1999. The drugs are described according to technical appearance (colour, logo, score, diameter) and content of synthetic drugs. All illegal tablets and capsules received during the period 1995-1999 (109 cases containing 192 different samples) were examined. MDMA was the most common drug and was seen during the entire period. Amphetamine was the second most common drug and has been frequently detected during the the last two years. Drugs like MDE, MBDB, BDB, and 2-CB were rarely seen and they disappeared quickly from the illegal market. MDA appeared on the market at the end of 1999. Only 53% of the tablets contained MDMA as the sole drug. Eighty-one percent of the tablets/capsules contained only one synthetic drug, whereas 13% contained a mixture of two or more synthetic drugs. Six per cent of the samples did not contain a euphoric drug/designer drug. The content of MDMA, MDE, and amphetamine in the tablets varied greatly. MDMA is apparently the drug preferred by the users, but still only half of the tablets contained MDMA as the only drug. The rest of the tablets contained either another synthetic drug or a mixture of drugs. In conclusion, the increasing supply of various drugs with different and unpredictable effects and of miscellaneous quality brings about the risk of serious and complicated intoxications.

Future Challenges and Opportunities in Online Prescription Drug Promotion Research

Science.gov (United States)

Southwell, Brian G.; Rupert, Douglas J.

2016-01-01

Despite increased availability of online promotional tools for prescription drug marketers, evidence on online prescription drug promotion is far from settled or conclusive. We highlight ways in which online prescription drug promotion is similar to conventional broadcast and print advertising and ways in which it differs. We also highlight five key areas for future research: branded drug website influence on consumer knowledge and behavior, interactive features on branded drug websites, mobile viewing of branded websites and mobile advertisements, online promotion and non-US audiences, and social media and medication decisions. PMID:26927597

Thermodynamic Studies for Drug Design and Screening

Science.gov (United States)

Garbett, Nichola C.; Chaires, Jonathan B.

2012-01-01

Introduction A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. Areas covered This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 – 2011 using the Science Citation Index and PUBMED and the keywords listed below. Expert opinion The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically-driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development towards an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. PMID:22458502

Thermodynamic studies for drug design and screening.

Science.gov (United States)

Garbett, Nichola C; Chaires, Jonathan B

2012-04-01

A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 - 2011 using the Science Citation Index and PUBMED and the keywords listed below. The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development toward an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in the design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. © 2012 Informa UK, Ltd.

Protein Crystallography: A 'Must' Technology for Drug Design

International Nuclear Information System (INIS)

Matsuzaki, Takao

2004-01-01

The history of drug-related protein crystallography and drug design is reviewed to show that 'Lead Generation' is high-lighted in the pharmaceutical industry nowadays. A new drug design method has been developed. The method gave very high success rate; 10-60 % gave < 100 μM, 90 % gave < 10 mM. The crystal structures of drug-protein complexes have become even more important to give solid experimental bases for e.g. 1,000 designed structures and to find the new mechanisms of drug action

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

Science.gov (United States)

Tomioka, Haruaki; Namba, Kenji

2006-12-01

latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The

Dosage design - past, present and future

International Nuclear Information System (INIS)

Ganderton, D.

1982-01-01

The design criteria to be considered in the formulation of drugs is discussed eg. the porosity, density, solubility and compressibility of tablets. Structure related to function. The absorbability of drug surfaces in the intestinal tract and the relationship of this to the pH of stomach contents. Particle size and the role of release of a drug for maximum therapeutic effect. Pharmacodynamic intensity and the use of polymers as matrix materials for slow-release drugs. Sites of administration and targeting of drugs, and the physiological response of the body are all important. (U.K.)

Use of prescription drugs and future delinquency among adolescent offenders.

Science.gov (United States)

Drazdowski, Tess K; Jäggi, Lena; Borre, Alicia; Kliewer, Wendy L

2015-01-01

Non-medical use of prescription drugs (NMUPD) by adolescents is a significant public health concern. The present study investigated the profile of NMUPD in 1349 adolescent offenders from the Pathways to Desistance project, and whether NMUPD predicted future delinquency using longitudinal data. Results indicated that increased frequency and recency of NMUPD in adolescent offenders are related to some demographic factors, as well as increased risk for violence exposure, mental health diagnoses, other drug use, and previous delinquency, suggesting that severity of NMUPD is important to consider. However, ANCOVA analyses found that NMUPD was not a significant predictor of drug-related, non-aggressive, or aggressive delinquency 12 months later beyond other known correlates of delinquency. Age, sex, exposure to violence, lower socioeconomic status, more alcohol use, and having delinquency histories were more important than NMUPD in predicting future delinquency. These findings suggest that although NMUPD is an important risk factor relating to many correlates of delinquency, it does not predict future delinquency beyond other known risk factors. Copyright © 2014 Elsevier Inc. All rights reserved.

In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts

Science.gov (United States)

Yang, Hongbin; Sun, Lixia; Li, Weihua; Liu, Guixia; Tang, Yun

2018-02-01

For a drug, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts

Directory of Open Access Journals (Sweden)

Hongbin Yang

2018-02-01

Full Text Available During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts.

Science.gov (United States)

Yang, Hongbin; Sun, Lixia; Li, Weihua; Liu, Guixia; Tang, Yun

2018-01-01

During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future.

Antimalarial drug policy in India: Past, present & future

Directory of Open Access Journals (Sweden)

Anupkumar R Anvikar

2014-01-01

Full Text Available The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17 th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions.

Accounting for the drug life cycle and future drug prices in cost-effectiveness analysis.

Science.gov (United States)

Hoyle, Martin

2011-01-01

Economic evaluations of health technologies typically assume constant real drug prices and model only the cohort of patients currently eligible for treatment. It has recently been suggested that, in the UK, we should assume that real drug prices decrease at 4% per annum and, in New Zealand, that real drug prices decrease at 2% per annum and at patent expiry the drug price falls. It has also recently been suggested that we should model multiple future incident cohorts. In this article, the cost effectiveness of drugs is modelled based on these ideas. Algebraic expressions are developed to capture all costs and benefits over the entire life cycle of a new drug. The lifetime of a new drug in the UK, a key model parameter, is estimated as 33 years, based on the historical lifetime of drugs in England over the last 27 years. Under the proposed methodology, cost effectiveness is calculated for seven new drugs recently appraised in the UK. Cost effectiveness as assessed in the future is also estimated. Whilst the article is framed in mathematics, the findings and recommendations are also explained in non-mathematical language. The 'life-cycle correction factor' is introduced, which is used to convert estimates of cost effectiveness as traditionally calculated into estimates under the proposed methodology. Under the proposed methodology, all seven drugs appear far more cost effective in the UK than published. For example, the incremental cost-effectiveness ratio decreases by 46%, from £61, 900 to £33, 500 per QALY, for cinacalcet versus best supportive care for end-stage renal disease, and by 45%, from £31,100 to £17,000 per QALY, for imatinib versus interferon-α for chronic myeloid leukaemia. Assuming real drug prices decrease over time, the chance that a drug is publicly funded increases over time, and is greater when modelling multiple cohorts than with a single cohort. Using the methodology (compared with traditional methodology) all drugs in the UK and New

"9th Annual Congress on Drug Formulation & Drug Design"

OpenAIRE

Monty Karl

2017-01-01

Conference Series has been instrumental in conducting international meetings for seven years, and very excited to expand Europe, America and Asia Pacific continents. Previous meetings were held in major cities like Belgium, Tokyo, Madrid, with success the meetings again scheduled in three continents. It’s time to announce 9th Annual Congress on Drug Formulation & Drug Design October 19-21, 2017 Seoul, South Korea . Drug Formulation 2017 is a 3-day event offering the Exhibition, at venue to sh...

21 CFR 516.29 - Termination of MUMS-drug designation.

Science.gov (United States)

2010-04-01

... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.29 Termination of MUMS-drug designation. (a... exclusive marketing rights under this subpart. (d) FDA may terminate designation if it independently...

Designing the molecular future

OpenAIRE

Schneider Gisbert

2011-01-01

Approximately 25 years ago the first computer applications were conceived for the purpose of automated 'de novo' drug design prominent pioneering tools being ALADDIN CAVEAT GENOA and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand receptor interaction modeling like GRID MCSS DOCK and CoMFA which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking ...

Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.

Science.gov (United States)

Huang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, Xinyong

2015-12-01

The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.

Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

Science.gov (United States)

Seely, Kathryn A; Prather, Paul L; James, Laura P; Moran, Jeffery H

2011-02-01

The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.

4D-QSAR: Perspectives in Drug Design

Directory of Open Access Journals (Sweden)

Carolina H. Andrade

2010-05-01

Full Text Available Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure–activity relationship (QSAR formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design.

The impact of genetics on future drug discovery in schizophrenia.

Science.gov (United States)

Matsumoto, Mitsuyuki; Walton, Noah M; Yamada, Hiroshi; Kondo, Yuji; Marek, Gerard J; Tajinda, Katsunori

2017-07-01

Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations. Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs. Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

Classifying new anti-tuberculosis drugs: rationale and future perspectives

Directory of Open Access Journals (Sweden)

Simon Tiberi

2017-03-01

Full Text Available The classification of anti-tuberculosis (TB drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR and extensively drug-resistant (XDR TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2–5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed.

The impact of ageing and changing utilization patterns on future cardiovascular drug expenditure: a pharmacoepidemiological projection approach

DEFF Research Database (Denmark)

Kildemoes, Helle Wallach; Andersen, Morten; Støvring, Henrik

2010-01-01

To develop a method for projecting the impact of ageing and changing drug utilization patterns on future drug expenditure.......To develop a method for projecting the impact of ageing and changing drug utilization patterns on future drug expenditure....

Designing Firms to Fit the Future

Directory of Open Access Journals (Sweden)

Raymond E. Miles

2012-08-01

Full Text Available Most firms identify market opportunities for their new technologies after they have been developed. This article discusses the design of a “futures group” which can help to synchronize a firm’s technology and market development. A futures group designed to span more than one organization could lead to simultaneous market development for multiple technologies.

Computer aided drug design

Science.gov (United States)

Jain, A.

2017-08-01

Computer based method can help in discovery of leads and can potentially eliminate chemical synthesis and screening of many irrelevant compounds, and in this way, it save time as well as cost. Molecular modeling systems are powerful tools for building, visualizing, analyzing and storing models of complex molecular structure that can help to interpretate structure activity relationship. The use of various techniques of molecular mechanics and dynamics and software in Computer aided drug design along with statistics analysis is powerful tool for the medicinal chemistry to synthesis therapeutic and effective drugs with minimum side effect.

Modeling chemical reactions for drug design.

Science.gov (United States)

Gasteiger, Johann

2007-01-01

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

Polymer-drug conjugates: origins, progress to date and future directions.

Science.gov (United States)

Kopeček, Jindřich

2013-01-01

This overview focuses on bioconjugates of water-soluble polymers with low molecular weight drugs and proteins. After a short discussion of the origins of the field, the state-of-the-art is reviewed. Then research directions needed for the acceleration of the translation of nanomedicines into the clinic are outlined. Two most important directions, synthesis of backbone degradable polymer carriers and drug-free macromolecular therapeutics, a new paradigm in drug delivery, are discussed in detail. Finally, the future perspectives of the field are briefly discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

Science.gov (United States)

Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

2013-05-01

Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

Target based drug design - a reality in virtual sphere.

Science.gov (United States)

Verma, Saroj; Prabhakar, Yenamandra S

2015-01-01

The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

Editorial: in silico drug design and medicinal chemistry).

Science.gov (United States)

Singla, Rajeev K

2015-01-01

Medicinal chemistry is not limited to molecules, their structures and design but also highly cohesive to pharmacological activities. The potency of a molecule varies by its structure. Hence structural activity relationship is the sub-branch which deals with the estimation of ability of a molecule in depicting any pharmacological activity. In silico drug design is a novel technique which is employed in designing a molecule by using computer aided software’s and bringing a superior and potent molecule. In recent years, in silico drug design has been merged with medicinal chemistry especially by the techniques like ligand based strategy to isolate the required structures. By such strategic techniques, there are high chances of delivering high throughput screening which involves of screening large number of molecules in a very less time. Involvement of such techniques would be a boon for development of new drug entity as it can aid in development of newer, safe, effective and potent drug molecules. Hence, the present issue is aimed to emphasize the cohesion between in silico drug design and it significance in medicinal chemistry. The articles which would be published will mainly focus on the role of in silico drug design techniques in the development of molecules to target various disease and disorders. Molecules can from natural/ synthetic/semi synthetic origin. Articles will be a treasure box consisting of employment of computational methods for unprecedented molecules. The issue will be sure an endorsement for international readership and researchers.

Optimization and design of ibuprofen-loaded nanostructured lipid carriers using a hybrid-design approach for ocular drug delivery

Science.gov (United States)

Rathod, Vishal

The objective of the present project was to develop the Ibuprofen-loaded Nanostructured Lipid Carrier (IBU-NLCs) for topical ocular delivery based on substantial pre-formulation screening of the components and understanding the interplay between the formulation and process variables. The BCS Class II drug: Ibuprofen was selected as the model drug for the current study. IBU-NLCs were prepared by melt emulsification and ultrasonication technique. Extensive pre-formulation studies were performed to screen the lipid components (solid and liquid) based on drug's solubility and affinity as well as components compatibility. The results from DSC & XRD assisted in selecting the most suitable ratio to be utilized for future studies. DynasanRTM 114 was selected as the solid lipid & MiglyolRTM 840 was selected as the liquid lipid based on preliminary lipid screening. The ratio of 6:4 was predicted to be the best based on its crystallinity index and the thermal events. As there are many variables involved for further optimization of the formulation, a single design approach is not always adequate. A hybrid-design approach was applied by employing the Plackett Burman design (PBD) for preliminary screening of 7 critical variables, followed by Box-Behnken design (BBD), a sub-type of response surface methodology (RSM) design using 2 relatively significant variables from the former design and incorporating Surfactant/Co-surfactant ratio as the third variable. Comparatively, KolliphorRTM HS15 demonstrated lower Mean Particle Size (PS) & Polydispersity Index (PDI) and KolliphorRTM P188 resulted in Zeta Potential (ZP) ibuprofen thereafter over several hours. These values also confirm that the production method, and all other selected variables, effectively promoted the incorporation of ibuprofen in NLC. Quality by Design (QbD) approach was successfully implemented in developing a robust ophthalmic formulation with superior physicochemical and morphometric properties. NLCs as the

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.

Targeted proteins for diabetes drug design

Science.gov (United States)

Doan Trang Nguyen, Ngoc; Thi Le, Ly

2012-03-01

Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

Targeted proteins for diabetes drug design

International Nuclear Information System (INIS)

Trang Nguyen, Ngoc Doan; Le, Ly Thi

2012-01-01

Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people. (review)

Designing the Future

Directory of Open Access Journals (Sweden)

Friso de Zeeuw

2010-04-01

Full Text Available The Netherlands has a tradition in public spatial planning and design. In the past 20 years, we have seen an increasing role for the market in this field, and more recently, growing attention for sustainability. Sustainability has become an economic factor. Not only at the building level, but also on the level of large-scale area development projects. More and more local governments have high ambitions for sustainable development. Increasingly, during project development, buildings are developed on a sustainable basis. Most of the time, the focus in this approach is on energy. However, sustainability also comprises social aspects. Energy measures have a direct relation to an economic factor such as investment costs, and payback time can be calculated. The economic aspects of social sustainability are more complex. Therefore, for all sustainability development projects, especially in large-scale projects planned over a longer period, it is necessary to make presumptions, which are less reliable as the planning period is extended. For future larger-scale developments, experience in the Netherlands points to two design approaches: ‘backcasting’, or using a growth model (or a combination of these two. The power of design is the ability to imagine possible scenarios for the future. The layer approach helps to integrate sustainability into public spatial planning. And more specifically, Urban Design Management (UDM supports an integrative and collaborative approach also on the operational level of a project in which public and market partners work together. This article outlines how design, based on these approaches, can contribute to sustainable development based on the ‘new playing field’, where spatial problems should be solved in networks. Dutch projects in Almere (Benoordenhout and Rijswijk are used to illustrate this approach.

Defining Patient Centric Pharmaceutical Drug Product Design.

Science.gov (United States)

Stegemann, Sven; Ternik, Robert L; Onder, Graziano; Khan, Mansoor A; van Riet-Nales, Diana A

2016-09-01

The term "patient centered," "patient centric," or "patient centricity" is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient's quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient's needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved.

Organic carbamates in drug design and medicinal chemistry.

Science.gov (United States)

Ghosh, Arun K; Brindisi, Margherita

2015-04-09

The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design.

Science.gov (United States)

Pihan, Emilie; Colliandre, Lionel; Guichou, Jean-François; Douguet, Dominique

2012-06-01

In the drug discovery field, new uses for old drugs, selective optimization of side activities and fragment-based drug design (FBDD) have proved to be successful alternatives to high-throughput screening. e-Drug3D is a database of 3D chemical structures of drugs that provides several collections of ready-to-screen SD files of drugs and commercial drug fragments. They are natural inputs in studies dedicated to drug repurposing and FBDD. e-Drug3D collections are freely available at http://chemoinfo.ipmc.cnrs.fr/e-drug3d.html either for download or for direct in silico web-based screenings.

Crystallography and Drug Design

Indian Academy of Sciences (India)

Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 12. Crystallography and Drug Design. K Suguna. General Article Volume 19 Issue 12 December 2014 pp 1093-1103. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/reso/019/12/1093-1103. Keywords.

"Not for human consumption": a review of emerging designer drugs.

Science.gov (United States)

Musselman, Megan E; Hampton, Jeremy P

2014-07-01

Synthetic, or "designer" drugs, are created by manipulating the chemical structures of other psychoactive drugs so that the resulting product is structurally similar but not identical to illegal psychoactive drugs. Originally developed in the 1960s as a way to evade existing drug laws, the use of designer drugs has increased dramatically over the past few years. These drugs are deceptively packaged as "research chemicals," "incense," "bath salts," or "plant food," among other names, with labels that may contain warnings such as "not for human consumption" or "not for sale to minors." The clinical effects of most new designer drugs can be described as either hallucinogenic, stimulant, or opioid-like. They may also have a combination of these effects due to designer side-chain substitutions. The easy accessibility and rapid emergence of new designer drugs have created challenges for health care providers when treating patients presenting with acute toxicity from these substances, many of which can produce significant and/or life-threatening adverse effects. Moreover, the health care provider has no way to verify the contents and/or potency of the agent ingested because it can vary between packages and distributors. Therefore, a thorough knowledge of the available designer drugs, common signs and symptoms of toxicity associated with these agents, and potential effective treatment modalities are essential to appropriately manage these patients. © 2014 Pharmacotherapy Publications, Inc.

Drug design: Insights from atomistic simulations

International Nuclear Information System (INIS)

Collu, F.; Spiga, E.; Kumar, A.; Hajjar, E.; Vargiu, A.V.; Ceccarelli, M.; Ruggerone, P.

2009-01-01

Computer simulations have become a widely used and powerful tool to study the behaviour of many-particle and many-interaction systems and processes such as nucleic acid dynamics, drug-DNA interactions, enzymatic processes, membrane, antibiotics. The increased reliability of computational techniques has made possible to plane a bottom-up approach in drug design, i.e. designing molecules with improved properties starting from the knowledge of the molecular mechanisms. However, the in silico techniques have to face the fact that the number of degrees of freedom involved in biological systems is very large while the time scale of several biological processes is not accessible to standard simulations. Algorithms and methods have been developed and are still under construction to bridge these gaps. Here we review the activities of our group focussed on the time-scale bottleneck and, in particular, on the use of the meta dynamics scheme that allows the investigation of rare events in reasonable computer time without reducing the accuracy of the calculation. In particular, we have devoted particular attention to the characterization at microscopic level of translocation of antibiotics through membrane pores, aiming at the identification of structural and dynamical features helpful for a rational drug design.

Projecting future drug expenditures--2009.

Science.gov (United States)

Hoffman, James M; Shah, Nilay D; Vermeulen, Lee C; Doloresco, Fred; Martin, Patrick K; Blake, Sharon; Matusiak, Linda; Hunkler, Robert J; Schumock, Glen T

2009-02-01

Drug expenditure trends in 2007 and 2008, projected drug expenditures for 2009, and factors likely to influence drug expenditures are discussed. Various factors are likely to influence drug expenditures in 2009, including drugs in development, the diffusion of new drugs, drug safety concerns, generic drugs, Medicare Part D, and changes in the drug supply chain. The increasing availability of important generic drugs and drug safety concerns continue to moderate growth in drug expenditures. The drug supply chain remains dynamic and may influence drug expenditures, particularly in specialized therapeutic areas. Initial data suggest that the Medicare Part D benefit has influenced drug expenditures, but the ultimate impact of the benefit on drug expenditures remains unclear. From 2006 to 2007, total U.S. drug expenditures increased by 4.0%, with total spending rising from $276 billion to $287 billion. Drug expenditures in clinics continue to grow more rapidly than in other settings, with a 9.9% increase from 2006 to 2007. Hospital drug expenditures increased at a moderate rate of only 1.6% from 2006 to 2007; through the first nine months of 2008, hospital drug expenditures increased by only 2.8% compared with the same period in 2007. In 2009, we project a 0-2% increase in drug expenditures in outpatient settings, a 1-3% increase in expenditures for clinic-administered drugs, and a 1-3% increase in hospital drug expenditures.

Computer aided architectural design : futures 2001

NARCIS (Netherlands)

Vries, de B.; Leeuwen, van J.P.; Achten, H.H.

2001-01-01

CAAD Futures is a bi-annual conference that aims to promote the advancement of computer-aided architectural design in the service of those concerned with the quality of the built environment. The conferences are organized under the auspices of the CAAD Futures Foundation, which has its secretariat

Molecular Rift: Virtual Reality for Drug Designers.

Science.gov (United States)

Norrby, Magnus; Grebner, Christoph; Eriksson, Joakim; Boström, Jonas

2015-11-23

Recent advances in interaction design have created new ways to use computers. One example is the ability to create enhanced 3D environments that simulate physical presence in the real world--a virtual reality. This is relevant to drug discovery since molecular models are frequently used to obtain deeper understandings of, say, ligand-protein complexes. We have developed a tool (Molecular Rift), which creates a virtual reality environment steered with hand movements. Oculus Rift, a head-mounted display, is used to create the virtual settings. The program is controlled by gesture-recognition, using the gaming sensor MS Kinect v2, eliminating the need for standard input devices. The Open Babel toolkit was integrated to provide access to powerful cheminformatics functions. Molecular Rift was developed with a focus on usability, including iterative test-group evaluations. We conclude with reflections on virtual reality's future capabilities in chemistry and education. Molecular Rift is open source and can be downloaded from GitHub.

Designer Drug Confusion: A Focus on MDMA.

Science.gov (United States)

Beck, Jerome; Morgan, Patricia A.

1986-01-01

Discusses the competing definitions and issues surrounding various designer drugs, primarily 3, 4-methylenedioxy-methamphetamine (MDMA). Offers a rationale for why interest in MDMA, which possesses both stimulant and psychedelic properties, will continue to grow despite the drug's recent illegality and increasing evidence of neurotoxicity.…

Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

Directory of Open Access Journals (Sweden)

Avinaba Mukherjee

2016-03-01

Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

EcoDesign and future environmental impacts

DEFF Research Database (Denmark)

Jeswiet, Jack; Hauschild, Michael Zwicky

2005-01-01

This paper describes the relation between EcoDesign and Life Cycle Engineering; both include Product Engineering as a focal point. Product Engineering includes both product design and manufacture, two fields which are changing quickly. In addition, this paper shows where future changes can be exp...

Nonthionamide Drugs for the Treatment of Hyperthyroidism: From Present to Future

Directory of Open Access Journals (Sweden)

Nattakarn Suwansaksri

2018-01-01

Full Text Available Hyperthyroidism is a common endocrine disease. Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, nonthionamide antithyroid drugs (NTADs still have an important role in controlling hyperthyroidism in clinical practice. Furthermore, some situations such as thyroid storm or preoperative preparation require a rapid decrease in thyroid hormone by combination treatment with multiple classes of antithyroid drugs. NTADs include iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoid, and cholestyramine. In this narrative review, we summarize the mechanisms of action, indications, dosages, and side effects of currently used NTADs for the treatment of hyperthyroidism. In addition, we also describe the state-of-the-art in future drugs under development including rituximab, small-molecule ligands (SMLs, and monoclonal antibodies with a thyroid-stimulating hormone receptor (TSHR antagonist effect.

Design of Drug Delivery Methods for the Brain and Central Nervous System

Science.gov (United States)

Lueshen, Eric

Due to the impermeability of the blood-brain barrier (BBB) to macromolecules delivered systemically, drug delivery to the brain and central nervous system (CNS) is quite difficult and has become an area of intense research. Techniques such as convection-enhanced intraparenchymal delivery and intrathecal magnetic drug targeting offer a means of circumventing the blood-brain barrier for targeted delivery of therapeutics. This dissertation focuses on three aspects of drug delivery: pharmacokinetics, convection-enhanced delivery, and intrathecal magnetic drug targeting. Classical pharmacokinetics mainly uses black-box curve fitting techniques without biochemical or biological basis. This dissertation advances the state-of-the-art of pharmacokinetics and pharmacodynamics by incorporating first principles and biochemical/biotransport mechanisms in the prediction of drug fate in vivo. A whole body physiologically-based pharmacokinetics (PBPK) modeling framework is engineered which creates multiscale mathematical models for entire organisms composed of organs, tissues, and a detailed vasculature network to predict drug bioaccumulation and to rigorously determine kinetic parameters. These models can be specialized to account for species, weight, gender, age, and pathology. Systematic individual therapy design using the proposed mechanistic PBPK modeling framework is also a possibility. Biochemical, anatomical, and physiological scaling laws are also developed to accurately project drug kinetics in humans from small animal experiments. Our promising results demonstrate that the whole-body mechanistic PBPK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool. Convection

Therapeutic drug monitoring in pediatric IBD: current application and future perspectives.

Science.gov (United States)

Lega, Sara; Bramuzzo, Matteo; Dubinsky, Marla

2017-09-11

As the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine wherein serum drug concentrations are used to guide drug dosing on an individual basis. The concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti-TNFs therapies. In the era of biologics, TDM entered the clinical field to assist clinicians managing anti-TNF failure and its role is now moving toward the concept of "proactive" TDM with the goal to optimize drug exposure and prevent loss of response. Research in TDM is rapidly expanding: while the role of TDM with new biologics is under investigation, preliminary data suggest that software-systems support tools could be an opportunity to guide dosing choices and maximize the cost-benefit profile of therapies in the near future. The review discusses the current knowledge that poses the rationale for the use of TDM and the present and future role of TDM-based approaches in the management of pediatric IBD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

Science.gov (United States)

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future.

Science.gov (United States)

Hol, Wim G J

2015-05-01

Parasitic protozoa cause a range of diseases which threaten billions of human beings. They are responsible for tremendous mortality and morbidity in the least-developed areas of the world. Presented here is an overview of the evolution over the last three to four decades of structure-guided design of inhibitors, leads and drug candidates aiming at targets from parasitic protozoa. Target selection is a crucial and multi-faceted aspect of structure-guided drug design. The major impact of advances in molecular biology, genome sequencing and high-throughput screening is touched upon. The most advanced crystallographic techniques, including XFEL, have already been applied to structure determinations of drug targets from parasitic protozoa. Even cryo-electron microscopy is contributing to our understanding of the mode of binding of inhibitors to parasite ribosomes. A number of projects have been selected to illustrate how structural information has assisted in arriving at promising compounds that are currently being evaluated by pharmacological, pharmacodynamic and safety tests to assess their suitability as pharmaceutical agents. Structure-guided approaches are also applied to incorporate properties into compounds such that they are less likely to become the victim of resistance mechanisms. A great increase in the number of novel antiparasitic compounds will be needed in the future. These should then be combined into various multi-compound therapeutics to circumvent the diverse resistance mechanisms that render single-compound, or even multi-compound, drugs ineffective. The future should also see (i) an increase in the number of projects with a tight integration of structural biology, medicinal chemistry, parasitology and pharmaceutical sciences; (ii) the education of more `medicinal structural biologists' who are familiar with the properties that compounds need to have for a high probability of success in the later steps of the drug-development process; and (iii) the

Design storytelling with future scenario development; envisioning "the museum"

NARCIS (Netherlands)

Eggink, Wouter; Albert de la Bruheze, Adri A.

2015-01-01

There are different ways to tell stories with design. This paper shows possibilities of telling stories by envisioning the future. Overall, design has the very ability to envision, visualize and express things that do not exist yet. We introduce the Future Scenario Development Design methodology as

Metal complexes in cancer therapy – an update from drug design perspective

Directory of Open Access Journals (Sweden)

Ndagi U

2017-03-01

Full Text Available Umar Ndagi, Ndumiso Mhlongo, Mahmoud E Soliman Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa Abstract: In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective

Pyrimidines in antimalarial drug design

CSIR Research Space (South Africa)

Moleele, SS

2008-09-01

Full Text Available of the routes attempted are shown in Scheme 1. Pyrimidines In Antimalarial Drug Design S S Moleele1, D Gravestock1, A L Rousseau1, R L Van Zyl2 1Discovery Chemistry, CSIR, Biosciences, Private Bag X2, Modderfontein, 1645, South Africa; SMoleele@csir.co.za 2...

The future of drugs: recreational drug use and sexual health among gay and other men who have sex with men.

Science.gov (United States)

Race, Kane; Lea, Toby; Murphy, Dean; Pienaar, Kiran

2017-02-01

There are complex historical connections between sexual minoritisation and desires to chemically alter bodily experience. For gay men, drug and alcohol use can be a creative or experimental response to social marginalisation - and not necessarily a problematic one in every instance. Numerous studies have found that infection with HIV and other sexually transmissible infections (STIs) is more likely among gay and men who have sex with men (MSM) who use recreational drugs than those who do not, but the causal nature of these relations is uncertain. Sexualised drug use is associated with a range of other problems, including dependence, mental health issues, accident and overdose. A growing body of work in the Alcohol and Other Drugs (AOD) field demonstrates the action of drugs and their purported effects to be a product of their relations with various other actors, contexts and practices. Given these contingencies, it is impossible to predict the future of drugs or their effect on the sexual health of gay and MSM with any degree of certainty. This article outlines some of the conditions most likely to mediate such futures in the medium term. Public funding for lesbian, gay, bisexual, transgender and queer drug issues should not remain restricted to questions of HIV prevention and sexual health. It should be expanded to equip sexual health and AOD service providers with the cultural and sexual literacy to mitigate stigma and allow them to respond constructively to drug problems among sexual and gender minorities as a matter of priority.

Generative Recurrent Networks for De Novo Drug Design.

Science.gov (United States)

Gupta, Anvita; Müller, Alex T; Huisman, Berend J H; Fuchs, Jens A; Schneider, Petra; Schneider, Gisbert

2018-01-01

Generative artificial intelligence models present a fresh approach to chemogenomics and de novo drug design, as they provide researchers with the ability to narrow down their search of the chemical space and focus on regions of interest. We present a method for molecular de novo design that utilizes generative recurrent neural networks (RNN) containing long short-term memory (LSTM) cells. This computational model captured the syntax of molecular representation in terms of SMILES strings with close to perfect accuracy. The learned pattern probabilities can be used for de novo SMILES generation. This molecular design concept eliminates the need for virtual compound library enumeration. By employing transfer learning, we fine-tuned the RNN's predictions for specific molecular targets. This approach enables virtual compound design without requiring secondary or external activity prediction, which could introduce error or unwanted bias. The results obtained advocate this generative RNN-LSTM system for high-impact use cases, such as low-data drug discovery, fragment based molecular design, and hit-to-lead optimization for diverse drug targets. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Opportunities and Challenges for Drug Development: Public-Private Partnerships, Adaptive Designs and Big Data.

Science.gov (United States)

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.

Opportunities and challenges for drug development: public-private partnerships, adaptive designs and big data

Directory of Open Access Journals (Sweden)

Oktay Yildirim

2016-12-01

Full Text Available Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research & Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e. public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.

Opportunities and Challenges for Drug Development: Public–Private Partnerships, Adaptive Designs and Big Data

Science.gov (United States)

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C.

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public–private partnerships, adaptive designs and big data. Public–private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development. PMID:27999543

Anti-obesity drugs: past, present and future

Directory of Open Access Journals (Sweden)

R. John Rodgers

2012-09-01

Full Text Available The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK, peptide YY (PYY and glucagon-like peptide-1 (GLP-1, and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent

Physics and Its Interfaces with Medicinal Chemistry and Drug Design

Science.gov (United States)

Santos, Ricardo N.; Andricopulo, Adriano D.

2013-08-01

Medicinal chemistry is a multidisciplinary subject that integrates knowledge from a variety of fields of science, including, but not limited to, chemistry, biology, and physics. The area of drug design involves the cooperative work of scientists with a diverse range of backgrounds and technical skills, trying to tackle complex problems using an integration of approaches and methods. One important contribution to this field comes from physics through studies that attempt to identify and quantify the molecular interactions between small molecules (drugs) and biological targets (receptors), such as the forces that govern the interactions, the thermodynamics of the drug-receptor interactions, and so on. In this context, the interfaces of physics, medicinal chemistry, and drug design are of vital importance for the development of drugs that not only have the right chemistry but also the right intermolecular properties to interact at the macromolecular level, providing useful information about the principles and molecular mechanisms underlying the therapeutic action of drugs. This article highlights some of the most important connections between physics and medicinal chemistry in the design of new drugs.

Swallowable smart pills for local drug delivery: present status and future perspectives.

Science.gov (United States)

Goffredo, Rosa; Accoto, Dino; Guglielmelli, Eugenio

2015-01-01

Smart pills were originally developed for diagnosis; however, they are increasingly being applied to therapy - more specifically drug delivery. In addition to smart drug delivery systems, current research is also looking into localization systems for reaching the target areas, novel locomotion mechanisms and positioning systems. Focusing on the major application fields of such devices, this article reviews smart pills developed for local drug delivery. The review begins with the analysis of the medical needs and socio-economic benefits associated with the use of such devices and moves onto the discussion of the main implemented technological solutions with special attention given to locomotion systems, drug delivery systems and power supply. Finally, desired technical features of a fully autonomous robotic capsule for local drug delivery are defined and future research trends are highlighted.

Fragment-based drug discovery and molecular docking in drug design.

Science.gov (United States)

Wang, Tao; Wu, Mian-Bin; Chen, Zheng-Jie; Chen, Hua; Lin, Jian-Ping; Yang, Li-Rong

2015-01-01

Fragment-based drug discovery (FBDD) has caused a revolution in the process of drug discovery and design, with many FBDD leads being developed into clinical trials or approved in the past few years. Compared with traditional high-throughput screening, it displays obvious advantages such as efficiently covering chemical space, achieving higher hit rates, and so forth. In this review, we focus on the most recent developments of FBDD for improving drug discovery, illustrating the process and the importance of FBDD. In particular, the computational strategies applied in the process of FBDD and molecular-docking programs are highlighted elaborately. In most cases, docking is used for predicting the ligand-receptor interaction modes and hit identification by structurebased virtual screening. The successful cases of typical significance and the hits identified most recently are discussed.

Design Anthropology, Emerging Technologies and Alternative Computational Futures

DEFF Research Database (Denmark)

Smith, Rachel Charlotte

Emerging technologies are providing a new field for design anthropological inquiry that unite experiences, imaginaries and materialities in complex way and demands new approaches to developing sustainable computational futures.......Emerging technologies are providing a new field for design anthropological inquiry that unite experiences, imaginaries and materialities in complex way and demands new approaches to developing sustainable computational futures....

SMART drug delivery systems: Back to the future vs. clinical reality

NARCIS (Netherlands)

Lammers, Twan Gerardus Gertudis Maria

2013-01-01

Recent advances in nanotechnology and material science have re-ignited interest in drug delivery research. Arguably, however, hardly any of the systems developed and strategies proposed are really relevant for shaping the future (clinical) face of the nanomedicine field. Consequently, as outlined in

Designing the Future of Democracy

DEFF Research Database (Denmark)

Pichlmair, Martin

2015-01-01

Creating a simulation of Democracy and its future challenges is a fruitful exercise in design. This short paper describes a different use of a simulation that the traditional training via playing. Instead of playing, the creation of the simulation is at the center of attention....

Reforming private drug coverage in Canada: inefficient drug benefit design and the barriers to change in unionized settings.

Science.gov (United States)

O'Brady, Sean; Gagnon, Marc-André; Cassels, Alan

2015-02-01

Prescription drugs are the highest single cost component for employees' benefits packages in Canada. While industry literature considers cost-containment for prescription drug costs to be a priority for insurers and employers, the implementation of cost-containment measures for private drug plans in Canada remains more of a myth than a reality. Through 18 semi-structured phone interviews conducted with experts from private sector companies, unions, insurers and plan advisors, this study explores the reasons behind this incapacity to implement cost-containment measures by examining how private sector employers negotiate drug benefit design in unionized settings. Respondents were asked questions on how employee benefits are negotiated; the relationships between the players who influence drug benefit design; the role of these players' strategies in influencing plan design; the broad system that underpins drug benefit design; and the potential for a universal pharmacare program in Canada. The study shows that there is consensus about the need to educate employees and employers, more collaboration and data-sharing between these two sets of players, and for external intervention from government to help transform established norms in terms of private drug plan design. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The Future of Design: Unframed Problem Solving in Design Education

DEFF Research Database (Denmark)

Friis, Silje Alberthe Kamille; Gelting, Anne Katrine Gøtzsche

2016-01-01

The present paper sets out to investigate the impact and significance of a 3rd semester course in design methods, complex problem solving, and cross-disciplinary collaboration to the students within six design disciplines as experienced by the students three years later. The course reflects a shi......, society, and technology influencing the future disciplines and practices of design and thus the professional roles that they themselves might take....

Age and impulsive behavior in drug addiction: A review of past research and future directions.

Science.gov (United States)

Argyriou, Evangelia; Um, Miji; Carron, Claire; Cyders, Melissa A

2018-01-01

Impulsive behavior is implicated in the initiation, maintenance, and relapse of drug-seeking behaviors involved in drug addiction. Research shows that changes in impulsive behavior across the lifespan contribute to drug use and addiction. The goal of this review is to examine existing research on the relationship between impulsive behavior and drug use across the lifespan and to recommend directions for future research. Three domains of impulsive behavior are explored in this review: impulsive behavior-related personality traits, delay discounting, and prepotent response inhibition. First, we present previous research on these three domains of impulsive behavior and drug use across developmental stages. Then, we discuss how changes in impulsive behavior across the lifespan are implicated in the progression of drug use and addiction. Finally, we discuss the relatively limited attention given to middle-to-older adults in the current literature, consider the validity of the measures used to assess impulsive behavior in middle-to-older adulthood, and suggest recommendations for future research. Copyright © 2017 Elsevier Inc. All rights reserved.

A Novel Design for Drug-Drug Interaction Alerts Improves Prescribing Efficiency.

Science.gov (United States)

Russ, Alissa L; Chen, Siying; Melton, Brittany L; Johnson, Elizabette G; Spina, Jeffrey R; Weiner, Michael; Zillich, Alan J

2015-09-01

Drug-drug interactions (DDIs) are common in clinical care and pose serious risks for patients. Electronic health records display DDI alerts that can influence prescribers, but the interface design of DDI alerts has largely been unstudied. In this study, the objective was to apply human factors engineering principles to alert design. It was hypothesized that redesigned DDI alerts would significantly improve prescribers' efficiency and reduce prescribing errors. In a counterbalanced, crossover study with prescribers, two DDI alert designs were evaluated. Department of Veterans Affairs (VA) prescribers were video recorded as they completed fictitious patient scenarios, which included DDI alerts of varying severity. Efficiency was measured from time-stamped recordings. Prescribing errors were evaluated against predefined criteria. Efficiency and prescribing errors were analyzed with the Wilcoxon signed-rank test. Other usability data were collected on the adequacy of alert content, prescribers' use of the DDI monograph, and alert navigation. Twenty prescribers completed patient scenarios for both designs. Prescribers resolved redesigned alerts in about half the time (redesign: 52 seconds versus original design: 97 seconds; p<.001). Prescribing errors were not significantly different between the two designs. Usability results indicate that DDI alerts might be enhanced by facilitating easier access to laboratory data and dosing information and by allowing prescribers to cancel either interacting medication directly from the alert. Results also suggest that neither design provided adequate information for decision making via the primary interface. Applying human factors principles to DDI alerts improved overall efficiency. Aspects of DDI alert design that could be further enhanced prior to implementation were also identified.

A drug's life: the pathway to drug approval.

Science.gov (United States)

Keng, Michael K; Wenzell, Candice M; Sekeres, Mikkael A

2013-10-01

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.

Designer drugs: how dangerous are they?

NARCIS (Netherlands)

Reneman, L.

2003-01-01

Of the designer drugs, the amphetamine analogues are the most popular and extensively studied, ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in particular. They are used recreationally with increasing popularity despite animal studies showing neurotoxic effects to serotonin (5-HT) and/or

The Open Form Inducer Approach for Structure-Based Drug Design.

Directory of Open Access Journals (Sweden)

Daniel Ken Inaoka

Full Text Available Many open form (OF structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen co-crystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank.

MPD3: a useful medicinal plants database for drug designing.

Science.gov (United States)

Mumtaz, Arooj; Ashfaq, Usman Ali; Ul Qamar, Muhammad Tahir; Anwar, Farooq; Gulzar, Faisal; Ali, Muhammad Amjad; Saari, Nazamid; Pervez, Muhammad Tariq

2017-06-01

Medicinal plants are the main natural pools for the discovery and development of new drugs. In the modern era of computer-aided drug designing (CADD), there is need of prompt efforts to design and construct useful database management system that allows proper data storage, retrieval and management with user-friendly interface. An inclusive database having information about classification, activity and ready-to-dock library of medicinal plant's phytochemicals is therefore required to assist the researchers in the field of CADD. The present work was designed to merge activities of phytochemicals from medicinal plants, their targets and literature references into a single comprehensive database named as Medicinal Plants Database for Drug Designing (MPD3). The newly designed online and downloadable MPD3 contains information about more than 5000 phytochemicals from around 1000 medicinal plants with 80 different activities, more than 900 literature references and 200 plus targets. The designed database is deemed to be very useful for the researchers who are engaged in medicinal plants research, CADD and drug discovery/development with ease of operation and increased efficiency. The designed MPD3 is a comprehensive database which provides most of the information related to the medicinal plants at a single platform. MPD3 is freely available at: http://bioinform.info .

The future-essay as a design tool

DEFF Research Database (Denmark)

Thomsen, Bente Dahl; Kappel, Anne

2007-01-01

The aim of this paper is to present scenarios, photo-essays and future-essays as tools in communication, and as tools for clarifying the use of products in the future and the aesthetic qualities in the programme. In the design process, the programme is a description of the function, the condition...

76 FR 44613 - Designation of Eight Counties as High Intensity Drug Trafficking Areas

Science.gov (United States)

2011-07-26

... OFFICE OF NATIONAL DRUG CONTROL POLICY Designation of Eight Counties as High Intensity Drug Trafficking Areas AGENCY: Office of National Drug Control Policy. ACTION: Notice. SUMMARY: The Director of the Office of National Drug Control Policy has designated eight additional counties as High Intensity Drug...

Connecting drug delivery reality to smart materials design.

Science.gov (United States)

Grainger, David W

2013-09-15

Inflated claims to both design and mechanistic novelty in drug delivery and imaging systems, including most nanotechnologies, are not supported by the generally poor translation of these systems to clinical efficacy. The "form begets function" design paradigm is seductive but perhaps over-simplistic in translation to pharmaceutical efficacy. Most innovations show few clinically important distinctions in their therapeutic benefits in relevant preclinical disease and delivery models, despite frequent claims to the contrary. Long-standing challenges in drug delivery issues must enlist more realistic, back-to-basics approaches to address fundamental materials properties in complex biological systems, preclinical test beds, and analytical methods to more reliably determine fundamental pharmaceutical figures of merit, including drug carrier purity and batch-batch variability, agent biodistribution, therapeutic index (safety), and efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

Participatory Design in Emergency Medical Service: Designing for Future Practice

DEFF Research Database (Denmark)

Kristensen, Margit; Kyng, Morten; Palen, Leysia Ann

2006-01-01

address challenges identified by disaster sociologists when designing for major incidents. Through qualitative research and participatory design, we have ex-amined the features of EMS work and technology use in different emergency situations from the perspective of mul-tiple actors. We conceptualize...... victims in incidents—and particularly in major incidents, where on-site medical as-sessments is highly incomplete—as boundary objects over which the complex and imperfect work of coordination is done. As an outcome of our participatory design approach, we describe a set of designs in support of future EMS...

Computer-aided drug design at Boehringer Ingelheim

Science.gov (United States)

Muegge, Ingo; Bergner, Andreas; Kriegl, Jan M.

2017-03-01

Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI. In particular, virtual screening in vast chemical spaces, which can be accessed by combinatorial chemistry, has added a new option for the identification of hits in many projects. Recently, a new framework has been implemented allowing fast, interactive predictions of relevant on and off target endpoints and other optimization parameters. In addition to the introduction of this new framework at BI, CADD has been focusing on the enablement of medicinal chemists to independently perform an increasing amount of molecular modeling and design work. This is made possible through the deployment of MOE as a global modeling platform, allowing computational and medicinal chemists to freely share ideas and modeling results. Furthermore, a central communication layer called the computational chemistry framework provides broad access to predictive models and other computational services.

Fragment-based drug design.

Science.gov (United States)

Feyfant, Eric; Cross, Jason B; Paris, Kevin; Tsao, Désirée H H

2011-01-01

Fragment-based drug design (FBDD), which is comprised of both fragment screening and the use of fragment hits to design leads, began more than 15 years ago and has been steadily gaining in popularity and utility. Its origin lies on the fact that the coverage of chemical space and the binding efficiency of hits are directly related to the size of the compounds screened. Nevertheless, FBDD still faces challenges, among them developing fragment screening libraries that ensure optimal coverage of chemical space, physical properties and chemical tractability. Fragment screening also requires sensitive assays, often biophysical in nature, to detect weak binders. In this chapter we will introduce the technologies used to address these challenges and outline the experimental advantages that make FBDD one of the most popular new hit-to-lead process.

Intratumor heterogeneity alters most effective drugs in designed combinations.

Science.gov (United States)

Zhao, Boyang; Hemann, Michael T; Lauffenburger, Douglas A

2014-07-22

The substantial spatial and temporal heterogeneity observed in patient tumors poses considerable challenges for the design of effective drug combinations with predictable outcomes. Currently, the implications of tissue heterogeneity and sampling bias during diagnosis are unclear for selection and subsequent performance of potential combination therapies. Here, we apply a multiobjective computational optimization approach integrated with empirical information on efficacy and toxicity for individual drugs with respect to a spectrum of genetic perturbations, enabling derivation of optimal drug combinations for heterogeneous tumors comprising distributions of subpopulations possessing these perturbations. Analysis across probabilistic samplings from the spectrum of various possible distributions reveals that the most beneficial (considering both efficacy and toxicity) set of drugs changes as the complexity of genetic heterogeneity increases. Importantly, a significant likelihood arises that a drug selected as the most beneficial single agent with respect to the predominant subpopulation in fact does not reside within the most broadly useful drug combinations for heterogeneous tumors. The underlying explanation appears to be that heterogeneity essentially homogenizes the benefit of drug combinations, reducing the special advantage of a particular drug on a specific subpopulation. Thus, this study underscores the importance of considering heterogeneity in choosing drug combinations and offers a principled approach toward designing the most likely beneficial set, even if the subpopulation distribution is not precisely known.

Designing future learning. A posthumanist approach to researching design processes

DEFF Research Database (Denmark)

Juelskjær, Malou

I investigate how a design process – leading up to the design of a new education building - enact, transform and highlight tacit everyday practices and experiences in an education setting, whereby becoming an art of managing. I apply a post-humanist performative perspective, highlighting entangled...... agencies rather than focusing on human agency. I focus on the design process rather than the designer. The design process accelerated and performed past and future experiences of schooling, learning, teaching. This called for analytical attention to agential forces of not only the material but also...... and temporalities matter in design processes. Furthermore, the analysis emphasise how design translate affective economies and that attention to those affective economies are vital for the result of the design process....

Designing Adaptable Ships: Modularity and Flexibility in Future Ship Designs

Science.gov (United States)

2016-01-01

with motors, belts, shafts , seals, valves, hose spindles , and switches. If ship installation is not installed, the system will be status quo. Ship...Impact: the current centrifugal purifiers (Alfa-Laval) have experienced frequent failures with motor, belts, shafts , seals, valves, hose spindles ... Designing Adaptable Ships Modularity and Flexibility in Future Ship Designs John F. Schank, Scott Savitz, Ken Munson, Brian Perkinson, James

New designer drugs (synthetic cannabinoids and synthetic cathinones): review of literature.

Science.gov (United States)

Cottencin, Olivier; Rolland, Benjamin; Karila, Laurent

2014-01-01

New designer drugs (synthetic cannabinoids and synthetic cathinones) are new "legal highs" that are sold online for recreational public or private use. Synthetic cannabinoids are psychoactive herbal and chemical products that mimic the effects of cannabis when used. These drugs are available on the Internet or in head shops as incense or air fresheners to circumvent the law. Cathinone is a naturally occurring beta-ketone amphetamine analog found in the leaves of the Catha edulis plant. Synthetic cathinones are phenylalkylamine derivatives that may possess amphetamine-like properties. These drugs are sold online as bath salts. Designer drugs are often labeled as "not for human consumption" to circumvent drug abuse legislation. The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the availability via the Internet are the main features that attract users, but the number of intoxicated people presenting with emergencies is increasing. There is evidence that negative health and social consequences may affect recreational and chronic users. The addictive potential of designer drugs is not negligible.

Design Creativity: Future Directions for Integrated Visualisation

Directory of Open Access Journals (Sweden)

Jack Steven Goulding

2015-11-01

Full Text Available The Architecture, Engineering and Construction (AEC sectors are facing unprecedented challenges, not just with increased complexity of projects per se, but design-related integration. This requires stakeholders to radically re-think their existing business models (and thinking that underpins them, but also the technological challenges and skills required to deliver these projects. Whilst opponents will no doubt cite that this is nothing new as the sector as a whole has always had to respond to change; the counter to this is that design ‘creativity’ is now much more dependent on integration from day one. Given this, collaborative processes embedded in Building Information Modelling (BIM models have been proffered as a panacea solution to embrace this change and deliver streamlined integration. The veracity of design teams’ “project data” is increasingly becoming paramount - not only for the coordination of design, processes, engineering services, fabrication, construction, and maintenance; but more importantly, facilitate ‘true’ project integration and interchange – the actualisation of which will require firm consensus and commitment. This Special Issue envisions some of these issues, challenges and opportunities (from a future landscape perspective, by highlighting a raft of concomitant factors, which include: technological challenges, design visualisation and integration, future digital tools, new and anticipated operating environments, and training requirements needed to deliver these aspirations. A fundamental part of this Special Issue’s ‘call’ was to capture best practice in order to demonstrate how design, visualisation and delivery processes (and technologies affect the finished product viz: design outcome, design procedures, production methodologies and construction implementation. In this respect, the use of virtual environments are now particularly effective at supporting the design and delivery processes. In

Medicines by Design

Science.gov (United States)

... Home > Science Education > Medicines By Design Medicines By Design Spotlight Nature's Medicine Cabinet A Medicine's Life Inside ... hunt for drugs of the future. Medicines By Design in PDF | E-PUB Tell Us What You ...

75 FR 52780 - Designation of Nine Counties as High Intensity Drug Trafficking Areas

Science.gov (United States)

2010-08-27

... EXECUTIVE OFFICE OF THE PRESIDENT Office of National Drug Control Policy Designation of Nine Counties as High Intensity Drug Trafficking Areas ACTION: Notice. SUMMARY: The Director of the Office of National Drug Control Policy designated nine additional counties as High Drug Trafficking Areas pursuant to...

75 FR 21368 - Designation of Five Counties as High Intensity Drug Trafficking Areas

Science.gov (United States)

2010-04-23

... EXECUTIVE OFFICE OF THE PRESIDENT Office of National Drug Control Policy Designation of Five Counties as High Intensity Drug Trafficking Areas ACTION: Notice. SUMMARY: The Director of the Office of National Drug Control Policy designated five additional counties as High Drug Trafficking Areas pursuant to...

RECENT ADVANCES TOWARDS THE RATIONAL DESIGN OF PEPTIDE DRUGS

OpenAIRE

YEŞİLADA, Akgül; ÖZKANLI, Fügen

2004-01-01

In this review, after a short introduction to definition and physiological roles of regulatory peptides, problems faced during the development of peptide drugs, studies directed to solve these problems and rational design of peptide drugs with special emphesis on peptidomimetics are mentioned

The evolution of drug design at Merck Research Laboratories.

Science.gov (United States)

Brown, Frank K; Sherer, Edward C; Johnson, Scott A; Holloway, M Katharine; Sherborne, Bradley S

2017-03-01

On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.

The evolution of drug design at Merck Research Laboratories

Science.gov (United States)

Brown, Frank K.; Sherer, Edward C.; Johnson, Scott A.; Holloway, M. Katharine; Sherborne, Bradley S.

2017-03-01

On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.

The future of the IMS Learning Design specification: a critical look

NARCIS (Netherlands)

Sloep, Peter

2009-01-01

P. B. Sloep (2009). The future of the IMS Learning Design specification: a critical look. Presentation at the IMS Learning Design seminar 'The future of IMS Learning Design'. December, 10, 2009, Wollongong, Australia: University of Wollongong.

Introducing rapid diagnostic tests for malaria into drug shops in Uganda: design and implementation of a cluster randomized trial.

Science.gov (United States)

Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare I R; Hansen, Kristian S; Lal, Sham; Cundill, Bonnie; Lynch, Caroline A; Clarke, Siân E

2014-07-29

An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges

Pharmacotherapies for decreasing maladaptive choice in drug addiction: Targeting the behavior and the drug.

Science.gov (United States)

Perkins, Frank N; Freeman, Kevin B

2018-01-01

Drug addiction can be conceptualized as a disorder of maladaptive decision making in which drugs are chosen at the expense of pro-social, nondrug alternatives. The study of decision making in drug addiction has focused largely on the role of impulsivity as a facilitator of addiction, in particular the tendency for drug abusers to choose small, immediate gains over larger but delayed outcomes (i.e., delay discounting). A parallel line of work, also focused on decision making in drug addiction, has focused on identifying the determinants underlying the choice to take drugs over nondrug alternatives (i.e., drug vs. nondrug choice). Both tracks of research have been valuable tools in the development of pharmacotherapies for treating maladaptive decision making in drug addiction, and a number of common drugs have been studied in both designs. However, we have observed that there is little uniformity in the administration regimens of potential treatments between the designs, which hinders congruence in the development of single treatment strategies to reduce both impulsive behavior and drug choice. The current review provides an overview of the drugs that have been tested in both delay-discounting and drug-choice designs, and focuses on drugs that reduced the maladaptive choice in both designs. Suggestions to enhance congruence between the findings in future studies are provided. Finally, we propose the use of a hybridized, experimental approach that may enable researchers to test the effectiveness of therapeutics at decreasing impulsive and drug choice in a single design. Published by Elsevier Inc.

Design Rework Prediction in Concurrent Design Environment: Current Trends and Future Research Directions

OpenAIRE

Arundachawat, Panumas; Roy, Rajkumar; Al-Ashaab, Ahmed; Shehab, Essam

2009-01-01

Organised by: Cranfield University This paper aims to present state-of-the-art and formulate future research areas on design rework in concurrent design environment. Related literatures are analysed to extract the key factors which impact design rework. Design rework occurs due to changes from upstream design activities and/or by feedbacks from downstream design activities. Design rework is considered as negative iteration; therefore, value in design activities will be increase...

21 CFR 516.36 - Insufficient quantities of MUMS-designated drugs.

Science.gov (United States)

2010-04-01

... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.36 Insufficient quantities of... the 7-year period of exclusive marketing rights. (b) If, within the time that FDA specifies, the...

Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods.

Science.gov (United States)

Moitessier, Nicolas; Pottel, Joshua; Therrien, Eric; Englebienne, Pablo; Liu, Zhaomin; Tomberg, Anna; Corbeil, Christopher R

2016-09-20

Computational methods for docking small molecules to proteins are prominent in drug discovery. There are hundreds, if not thousands, of documented examples-and several pertinent cases within our research program. Fifteen years ago, our first docking-guided drug design project yielded nanomolar metalloproteinase inhibitors and illustrated the potential of structure-based drug design. Subsequent applications of docking programs to the design of integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA demonstrated that available docking programs needed significant improvement. At that time, docking programs primarily considered flexible ligands and rigid proteins. We demonstrated that accounting for protein flexibility, employing displaceable water molecules, and using ligand-based pharmacophores improved the docking accuracy of existing methods-enabling the design of bioactive molecules. The success prompted the development of our own program, Fitted, implementing all of these aspects. The primary motivation has always been to respond to the needs of drug design studies; the majority of the concepts behind the evolution of Fitted are rooted in medicinal chemistry projects and collaborations. Several examples follow: (1) Searching for HDAC inhibitors led us to develop methods considering drug-zinc coordination and its effect on the pKa of surrounding residues. (2) Targeting covalent prolyl oligopeptidase (POP) inhibitors prompted an update to Fitted to identify reactive groups and form bonds with a given residue (e.g., a catalytic residue) when the geometry allows it. Fitted-the first fully automated covalent docking program-was successfully applied to the discovery of four new classes of covalent POP inhibitors. As a result, efficient stereoselective syntheses of a few screening hits were prioritized rather than synthesizing large chemical libraries-yielding nanomolar inhibitors. (3) In order to study the metabolism of POP inhibitors by

Clinic exam room design: present and future.

Science.gov (United States)

Freihoefer, Kara; Nyberg, Gary; Vickery, Christine

2013-01-01

This article aims to deconstruct various design qualities and strategies of clinic exam rooms, and discuss how they influence users' interaction and behavior in the space. Relevant literature supports the advantages and disadvantages of different design strategies. Annotated exam room prototypes illustrate the design qualities and strategies discussed. Advancements in technology and medicine, along with new legislative policies, are influencing the way care providers deliver care and ultimately clinic exam room designs. The patient-centered medical home model has encouraged primary care providers to make patients more active leaders of their health plan which will influence the overall functionality and configuration of clinic exam rooms. Specific design qualities discussed include overall size, location of doors and privacy curtains, positioning of exam tables, influence of technology in the consultation area, types of seating, and placement of sink and hand sanitizing dispensers. In addition, future trends of exam room prototypes are presented. There is a general lack of published evidence to support design professionals' design solutions for outpatient exam rooms. Future research should investigate such topics as the location of exam tables and privacy curtains as they relate to patient privacy; typical size and location of consultation table as it relates to patient connection and communication; and placement of sinks and sanitization dispensers as they relate to frequency and patterns of usage. Literature review, outpatient, technology, visual privacy.

Design and Evaluation of Chitosan-Based Novel pHSensitive Drug ...

African Journals Online (AJOL)

Design and Evaluation of Chitosan-Based Novel pHSensitive Drug Carrier for Sustained ... Scanning electron microscopy(SEM),Raman spectroscopy for particle size analysis. Swelling ratio, Effect of drug loading on encapsulation efficiency

CRITICAL ASSESSMENT OF CONTRIBUTION FROM INDIAN PUBLICATIONS: THE ROLE OF IN SILICO DESIGNING METHODS LEADING TO DRUGS OR DRUG-LIKE COMPOUNDS USING TEXT BASED MINING AND ASSOCIATION

Directory of Open Access Journals (Sweden)

Pawan Kumar

2017-09-01

Full Text Available Over the several decades, India is constantly challenged by communicable and non-communicable diseases which are originated either by poor lifestyle or by environmental factors. The pools of diseases are constantly posing serious threats to mankind especially among the poverty-stricken families. Scientific communities across the globe are working continuously to design drug molecules to overcome the burden of these life threaten diseases. In last three decades, many computational algorithms and tools have been developed to identify potential drug targets and their inhibitors. It is believed that computational techniques have reduced the time and money required to develop an inhibitor into drug. However, applicability and deliverability of these in silico techniques in rational drug designing are not fully evaluated. In the present study, PubMed/Medline extracted data driven analysis has been performed to highlight the influence and progress of the theoretical methods in the field of drug discovery across India and compared with the world. Drug discovery related keyword dictionary has been built and utilized to select only drug discovery related PubMed abstract. A second keyword set (related to bioinformatics tools is used for normalized pointwise mutual information (PMI based association analysis. Observations show that drug discovery has been an interdisciplinary research and used many tools starting with QSAR, docking, pharmacophore, Molecular Simulations etc. The publications contributed from India (2% are similar as compared to the contribution in total world publications, suggesting large scope in future. Data coverage as represented since 1990-2015 in PubMed as indicated by number of publications associated with drug discovery is almost same in world and India (~75%. Emerging institutes/Universities are contributing since last 10 years as observed from Indian publication list. However, this method has many limitations as discussed.

A structural keystone for drug design

Directory of Open Access Journals (Sweden)

Rother Kristian

2006-06-01

Full Text Available 3D-structures of proteins and potential ligands are the cornerstones of rational drug design. The first brick to build upon is selecting a protein target and finding out whether biologically active compounds are known. Both tasks require more information than the structures themselves provide. For this purpose we have built a web resource bridging protein and ligand databases. It consists of three parts: i A data warehouse on annotation of protein structures that integrates many well-known databases such as Swiss-Prot, SCOP, ENZYME and others. ii A conformational library of structures of approved drugs. iii A conformational library of ligands from the PDB, linking the realms of proteins and small molecules.

Bioreactor design and optimization – a future perspective

DEFF Research Database (Denmark)

Gernaey, Krist

2011-01-01

Bioreactor design and optimisation are essential in translating the experience gained from lab or pilot scale experiments to efficient production processes in industrial scale bioreactors. This article gives a future perspective on bioreactor design and optimisation, where it is foreseen...

Bigger Data, Collaborative Tools and the Future of Predictive Drug Discovery

Science.gov (United States)

Clark, Alex M.; Swamidass, S. Joshua; Litterman, Nadia; Williams, Antony J.

2014-01-01

Over the past decade we have seen a growth in the provision of chemistry data and cheminformatics tools as either free websites or software as a service (SaaS) commercial offerings. These have transformed how we find molecule-related data and use such tools in our research. There have also been efforts to improve collaboration between researchers either openly or through secure transactions using commercial tools. A major challenge in the future will be how such databases and software approaches handle larger amounts of data as it accumulates from high throughput screening and enables the user to draw insights, enable predictions and move projects forward. We now discuss how information from some drug discovery datasets can be made more accessible and how privacy of data should not overwhelm the desire to share it at an appropriate time with collaborators. We also discuss additional software tools that could be made available and provide our thoughts on the future of predictive drug discovery in this age of big data. We use some examples from our own research on neglected diseases, collaborations, mobile apps and algorithm development to illustrate these ideas. PMID:24943138

LEGO-inspired drug design: Discovery of novel fungal Plasma membrane H+-ATPase (Pma1) inhibitors from small molecule libraries: An introduction of HFSA-SBS_DOS-RD strategy in drug discovery

DEFF Research Database (Denmark)

Tung, Truong Thanh; Dao, Trong Tuan; Palmgren, Michael B.

to extracellular, this enzyme generates a transmembrane electrochem. gradient, as a consequence, fungi can uptake nutrients by secondary transport systems. Until now, only low resoln. of protein structure has been reported, and notably there a no report of co-crystal structure of Pma1 with inhibitors. Therefore......-oriented synthesis (SBS_DOS) and rational design (RD), so called HFSA-SBS_DOS-RD strategy in drug discovery and development process. Using HFSA-SBS_DOS-RD, our group successfully designed, synthesized, and performed SAR studies of novel compds. potent Pma1 inhibitors. An expeditious, high yield and scalable...... microwave-assisted synthesis was developed and applied for synthesis of library compds. To our delight, ours compd. libraries were able to inhibit Pma1 activity and growth inhibitory activity of C. albican and S. cerevisiae revealed the most promising example for future development of antifungal drugs...

Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

Science.gov (United States)

Kesisoglou, Filippos; Mitra, Amitava

2015-09-01

Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Design optimization of a novel pMDI actuator for systemic drug delivery.

Science.gov (United States)

Kakade, Prashant P; Versteeg, Henk K; Hargrave, Graham K; Genova, Perry; Williams Iii, Robert C; Deaton, Daniel

2007-01-01

Pressurized metered dose inhalers (pMDIs) are the most widely prescribed and economical respiratory drug delivery systems. Conventional pMDI actuators-those based on "two-orifice-and-sump" designs-produce an aerosol with a reasonable respirable fraction, but with high aerosol velocity. The latter is responsible for high oropharyngeal deposition, and consequently low drug delivery efficiency. Kos' pMDI technology is based on a proprietary vortex nozzle actuator (VNA), an innovative actuator configuration that seeks to reduce aerosol plume velocity, thereby promoting deep lung deposition. Using VNA development as a case study, this paper presents a systematic design optimization process to improve the actuator performance through use of advanced optical characterization tools. The optimization effort mainly relied on laser-based optical diagnostics to provide an improved understanding of the fundamentals of aerosol formation and interplay of various geometrical factors. The performance of the optimized VNA design thus evolved was characterized using phase Doppler anemometry and cascade impaction. The aerosol velocities for both standard and optimized VNA designs were found to be comparable, with both notably less than conventional actuators. The optimized VNA design also significantly reduces drug deposition in the actuator as well as USP throat adapter, which in turn, leads to a significantly higher fine particle fraction than the standard design (78 +/- 3% vs. 63 +/- 2% on an ex valve basis). This improved drug delivery efficiency makes VNA technology a practical proposition as a systemic drug delivery platform. Thus, this paper demonstrates how advanced optical diagnostic and characterization tools can be used in the development of high efficiency aerosol drug delivery devices.

Synthetic approaches to the 2009 new drugs.

Science.gov (United States)

Liu, Kevin K-C; Sakya, Subas M; O'Donnell, Christopher J; Flick, Andrew C; Li, Jin

2011-02-01

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009. Copyright © 2011 Elsevier Ltd. All rights reserved.

Integrated Teaching of Structure-Based Drug Design and Biopharmaceutics: A Computer-Based Approach

Science.gov (United States)

Sutch, Brian T.; Romero, Rebecca M.; Neamati, Nouri; Haworth, Ian S.

2012-01-01

Rational drug design requires expertise in structural biology, medicinal chemistry, physiology, and related fields. In teaching structure-based drug design, it is important to develop an understanding of the need for early recognition of molecules with "drug-like" properties as a key component. That is, it is not merely sufficient to teach…

3D printed drug delivery and testing systems - a passing fad or the future?

Science.gov (United States)

Lim, Seng Han; Kathuria, Himanshu; Tan, Justin Jia Yao; Kang, Lifeng

2018-05-18

The US Food and Drug Administration approval of the first 3D printed tablet in 2015 has ignited growing interest in 3D printing, or additive manufacturing (AM), for drug delivery and testing systems. Beyond just a novel method for rapid prototyping, AM provides key advantages over traditional manufacturing of drug delivery and testing systems. These includes the ability to fabricate complex geometries to achieve variable drug release kinetics; ease of personalising pharmacotherapy for patient and lowering the cost for fabricating personalised dosages. Furthermore, AM allows fabrication of complex and micron-sized tissue scaffolds and models for drug testing systems that closely resemble in vivo conditions. However, there are several limitations such as regulatory concerns that may impede the progression to market. Here, we provide an overview of the advantages of AM drug delivery and testing, as compared to traditional manufacturing techniques. Also, we discuss the key challenges and future directions for AM enabled pharmaceutical applications. Copyright © 2018 Elsevier B.V. All rights reserved.

Quantum mechanics implementation in drug-design workflows: does it really help? [Corrigendum

Directory of Open Access Journals (Sweden)

Arodola OA

2017-11-01

Full Text Available Arodola OA, Soliman MES. Quantum mechanics implementation in drug-design workflows: does it really help? Drug Design, Development and Therapy. 2017;11:2551–2564.Figure 3 on page 2557 contains errors. The correct figure is shown.Read the original article

Considerations for Pharmacoepidemiological Studies of Drug-Cancer Associations

DEFF Research Database (Denmark)

Pottegård, Anton; Friis, Søren; Stürmer, Til

2018-01-01

and future perspectives. Aspects of data sources include assessment of complete history of drug use and data on dose and duration of drug use, allowing estimates of cumulative exposure. Outcome data from formal cancer registries are preferable, but cancer data from other sources, for example, patient......In this MiniReview, we provide general considerations for the planning and conduct of pharmacoepidemiological studies of associations between drug use and cancer development. We address data sources, study design, assessment of drug exposure, ascertainment of cancer outcomes, confounder adjustment...... or pathology registries, medical records or claims are also suitable. The two principal designs for observational studies evaluating drug-cancer associations are the cohort and case-control designs. A key challenge in studies of drug-cancer associations is the exposure assessment due to the typically long...

Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

Directory of Open Access Journals (Sweden)

Charles H. Williams

2011-04-01

Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

Fragment informatics and computational fragment-based drug design: an overview and update.

Science.gov (United States)

Sheng, Chunquan; Zhang, Wannian

2013-05-01

Fragment-based drug design (FBDD) is a promising approach for the discovery and optimization of lead compounds. Despite its successes, FBDD also faces some internal limitations and challenges. FBDD requires a high quality of target protein and good solubility of fragments. Biophysical techniques for fragment screening necessitate expensive detection equipment and the strategies for evolving fragment hits to leads remain to be improved. Regardless, FBDD is necessary for investigating larger chemical space and can be applied to challenging biological targets. In this scenario, cheminformatics and computational chemistry can be used as alternative approaches that can significantly improve the efficiency and success rate of lead discovery and optimization. Cheminformatics and computational tools assist FBDD in a very flexible manner. Computational FBDD can be used independently or in parallel with experimental FBDD for efficiently generating and optimizing leads. Computational FBDD can also be integrated into each step of experimental FBDD and help to play a synergistic role by maximizing its performance. This review will provide critical analysis of the complementarity between computational and experimental FBDD and highlight recent advances in new algorithms and successful examples of their applications. In particular, fragment-based cheminformatics tools, high-throughput fragment docking, and fragment-based de novo drug design will provide the focus of this review. We will also discuss the advantages and limitations of different methods and the trends in new developments that should inspire future research. © 2012 Wiley Periodicals, Inc.

Monitoring the Future National Survey Results on Drug Use, 1975-2010. Volume I, Secondary School Students

Science.gov (United States)

Johnston, Lloyd D.; O'Malley, Patrick M.; Bachman, Jerald G.; Schulenberg, John E.

2011-01-01

The Monitoring the Future (MTF) study involves an ongoing series of national surveys of American adolescents and adults that has provided the nation with a vital window into the important, but largely hidden, problem behaviors of illegal drug use, alcohol use, tobacco use, anabolic steroid use, and psychotherapeutic drug use. For more than a third…

Risk-informed design guidance for future reactor systems

International Nuclear Information System (INIS)

Delaney, Michael J.; Apostolakis, George E.; Driscoll, Michael J.

2005-01-01

Future reactor designs face an uncertain regulatory environment. It is anticipated that there will be some level of probabilistic insights in the regulations and supporting regulatory documents for Generation-IV nuclear reactors. Central to current regulations are design basis accidents (DBAs) and the general design criteria (GDC), which were established before probabilistic risk assessments (PRAs) were developed. These regulations implement a structuralist approach to safety through traditional defense in depth and large safety margins. In a rationalist approach to safety, accident frequencies are quantified and protective measures are introduced to make these frequencies acceptably low. Both approaches have advantages and disadvantages and future reactor design and licensing processes will have to implement a hybrid approach. This paper presents an iterative four-step risk-informed methodology to guide the design of future-reactor systems using a gas-cooled fast reactor emergency core cooling system as an example. This methodology helps designers to analyze alternative designs under potential risk-informed regulations and to anticipate design justifications the regulator may require during the licensing process. The analysis demonstrated the importance of common-cause failures and the need for guidance on how to change the quantitative impact of these potential failures on the frequency of accident sequences as the design changes. Deliberation is an important part of the four-step methodology because it supplements the quantitative results by allowing the inclusion in the design choice of elements such as best design practices and ease of online maintenance, which usually cannot be quantified. The case study showed that, in some instances, the structuralist and the rationalist approaches were inconsistent. In particular, GDC 35 treats the double-ended break of the largest pipe in the reactor coolant system with concurrent loss of offsite power and a single

[The role of biotechnology in pharmaceutical drug design].

Science.gov (United States)

Gaisser, Sibylle; Nusser, Michael

2010-01-01

Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

Dealing with sadness, madness and hostility. New psychotropic drug remedies for the future

NARCIS (Netherlands)

Loonen, A.J.M.

1992-01-01

The objective of this article is to present an overview of new forms of psychotropic drug therapy that may be expected to play a role in psychiatric practice in the 1990s. In predicting these future developments, three lines of approach have been followed. Firstly, progress in elucidating basic

Developing DIVE, a design-led futures technique for SMEs

NARCIS (Netherlands)

Mejia Sarmiento, J.R.; Pasman, G.J.; Hultink, H.J.; Stappers, P.J.; Vogel, C.; Muratovski, G.

2017-01-01

Futures techniques have long been used in large enterprises as designerly means to explore the future and guide innovation. In the automotive industry, for instance, the development of concept cars is a technique which has repeatedly proven its value. However, while big companies have broadly

Drug delivery across length scales.

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Delcassian, Derfogail; Patel, Asha K; Cortinas, Abel B; Langer, Robert

2018-02-20

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.

Design Disruption in Contested, Contingent and Contradictory Future-Making

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Yoko Akama

2015-10-01

Full Text Available This paper aims to problematize how we step into situations that are often contested, contingent and contradictory. In this context, how can we sharpen our sensitivity of the role design plays in generating understanding and future-making possibilities? Here, we employ the term disruption as a way to question our own knowledge construction and research practices in Design Anthropology and Participatory Design. We pursue disruption as a political and necessary consciousness when Design Anthropology meets Participatory Design and discuss the generative, reflexive and analytical dimensions of disruption through three vignettes. These vignettes raises questions of how we interrogate disruptions of power to consider different ways in which this manifests when entering into and participating in ongoing changing process. They also highlight the need to displace existing knowledge, rather than pursuing ‘mutual learning’ that had been a defining commitment of Participatory Design. Lastly, the vignettes reveal the need to disrupt the designer-researcher in order to surrender to contradiction and contingency as part of future-making.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs.

Science.gov (United States)

Quinn, Helen L; Bonham, Louise; Hughes, Carmel M; Donnelly, Ryan F

2015-10-01

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Historical Spice as a Future Drug: Therapeutic Potential of Piperlongumine.

Science.gov (United States)

Prasad, Sahdeo; Tyagi, Amit K

2016-01-01

Spice and spice-derived compounds have been identified and explored for their health benefits since centuries. One of the spice long pepper has been traditionally used to treat chronic bronchitis, asthma, constipation, gonorrhea, paralysis of the tongue, diarrhea, cholera, malaria, viral hepatitis, respiratory infections, stomach ache, diseases of the spleen, cough, and tumors. In this review, the evidences for the chemopreventive and chemotherapeutic potential of piperlongumine have been described. The active component piperlonguime has shown effective against various ailments including cancer, neurogenerative disease, arthritis, melanogenesis, lupus nephritis, and hyperlipidemic. These beneficial effects of piperlongumine is attributed to its ability to modulate several signaling molecules like reactive oxygen species, kinases, proteasome, proto-oncogenes, transcription factors, cell cycle, inflammatory molecules and cell growth and survival molecules. Piperlongumine also chemosensitizes to drugs resistant cancer cells. Overall the consumption of long peppers is therefore recommended for the prevention and treatment of various diseases including cancer, and thus piperlongumine may be a promising future candidate drug against cancer.

Future Smart Cooking Machine System Design

Directory of Open Access Journals (Sweden)

Dewi Agushinta R.

2013-11-01

Full Text Available There are many tools make human task get easier. Cooking has become a basic necessity for human beings, since food is one of basic human needs. Until now, the cooking equipment being used is still a hand tool. However everyone has slightly high activity. The presence of cooking tools that can do the cooking work by itself is now necessary. Future Smart Cooking Machine is an artificial intelligence machine that can do cooking work automatically. With this system design, the time is minimized and the ease of work is expected to be achieved. The development of this system is carried out with System Development Life Cycle (SDLC methods. Prototyping method used in this system is a throw-away prototyping approach. At the end of this research there will be produced a cooking machine system design including physical design engine and interface design.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

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Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Identification of designer drug 2C-E (4-ethyl-2, 5-dimethoxy-phenethylamine) in urine following a drug overdose.

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Van Vrancken, Michael J; Benavides, Raul; Wians, Frank H

2013-01-01

In recent years, access to information regarding acquisition and synthesis of newer designer drugs has been at an all-time high due largely to the Internet. As these drugs have become more prevalent, laboratory techniques have been developed and refined to identify and screen for this burgeoning population of drugs. This provides a unique opportunity for learning about many of these methods. Laboratory testing techniques and instrumentation are obscure to many health care professionals, yet their results are crucial. Here, we present a case of an overdose of an uncommon designer drug (2C-E) and discuss the basics of liquid chromatography and mass spectrometry, two important techniques used in isolating and identifying the drug. Although often overlooked and taken for granted, these techniques can play a pivotal role in the diagnosis and subsequent management of select patients.

Web-based services for drug design and discovery.

Science.gov (United States)

Frey, Jeremy G; Bird, Colin L

2011-09-01

Reviews of the development of drug discovery through the 20(th) century recognised the importance of chemistry and increasingly bioinformatics, but had relatively little to say about the importance of computing and networked computing in particular. However, the design and discovery of new drugs is arguably the most significant single application of bioinformatics and cheminformatics to have benefitted from the increases in the range and power of the computational techniques since the emergence of the World Wide Web, commonly now referred to as simply 'the Web'. Web services have enabled researchers to access shared resources and to deploy standardized calculations in their search for new drugs. This article first considers the fundamental principles of Web services and workflows, and then explores the facilities and resources that have evolved to meet the specific needs of chem- and bio-informatics. This strategy leads to a more detailed examination of the basic components that characterise molecules and the essential predictive techniques, followed by a discussion of the emerging networked services that transcend the basic provisions, and the growing trend towards embracing modern techniques, in particular the Semantic Web. In the opinion of the authors, the issues that require community action are: increasing the amount of chemical data available for open access; validating the data as provided; and developing more efficient links between the worlds of cheminformatics and bioinformatics. The goal is to create ever better drug design services.

Willingness to treat drug dependence and depression: comparisons of future health professionals

Directory of Open Access Journals (Sweden)

Ríos-Bedoya CF

2011-03-01

treat nicotine and alcohol dependence-affected patients as compared to depression-affected patients. Personal history was not associated with the students' willingness to treat, but men were less willing to treat. Drawing strength from the randomized reinforcer experimental design nested within this survey approach, the study evidence suggests potential nonparticipation bias in standard surveys on this topic.Conclusion: These results indicate that future health professionals may prefer to treat depression as opposed to drug dependence conditions. For SBIRT success, curriculum change with educational interventions may be needed to increase willingness to treat patients with neuropsychiatric conditions such as drug dependence. Future research requires attention to a possible problem of nonparticipation bias in surveys of this type.Keywords: alcohol dependence, nicotine dependence, depression, health professionals, stigma 

Phytosterols and anabolic agents versus designer drugs

Energy Technology Data Exchange (ETDEWEB)

Brabander, H.F. de [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium)]. E-mail: Hubert.DeBrabander@UGent.be; Verheyden, K. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium); Mortier, V. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium); Le Bizec, B. [LABERCA, Ecole Nationale Veterinaire de Nantes, BP 50707, F-44087 Nantes Cedex 03 (France); Verbeke, W. [Ghent University, Department of Agricultural Economics, Coupure links 653, B-9000 Ghent (Belgium); Courtheyn, D. [Federal Feed and Food Laboratory, Braemkasteelstraat 59, B-9050 Ghentbruges (Belgium); Noppe, H. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium)

2007-03-14

Cholesterol is a well-known component in fats of animal origin and it also is the precursor of natural hormones. Phytosterols appear in plants and only differ slightly in structure from cholesterol. An important difference however is the low absorption in the gut of phytosterols and their saturated derivatives, the phytostanols. As a result, there is time for all kind of reactions in faecal material inside and outside of the gut. Determination of the abuse of natural hormones may be based on gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Abuse of natural hormones changes the {sup 13}C/{sup 12}C ratio of some metabolites during a relatively long time. The formation of (natural) hormones in the gut may interfere with this method. Designer drugs are mainly known from sports doping. In animal fattening, designer drugs may be used as well. Small changes in the structure of (natural) hormones may lead to a new group of substances asking for new strategies for their detection and the constatation of their abuse.

Phytosterols and anabolic agents versus designer drugs

International Nuclear Information System (INIS)

Brabander, H.F. de; Verheyden, K.; Mortier, V.; Le Bizec, B.; Verbeke, W.; Courtheyn, D.; Noppe, H.

2007-01-01

Cholesterol is a well-known component in fats of animal origin and it also is the precursor of natural hormones. Phytosterols appear in plants and only differ slightly in structure from cholesterol. An important difference however is the low absorption in the gut of phytosterols and their saturated derivatives, the phytostanols. As a result, there is time for all kind of reactions in faecal material inside and outside of the gut. Determination of the abuse of natural hormones may be based on gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Abuse of natural hormones changes the 13 C/ 12 C ratio of some metabolites during a relatively long time. The formation of (natural) hormones in the gut may interfere with this method. Designer drugs are mainly known from sports doping. In animal fattening, designer drugs may be used as well. Small changes in the structure of (natural) hormones may lead to a new group of substances asking for new strategies for their detection and the constatation of their abuse

Anti-chemokine small molecule drugs: a promising future?

Science.gov (United States)

Proudfoot, Amanda E I; Power, Christine A; Schwarz, Matthias K

2010-03-01

Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry. Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review. In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future. In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.

Quantum mechanics implementation in drug-design workflows: does it really help?

Science.gov (United States)

Arodola, Olayide A; Soliman, Mahmoud Es

2017-01-01

The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry. However, the complexity of many protein-ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. The usefulness of quantum mechanics (QM) in drug-protein interaction cannot be overemphasized; however, this approach has little significance in some empirical methods. In this review, we discuss recent developments in, and application of, QM to medically relevant biomolecules. We critically discuss the different types of QM-based methods and their proposed application to incorporating them into drug-design and -discovery workflows while trying to answer a critical question: are QM-based methods of real help in drug-design and -discovery research and industry?

Towards appropriate design solutions for drug-resistant TB facilities in SA

CSIR Research Space (South Africa)

Parsons, SA

2010-07-01

Full Text Available South Africa has a high and increasing burden of both drugs-susceptible and drug-resistant tuberculosis. This disease has been declared an emergency in Africa. South Africa has committed itself to addressing this national crises by designing...

Drug design and discovery: translational biomedical science varies among countries.

Science.gov (United States)

Weaver, Ian N; Weaver, Donald F

2013-10-01

Drug design and discovery is an innovation process that translates the outcomes of fundamental biomedical research into therapeutics that are ultimately made available to people with medical disorders in many countries throughout the world. To identify which nations succeed, exceed, or fail at the drug design/discovery endeavor--more specifically, which countries, within the context of their national size and wealth, are "pulling their weight" when it comes to developing medications targeting the myriad of diseases that afflict humankind--we compiled and analyzed a comprehensive survey of all new drugs (small molecular entities and biologics) approved annually throughout the world over the 20-year period from 1991 to 2010. Based upon this analysis, we have devised prediction algorithms to ascertain which countries are successful (or not) in contributing to the worldwide need for effective new therapeutics. © 2013 Wiley Periodicals, Inc.

Design of a tripartite network for the prediction of drug targets

Science.gov (United States)

Kunimoto, Ryo; Bajorath, Jürgen

2018-02-01

Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

Molecular docking as a popular tool in drug design, an in silico travel

Directory of Open Access Journals (Sweden)

de Ruyck J

2016-06-01

Full Text Available Jerome de Ruyck, Guillaume Brysbaert, Ralf Blossey, Marc F Lensink University Lille, CNRS UMR8576 UGSF, Lille, FranceAbstract: New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism- or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents' synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.Keywords: structure-based drug design, protein–protein docking, quaternary structure prediction, residue interaction networks, RINs, water position

Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes.

Science.gov (United States)

Semighini, Evandro P; Resende, Jonathan A; de Andrade, Peterson; Morais, Pedro A B; Carvalho, Ivone; Taft, Carlton A; Silva, Carlos H T P

2011-04-01

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

Science.gov (United States)

Sarafianos, Stefan G; Das, Kalyan; Hughes, Stephen H; Arnold, Eddy

2004-12-01

HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

Current status and future prospects for enabling chemistry technology in the drug discovery process.

Science.gov (United States)

Djuric, Stevan W; Hutchins, Charles W; Talaty, Nari N

2016-01-01

This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of "dangerous" reagents. Also featured are advances in the "computer-assisted drug design" area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities.

Multimodal drugs and their future for Alzheimer's and Parkinson's disease.

Science.gov (United States)

Van der Schyf, Cornelis J; Geldenhuys, Werner J

2011-01-01

This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds. Copyright © 2011 Elsevier Inc. All rights reserved.

Peripheral Applications of Drug-Coated Balloons: Past, Present and Future

Energy Technology Data Exchange (ETDEWEB)

Krokidis, Miltiadis, E-mail: mkrokidis@hotmail.com; Spiliopoulos, Stavros, E-mail: stavspiliop@upatras.gr; Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr; Sabharwal, Tarun, E-mail: tarun_sabharwal@yahoo.co.uk [Guy' s and St. Thomas' Hospitals, NHS Foundation Trust, Department of Radiology (United Kingdom)

2013-04-15

Drug-coated balloon (DCB) technologies represent the latest and hottest development in the field of endovascular treatment of peripheral arterial disease. Initial experience with paclitaxel-coated balloon use in the femoral artery has demonstrated lower mid-term restenosis and superior mid-term clinical outcomes in terms of improved wound healing and reduced repeat angioplasty rates compared with standard balloon angioplasty. Many companies are presently developing and/or improving DCB catheters and therefore ongoing, technical improvements of the already existing platforms, new drugs, and innovative carriers are expected. The ongoing basic research studies and various multicenter randomized, controlled trials that are currently in progress will offer valuable scientific insights regarding the long-term effectiveness and other crucial issues, such as efficacy in various vascular beds, optimal balloon dosage, and post angioplasty antiplatelet therapy. Future applications of these devices also could include in-stent restenosis, anastomotic stenosis of surgical bypass, and benign stenoses of the central venous system. The authors envision that DCB angioplasty will evolve to a major paradigm shift in the endovascular treatment of occlusive vascular diseases.

Peripheral Applications of Drug-Coated Balloons: Past, Present and Future

International Nuclear Information System (INIS)

Krokidis, Miltiadis; Spiliopoulos, Stavros; Katsanos, Konstantinos; Sabharwal, Tarun

2013-01-01

Drug-coated balloon (DCB) technologies represent the latest and hottest development in the field of endovascular treatment of peripheral arterial disease. Initial experience with paclitaxel-coated balloon use in the femoral artery has demonstrated lower mid-term restenosis and superior mid-term clinical outcomes in terms of improved wound healing and reduced repeat angioplasty rates compared with standard balloon angioplasty. Many companies are presently developing and/or improving DCB catheters and therefore ongoing, technical improvements of the already existing platforms, new drugs, and innovative carriers are expected. The ongoing basic research studies and various multicenter randomized, controlled trials that are currently in progress will offer valuable scientific insights regarding the long-term effectiveness and other crucial issues, such as efficacy in various vascular beds, optimal balloon dosage, and post angioplasty antiplatelet therapy. Future applications of these devices also could include in-stent restenosis, anastomotic stenosis of surgical bypass, and benign stenoses of the central venous system. The authors envision that DCB angioplasty will evolve to a major paradigm shift in the endovascular treatment of occlusive vascular diseases.

Future of color in the visual arts, architecture, and design

Science.gov (United States)

Green-Armytage, Paul

2002-06-01

My brief for this report was to reflect on the congress from the point of view of the visual arts, architecture and design, and to say something about how I see the future of color in these fields. I will say a bit about the congress itself, a bit about some of the topics that particularly struck me, and a bit about the future - the future that seems likely and the future that I hope for.

The Future of Pharmaceutical Manufacturing Sciences

DEFF Research Database (Denmark)

Rantanen, Jukka; Khinast, Johannes

2015-01-01

The entire pharmaceutical sector is in an urgent need of both innovative technological solutions and fundamental scientific work, enabling the production of highly engineered drug products. Commercial-scale manufacturing of complex drug delivery systems (DDSs) using the existing technologies...... is challenging. This review covers important elements of manufacturing sciences, beginning with risk management strategies and design of experiments (DoE) techniques. Experimental techniques should, where possible, be supported by computational approaches. With that regard, state-of-art mechanistic process...... control solutions. Last part of the review addresses future manufacturing solutions, covering continuous processing and, specifically, hot-melt processing and printing-based technologies. Finally, challenges related to implementing these technologies as a part of future health care systems are discussed....

Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

Science.gov (United States)

Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

2005-10-01

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

A Practitioner’s View of the Future of Organization Design: Future Trends and Implications for Royal Dutch Shell

Directory of Open Access Journals (Sweden)

Jan Steinmetz

2012-05-01

Full Text Available Humanity is facing an increasingly challenging outlook for energy needs and the planet. Royal Dutch Shell is a global group of energy and petrochemicals companies with approximately 100,000 employees in more than 80 countries that is committed to help meet the challenges of the new energy environment in a sustainable and responsible manner. My statement will present some of the future trends and possible implications which can be seen for organization design within Royal Dutch Shell (Shell and which are applicable to other large, complex enterprises. It largely represents the personal views and reflections of a practitioner both inside and outside of Shell’s human resources (HR function in the United States. Using the lens of organization design, we will review the themes that emerged from the Shell Energy 2025 and Shell Energy 2050 global scenarios. Next, we will discuss Shell’s previous experience, challenges, and issues related to organization design, and how the recent redesign of the HR function has provided wider space and crisper focus to meet the challenges of the future. Finally, we will review the design challenges that the future trends impose upon the organization design practice. Although these challenges and implications are derived from experience working in Shell and its joint ventures, they are not confined solely to Shell. Because many of the challenges discussed below would benefit from scholarly research, the statement represents a practitioner’s view on how the future of organization design may play out.

Structure-based drug design for G protein-coupled receptors.

Science.gov (United States)

Congreve, Miles; Dias, João M; Marshall, Fiona H

2014-01-01

Our understanding of the structural biology of G protein-coupled receptors has undergone a transformation over the past 5 years. New protein-ligand complexes are described almost monthly in high profile journals. Appreciation of how small molecules and natural ligands bind to their receptors has the potential to impact enormously how medicinal chemists approach this major class of receptor targets. An outline of the key topics in this field and some recent examples of structure- and fragment-based drug design are described. A table is presented with example views of each G protein-coupled receptor for which there is a published X-ray structure, including interactions with small molecule antagonists, partial and full agonists. The possible implications of these new data for drug design are discussed. © 2014 Elsevier B.V. All rights reserved.

Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

Science.gov (United States)

Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

2018-03-15

Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So the current AD drug discovery research shifting towards new approach for better solution that simultaneously modulate more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs. Drug discovery project is tedious, costly and long term project. Moreover, multi target AD drug discovery added extra challenges such as good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off target side effect and crossing of the blood brain barrier. These hurdles may be addressed by insilico methods for efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here we are summarizing some of the most prominent and computationally explored single target against AD and further we discussed successful example of dual or multiple inhibitors for same targets. Moreover we focused on ligand and structure based computational approach to design MTDL against AD. However is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy are useful in future MTDLs drug discovery alone or in combination with fragment based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug

Design Project on Controlled-Release Drug Delivery Devices: Implementation, Management, and Learning Experiences

Science.gov (United States)

Xu, Qingxing; Liang, Youyun; Tong, Yen Wah; Wang, Chi-Hwa

2010-01-01

A design project that focuses on the subject of controlled-release drug delivery devices is presented for use in an undergraduate course on mass transfer. The purpose of the project is to introduce students to the various technologies used in the fabrication of drug delivery systems and provide a practical design exercise for understanding the…

Design of new polymeric formulations for drug nanocarriers

Science.gov (United States)

Mattu, C.; Li, R.; Sartori, S.; Boffito, M.; Ramtoola, Z.; Ciardelli, G.

2012-07-01

In this work, novel strategies for the design and characterization of complex nanosized drug delivery systems for the release of different formulations were proposed and investigated. Natural or synthetic polymers, such as chitosan, poly (D,L lactide) (PLA) and proprietary polyesterurethanes, were used to prepare carriers for different applications in nanomedicine.

Rainwater catchment system design using simulated future climate data

Science.gov (United States)

Wallace, Corey D.; Bailey, Ryan T.; Arabi, Mazdak

2015-10-01

Rainwater harvesting techniques are used worldwide to augment potable water supply, provide water for small-scale irrigation practices, increase rainwater-use efficiency for sustained crop growth in arid and semi-arid regions, decrease urban stormwater flow volumes, and in general to relieve dependency on urban water resources cycles. A number of methods have been established in recent years to estimate reliability of rainwater catchment systems (RWCS) and thereby properly size the components (roof catchment area, storage tank size) of the system for a given climatic region. These methods typically use historical or stochastically-generated rainfall patterns to quantify system performance and optimally size the system, with the latter accounting for possible rainfall scenarios based on statistical relationships of historical rainfall patterns. To design RWCS systems that can sustainably meet water demand under future climate conditions, this paper introduces a method that employs climatic data from general circulation models (GCMs) to develop a suite of catchment area vs. storage size design curves that capture uncertainty in future climate scenarios. Monthly rainfall data for the 2010-2050 time period is statistically downscaled to daily values using a Markov chain algorithm, with results used only from GCMs that yield rainfall patterns that are statistically consistent with historical rainfall patterns. The process is demonstrated through application to two climatic regions of the Federated States of Micronesia (FSM) in the western Pacific, wherein the majority of the population relies on rainwater harvesting for potable water supply. Through the use of design curves, communities can provide household RWCS that achieve a certain degree of storage reliability. The method described herein can be applied generally to any geographic region. It can be used to first, assess the future performance of existing household systems; and second, to design or modify systems

Designing an intuitive web application for drug discovery scientists.

Science.gov (United States)

Karamanis, Nikiforos; Pignatelli, Miguel; Carvalho-Silva, Denise; Rowland, Francis; Cham, Jennifer A; Dunham, Ian

2018-01-11

We discuss how we designed the Open Targets Platform (www.targetvalidation.org), an intuitive application for bench scientists working in early drug discovery. To meet the needs of our users, we applied lean user experience (UX) design methods: we started engaging with users very early and carried out research, design and evaluation activities within an iterative development process. We also emphasize the collaborative nature of applying lean UX design, which we believe is a foundation for success in this and many other scientific projects. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Engineering design of TFTR and it's impact on future tokamaks

International Nuclear Information System (INIS)

Sabado, M.M.

1981-01-01

TFTR is a second generation tokamak whose key objective is scientific break-even. TFTR is expected to be the first machine to demonstrate proper combination of plasma confinement time, density, and temperature to obtain this objective. A summary of major TFTR design parameters, including TFM, is presented, and their potential impact on future tokamaks discussed. Details of the updated engineering design and analysis of components are described. Status of major hardware fabrication, assembly installation and test are reviewed. TFTR features, technology, predicted performance and their potential implication for future tokamaks are summarized

Status of core nuclear design technology for future fuel

International Nuclear Information System (INIS)

Joo, Hyung Kook; Jung, Hyung Guk; Noh, Jae Man; Kim, Yeong Il; Kim, Taek Kyum; Gil, Choong Sup; Kim, Jung Do; Kim, Young Jin; Sohn, Dong Seong

1997-01-01

The effective utilization of nuclear resource is more important factor to be considered in the design of next generation PWR in addition to the epochal consideration on economics and safety. Assuming that MOX fuel can be considered as one of the future fuel corresponding to the above request, the establishment of basic technology for the MOX core design has been performed : : the specification of the technical problem through the preliminary core design and nuclear characteristic analysis of MOX, the development and verification of the neutron library for lattice code, and the acquisition of data to be used for verification of lattice and core analysis codes. The following further studies will be done in future: detailed verification of library E63LIB/A, development of the spectral history effect treatment module, extension of decay chain, development of new homogenization for the MOX fuel assembly. (author). 6 refs., 7 tabs., 2 figs

Grid Based Technologies for in silico Screening and Drug Design.

Science.gov (United States)

Potemkin, Vladimir; Grishina, Maria

2018-03-08

Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described. The design methods are implemented now at www.chemosophia.com web-site for online computational services. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Present status and future of hypnotic drug treatment for insomnia].

Science.gov (United States)

Uchiyama, Makoto; Konno, Michiko

2012-07-01

Pharmacological treatments of insomnia have become safer since the first benzodiazepine receptor agonist (BzRA) hypnotic was introduced in the 1960's. Though BzRAs could hardly cause a fatal condition even in cases of overdosing, they had inherited the arguments on addiction and withdrawal from the prior studies of barbiturate hypnotics that indicated they are strongly addictive. In the 2000s, it was repeatedly demonstrated that insomnia as well as sleep deprivation underlie the development and deterioration of comorbid diseases such as hypertension, cardiovascular diseases, diabetes and depression, and that the proper use of hypnotic drugs is unlikely to cause tolerance, addiction nor rebound phenomena, but likely to be associated with improvement of QOL. Thus, the 2005's consensus report on chronic insomnia by NIH has recommended general physicians to facilitate insomnia treatment to prevent the development of physical and/or mental disorders. The author reviewed in this article the efficacy and side effects of BzRA hypnotics, a hypnotic drug therapy combined with cognitive and behavioral interventions, uses of melatonin receptor agonist in general and sleep medicine practices, and future utilization of newly-developed orexin antagonists for insomnia treatment.

Measurement of Drug Craving in Persian Speaking Subjects; a Review on Current Experiences and Future Perspectives

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Masoomeh Maarefvand

2012-09-01

Full Text Available Background: Drug craving is considered as one of the main cores of drug dependency and addiction. Multidimensionality of drug craving, its cultural-bounded features and its intra individual rapidly changing nature makes it difficult to be measured. Nowadays, regarding different psychometric approaches, there are various instruments available for measurement of different aspects of drug craving but mainly for Latin-based languages in North America and European countries. High prevalence and special conditions, and unique subcultures in substance abuse and addiction in many countries, like Iran, make the design of culturally validated instruments for drug craving assessment priority. Materials and Methods: Comprehensive review on drug craving measurement instruments for Persian speaking subjects have been performed by searching in databases (ELSEVIER, Science Direct and Scientific Information Database (SID and investigating of related documents on regional experiences. Results: In this article seven main categories of drug craving instruments have been reviewed focusing on validated versions in Persian language including: self-reports, reinforcement “proxies”, drug self administration, psycho physiological responding, neurobiological responding, cognitive processing and expressive methods. Conclusion: Reviewing on weak and strength points of each instrument group and national and regional experiences shows that designing and validating a new series of ecologically-validated instruments for multidimensional measurement of drug craving in different addiction subcultures should be prioritized to cover current methodological gaps in substance abuse studies in Iran.

Drug Partitioning in Micellar Media and Its Implications in Rational Drug Design: Insights with Streptomycin.

Science.gov (United States)

Judy, Eva; Pagariya, Darshna; Kishore, Nand

2018-03-20

Oral bioavailability of a drug molecule requires its effective delivery to the target site. In general, majority of synthetically developed molecular entities have high hydrophobic nature as well as low bioavailability, therefore the need for suitable delivery vehicles arises. Self-assembled structures such as micelles, niosomes, and liposomes have been used as effective delivery vehicles and studied extensively. However, the information available in literature is mostly qualitative in nature. We have quantitatively investigated the partitioning of antibiotic drug streptomycin into cationic, nonionic, and a mixture of cationic and nonionic surfactant micelles and its interaction with the transport protein serum albumin upon subsequent delivery. A combination of calorimetry and spectroscopy has been used to obtain the thermodynamic signatures associated with partitioning and interaction with the protein and the resulting conformational changes in the latter. The results have been correlated with other class of drugs of different nature to understand the role of molecular features in the partitioning process. These studies are oriented toward understanding the physical chemistry of partitioning of a variety of drug molecules into suitable delivery vehicles and hence establishing structure-property-energetics relationships. Such studies provide general guidelines toward a broader goal of rational drug design.

Versatile Chemical Derivatizations to Design Glycol Chitosan-Based Drug Carriers

Directory of Open Access Journals (Sweden)

Sung Eun Kim

2017-10-01

Full Text Available Glycol chitosan (GC and its derivatives have been extensively investigated as safe and effective drug delivery carriers because of their unique physiochemical and biological properties. The reactive functional groups such as the amine and hydroxyl groups on the GC backbone allow for easy chemical modification with various chemical compounds (e.g., hydrophobic molecules, crosslinkers, and acid-sensitive and labile molecules, and the versatility in chemical modifications enables production of a wide range of GC-based drug carriers. This review summarizes the versatile chemical modification methods that can be used to design GC-based drug carriers and describes their recent applications in disease therapy.

Future Challenges and Opportunities in Online Prescription Drug Promotion Research Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters".

Science.gov (United States)

Southwell, Brian G; Rupert, Douglas J

2016-01-16

Despite increased availability of online promotional tools for prescription drug marketers, evidence on online prescription drug promotion is far from settled or conclusive. We highlight ways in which online prescription drug promotion is similar to conventional broadcast and print advertising and ways in which it differs. We also highlight five key areas for future research: branded drug website influence on consumer knowledge and behavior, interactive features on branded drug websites, mobile viewing of branded websites and mobile advertisements, online promotion and non-US audiences, and social media and medication decisions. © 2016 by Kerman University of Medical Sciences.

Targeting the dopamine D3 receptor: an overview of drug design strategies.

Science.gov (United States)

Cortés, Antoni; Moreno, Estefanía; Rodríguez-Ruiz, Mar; Canela, Enric I; Casadó, Vicent

2016-07-01

Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.

Future Challenges and Opportunities in Online Prescription Drug Promotion Research; Comment on “Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters”

Directory of Open Access Journals (Sweden)

Brian G. Southwell

2016-03-01

Full Text Available Despite increased availability of online promotional tools for prescription drug marketers, evidence on online prescription drug promotion is far from settled or conclusive. We highlight ways in which online prescription drug promotion is similar to conventional broadcast and print advertising and ways in which it differs. We also highlight five key areas for future research: branded drug website influence on consumer knowledge and behavior, interactive features on branded drug websites, mobile viewing of branded websites and mobile advertisements, online promotion and non-US audiences, and social media and medication decisions.

Mechatronic futures challenges and solutions for mechatronic systems and their designers

CERN Document Server

Bradley, David

2016-01-01

Offering a comprehensive overview of the challenges, risks and options facing the future of mechatronics, this book provides insights into how these issues are currently assessed and managed. Building on the previously published book ‘Mechatronics in Action,’ it identifies and discusses the key issues likely to impact on future mechatronic systems. It supports mechatronics practitioners in identifying key areas in design, modeling and technology and places these in the wider context of concepts such as cyber-physical systems and the Internet of Things. For educators it considers the potential effects of developments in these areas on mechatronic course design, and ways of integrating these. Written by experts in the field, it explores topics including systems integration, design, modeling, privacy, ethics and future application domains. Highlighting novel innovation directions, it is intended for academics, engineers and students working in the field of mechatronics, particularly those developing new conc...

Designing domestic buildings for future summers: Attitudes and opinions of building professionals

International Nuclear Information System (INIS)

Gul, Mehreen S.; Menzies, Gillian F.

2012-01-01

A changing climate will produce summertime overheating where conventional domestic building design approaches do not adequately address future warming risk. This risk cannot be fully identified and avoided unless future climate information and building related adaptation measures are considered. The Low Carbon Futures project is developing a tool that uses UKCP09 climate projections input to predict dwelling overheating risks. To enhance the usefulness of this tool for the building industry, and to better understand current building design processes, interviews were conducted with building professionals, allowing industry preferences for the tool to be sought and to provide clearer indications of proposed outcomes. This paper examines results from a questionnaire, focus groups and semi-structured interviews with building industry professionals. The research shows that the housing industry maintains adherence to traditional designing methods where overheating, whether current or future, is not considered a serious concern. No design stage detailed overheating assessments are currently undertaken to reduce the UK's increased room air-conditioner sales, despite drives for low energy/zero carbon homes. The collated feedback will help tailor the tool and its eventual outputs, with this paper attempting to converge on a set of recommendations for low carbon dwelling design with reduced overheating risk. - Highlights: ► Interviews to gauge attitudes of building professionals towards future warming. ► Client requirements, capital costs and regulations take priority in typical practice. ► No actions are currently taken to prevent overheating risks in the housing sector. ► Overheating risks in housing can be tackled by the use of dynamic modelling. ► The LCF tool further helps to adapt a dwelling to reduce future overheating risks.

Modern Prodrug Design for Targeted Oral Drug Delivery

Directory of Open Access Journals (Sweden)

Arik Dahan

2014-10-01

Full Text Available The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

Identification of designer drug 2C-E (4-ethyl-2, 5-dimethoxy-phenethylamine) in urine following a drug overdose

OpenAIRE

Van Vrancken, Michael J.; Benavides, Raul; Wians, Frank H.

2013-01-01

In recent years, access to information regarding acquisition and synthesis of newer designer drugs has been at an all-time high due largely to the Internet. As these drugs have become more prevalent, laboratory techniques have been developed and refined to identify and screen for this burgeoning population of drugs. This provides a unique opportunity for learning about many of these methods. Laboratory testing techniques and instrumentation are obscure to many health care professionals, yet t...

Safety aspects of designs for future light water reactors (evolutionary reactors)

International Nuclear Information System (INIS)

1993-07-01

The main purpose of this document is to describe the major innovations of proposed designs of future light water reactors, to describe specific safety characteristics and safety analysis methodologies, and to give a general overview of the most important safety aspects related to future reactors. The reactors considered in this report are limited to those intended for fixed station electrical power production, excluding most revolutionary concepts. More in depth discussion is devoted to those designs that are in a more advanced state of completion and have been more extensively described and analysed in the open literature. Other designs will be briefly described, as evidence of the large spectrum of new proposals. Some designs are similar; others implement unique features and require specific discussion (not all aspects of designs with unique features are fully discussed in this document). 131 refs, 22 figs

Bio-Inspired Multi-Functional Drug Transport Design Concept and Simulations.

Science.gov (United States)

Pidaparti, Ramana M; Cartin, Charles; Su, Guoguang

2017-04-25

In this study, we developed a microdevice concept for drug/fluidic transport taking an inspiration from supramolecular motor found in biological cells. Specifically, idealized multi-functional design geometry (nozzle/diffuser/nozzle) was developed for (i) fluidic/particle transport; (ii) particle separation; and (iii) droplet generation. Several design simulations were conducted to demonstrate the working principles of the multi-functional device. The design simulations illustrate that the proposed design concept is feasible for multi-functionality. However, further experimentation and optimization studies are needed to fully evaluate the multifunctional device concept for multiple applications.

From the past to the future: Integrating work experience into the design process.

Science.gov (United States)

Bittencourt, João Marcos; Duarte, Francisco; Béguin, Pascal

2017-01-01

Integrating work activity issues into design process is a broadly discussed theme in ergonomics. Participation is presented as the main means for such integration. However, a late participation can limit the development of both project solutions and future work activity. This article presents the concept of construction of experience aiming at the articulated development of future activities and project solutions. It is a non-teleological approach where the initial concepts will be transformed by the experience built up throughout the design process. The method applied was a case study of an ergonomic participation during the design of a new laboratory complex for biotechnology research. Data was obtained through analysis of records in a simulation process using a Lego scale model and interviews with project participants. The simulation process allowed for developing new ways of working and generating changes in the initial design solutions, which enable workers to adopt their own developed strategies for conducting work more safely and efficiently in the future work system. Each project decision either opens or closes a window of opportunities for developing a future activity. Construction of experience in a non-teleological design process allows for understanding the consequences of project solutions for future work.

Ten Questions about the Future of Art and Design Education.

Science.gov (United States)

Steers, John

1997-01-01

Asks ten questions about the future of art, crafts, and design education. Focuses on why art, crafts, and design education should be included in the curriculum; how the curriculum should be defined; and how art educators should respond to conflicting calls for cultural relativism and for cultural nationalism. (DSK)

Psychiatric aspects of designer drugs and new psychoactive substances consumption

Directory of Open Access Journals (Sweden)

Antsyborov A.V.

2017-02-01

Full Text Available according to the authors, appeared not long ago new psychoactive substances (designer drugs, including synthetic cannabinoids, derivatives of cathinone, phenethylamines, new stimulants, synthetic opioids, tryptamine derivatives, phencyclidine, piperazine, agonists of GABA (A/B receptors have become a serious problem for both consumers and doctors. Consumers of these substances are attracted primarily by the intensity of psychoactive effects, as well as «legal purity», which is declared by shadow producers. This indicates that there are some significant difficulties of laboratory typing of new surfactants. Designer drugs when ingested, can affect a range of neurotransmitter pathways/receptors: dopamine, cannabinoid (CB1, GABA(A/B, 5-HT2A, glutamate, and k-opioid receptors (KOR, the imbalance of which leads to the development of polymorphic psychotic disorders.

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.

Identification of novel Mycobacterium tuberculosis dihydrofolate reductase inhibitors through rational drug design

Directory of Open Access Journals (Sweden)

Mymoona Akhter

2016-01-01

Conclusion: Structure based drug design can be used as an effective tool for the design of new cheiocal entity. Number of novel agents have been identified as antitubercular agents whose mechanism of action needs to be ascertained.

Future prospects of therapeutic clinical trials in acute myeloid leukemia

Science.gov (United States)

Khan, Maliha; Mansoor, Armaghan-e-Rehman; Kadia, Tapan M

2017-01-01

Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future. PMID:27771959

Future steam generator designs. Single wall designs

International Nuclear Information System (INIS)

Hayden, O.

1978-01-01

The easily removable 'U' tube design style adopted in the UK for the existing PFR Steam Generators, the Replacement Units now in production and for the future CDFR, gives the operator an extremely valuable option in the event of a water/steam leak occurring inside the Steam Generator. He can choose to shut-down, attempt to find the leak, assess damage, repair, revalidate and return to service in situ, or he can elect to remove the defect unit and replace with a 'proven' spare before returning the circuit to power. With the latter approach the resultant outage time is a known entity of about two weeks. If a repair is attempted in situ, predictions of outage time can become a matter of guesswork since one has no 'guaranteed' method of leak location and the assessment of secondary damage may be very time consuming, depending on the size and type of the original leak together with the particular design style of the Steam Generator. A further significant advantage of the removable 'U' tube design concept is that periodic interchanging of bundles with a spare enables routine chemical cleaning and thorough scheduled tube inspections, with specimen tube sample removal if required for monitoring purposes. If necessary, bundle decontamination can be undertaken to assess engineering deterioration to various degrees of thoroughness ranging from 100% equivalent factory final assembly inspection, to partial decontamination operating via a glovebox type of maintenance bag arrangement, examining local points of both shell and tube areas of the bundle. Many lessons from the last five years' experience of PFR will be incorporated into the design of the CDFR and PFR Steam Generators have two very good examples of how the designer can ease or severely handicap the operator in coping with sodium/water leakages. Good, quick access to tube ends is achieved in the existing PFR Evaporator by simply unbolting the steam/water closure head, but on the superheater and reheater hand-caps have

Future steam generator designs. Single wall designs

Energy Technology Data Exchange (ETDEWEB)

Hayden, O [Nuclear Power Company Ltd, Warrington, Cheshire (United Kingdom)

1978-10-01

The easily removable 'U' tube design style adopted in the UK for the existing PFR Steam Generators, the Replacement Units now in production and for the future CDFR, gives the operator an extremely valuable option in the event of a water/steam leak occurring inside the Steam Generator. He can choose to shut-down, attempt to find the leak, assess damage, repair, revalidate and return to service in situ, or he can elect to remove the defect unit and replace with a 'proven' spare before returning the circuit to power. With the latter approach the resultant outage time is a known entity of about two weeks. If a repair is attempted in situ, predictions of outage time can become a matter of guesswork since one has no 'guaranteed' method of leak location and the assessment of secondary damage may be very time consuming, depending on the size and type of the original leak together with the particular design style of the Steam Generator. A further significant advantage of the removable 'U' tube design concept is that periodic interchanging of bundles with a spare enables routine chemical cleaning and thorough scheduled tube inspections, with specimen tube sample removal if required for monitoring purposes. If necessary, bundle decontamination can be undertaken to assess engineering deterioration to various degrees of thoroughness ranging from 100% equivalent factory final assembly inspection, to partial decontamination operating via a glovebox type of maintenance bag arrangement, examining local points of both shell and tube areas of the bundle. Many lessons from the last five years' experience of PFR will be incorporated into the design of the CDFR and PFR Steam Generators have two very good examples of how the designer can ease or severely handicap the operator in coping with sodium/water leakages. Good, quick access to tube ends is achieved in the existing PFR Evaporator by simply unbolting the steam/water closure head, but on the superheater and reheater hand-caps have

Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery

Directory of Open Access Journals (Sweden)

Nicholas Ekow Thomford

2018-05-01

Full Text Available The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of “active compound” has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of ‘organ-on chip’ and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug

Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery.

Science.gov (United States)

Thomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, Kevin

2018-05-25

The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compound" has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review

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

Directory of Open Access Journals (Sweden)

Lucianna Helene Santos

2015-11-01

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

French Health Technology Assessment of Antineoplastic Drugs Indicated in the Treatment of Solid Tumours: Perspective for Future Trends.

Science.gov (United States)

Chouaid, Christos; Borget, Isabelle; Braun, Eric; Bazil, Marie-Laure; Schaetz, Dominique; Rémuzat, Cécile; Toumi, Mondher

2016-08-01

France is one of the European countries that spend the most on oncology drugs. To keep pharmaceutical expenditure under control, Health Authorities highly scrutinize market access of costly medicines. To assess current and future trends in French health technology assessment (HTA) of antineoplastic drugs indicated in the treatment of solid tumours. A review of the SMR and ASMR drivers of the Transparency Committee (CT) opinions issued for antineoplastic drugs indicated in the treatment of solid tumours and approved between 2009 and 2014 was performed to assess current trends in French health technology assessment (HTA), complemented by an expert board consultation to capture the critical issues on the future of antineoplastic drugs HTA. Thirty-one drugs indicated for the treatment of solid tumours were identified (77 % targeted therapies). Initial CT assessments were available for 26 drugs. Four key items in the CT assessment were identified: 1) Clinical trial methodology; 2) Acceptance of progression-free survival (PFS) as a valuable endpoint; 3) Transferability of clinical trials in clinical practice; 4) Unpredictability of CT decisions. Experts raised the important development of personalised medicines in oncology and key challenges for oncology products to generate information expected from HTA perspective. The French system remains committed to its values and philosophy (access of all innovations for everybody) which are threatened by the increasing launch of innovative therapies and budget constraint. Both HTA decision framework evolution and revision of the current pricing process should be considered in France to cope with these new challenges.

Beyond THC: the new generation of cannabinoid designer drugs

Directory of Open Access Journals (Sweden)

Liana eFattore

2011-09-01

Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

Designing clinical trials to assess antiepileptic drugs as monotherapy : difficulties and solutions.

Science.gov (United States)

Perucca, Emilio

2008-01-01

Designing monotherapy trials in epilepsy is fraught with many hurdles, including diagnostic and classification difficulties, sparse information regarding the natural history of the disorder, and ethical objections to the use of placebo or a suboptimal comparator in a condition where the consequences of therapeutic failure can be serious. These issues are further complicated by regulatory differences between the US and the EU.In the US, the FDA considers that evidence of efficacy requires demonstration of superiority to a comparator. Because available antiepileptic drugs possess relatively high efficacy, in most settings it is unrealistic to expect that a new treatment will be superior to a standard treatment used at optimized dosages. To circumvent this problem, trial designs have been developed whereby patients in the control group are assigned to receive a suboptimal comparator and are required to exit from the trial if seizure deterioration occurs. This allows demonstration of a between-group difference in efficacy endpoints, such as time to exit or time to first seizure. Although these trials have come under increasing criticism because of ethical concerns, extensive information is now available on the outcome of patients with chronic epilepsy randomized to suboptimal treatment in similarly designed conversion to monotherapy trials. This has allowed the construction of a dataset of historical controls against which response to a fully active treatment can be compared. A number of studies using this novel approach are now in progress.In the EU, in addition to requiring data on conversion to monotherapy in refractory patients, the European Medicines Agency stipulates that a monotherapy indication in newly diagnosed epilepsy can only be granted if a candidate drug has shown at least a similar benefit/risk balance compared with an acknowledged standard at its optimal use during an assessment period of no less than 1 year. This has led to the implementation of

Colon-targeted oral drug delivery systems: design trends and approaches.

Science.gov (United States)

Amidon, Seth; Brown, Jack E; Dave, Vivek S

2015-08-01

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

A Prospective Method to Guide Small Molecule Drug Design

Science.gov (United States)

Johnson, Alan T.

2015-01-01

At present, small molecule drug design follows a retrospective path when considering what analogs are to be made around a current hit or lead molecule with the focus often on identifying a compound with higher intrinsic potency. What this approach overlooks is the simultaneous need to also improve the physicochemical (PC) and pharmacokinetic (PK)…

77 FR 9946 - Draft Guidance for Industry on Drug Interaction Studies-Study Design, Data Analysis, Implications...

Science.gov (United States)

2012-02-21

... industry entitled ``Drug Interaction Studies--Study Design, Data Analysis, Implications for Dosing, and... data analysis in the context of identifying potential drug interactions. The guidance also addresses... Studies--Study Design, Data Analysis, and Implications for Dosing and Labeling.'' Comments were received...

The role of illicit, licit, and designer drugs in the traffic in Hungary.

Science.gov (United States)

Institóris, László; Hidvégi, Előd; Dobos, Adrienn; Sija, Éva; Kereszty, Éva M; Tajti, László Balázs; Somogyi, Gábor Pál; Varga, Tibor

2017-06-01

The aim of this study was to investigate the prevalence and pattern of psychoactive substances among suspected DUID (Driving Under the Influence of Drugs) drivers in Hungary in 2014 and 2015. Blood and/or urine samples of 1252 suspected drivers (600 in 2014 and 652 in 2015) were analyzed for classical illicit and licit drugs, stimulant designer drugs (SDDs), and for synthetic cannabinoids, with 78.3% and 79.6% positive cases for at least one substance in 2014, and 2015, respectively. Impairment was proven in 39.2% (2014) and 35.7% (2015) of all drivers tested, based on the legal criteria of Hungary. Classical illicit drugs were found to be present in blood or urine of 89-61%, drivers tested. Drivers also tested positive for legal medications in 20-22%, SDDs in 21-28%, and synthetic cannabinoids in 15-19% of all cases. This indicates a drop in prevalence for classical illicit drugs and a slight but statistically non-significant increase for the other three substance groups. The distribution of drug types in each category were: [1] classical illicit drugs: cannabis (432), amphetamine (321), and cocaine (79); [2] medicines: alprazolam (94) and clonazepam (36); [3] SDDs: pentedrone (137) and α-PVP (33); [4] synthetic cannabinoids: AB-CHMINACA (46) and MDMB-CHMICA (30). The average age of illicit drug and SDD users was 30 years, while legal medications users were 36 years old on average, and the mean age of synthetic cannabinoid users was 26.5 years. The presence of both alcohol and at least one drug in samples was found in about 10% of the cases, both years. The ratio of multi-drug use was 33.0% in 2014 and 41.3% in 2015. Compared to former years the number of drivers who tested positive for drugs doubled in Hungary, but it is still low compared to alcohol positive cases. The relatively low detected rate of DUID can be explained by (1) combined alcohol consumption masking drug symptoms, (2) the absence of road-side tests for illicit and designer drugs and, (3) police

Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

DEFF Research Database (Denmark)

Narayanan, Dilip; Gani, Osman ABSM; Gruber, Franz XE

2017-01-01

encoded into molecular mechanics force fields. Cheminformatics analyses of binding data show EGFR to be dissimilar to ALK and MET, but its structure shows how it may be co-targeted with the addition of a covalent trap. This suggests a strategy for the design of a focussed chemical library based on a pan......Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however...... consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug...

submitter Can you afford to wait? Designing the collider of the future

CERN Document Server

Benedikt, Michael

2017-01-01

Designing a future circular collider is a next step in humanity’s quest to explain the world. This effort is not only about striving for a profound understanding of nature, but also about creating an exciting perspective for future generations.

Pill testing or drug checking in Australia: Acceptability of service design features.

Science.gov (United States)

Barratt, Monica J; Bruno, Raimondo; Ezard, Nadine; Ritter, Alison

2018-02-01

This study aimed to determine design features of a drug-checking service that would be feasible, attractive and likely to be used by Australian festival and nightlife attendees. Web survey of 851 Australians reporting use of psychostimulants and/or hallucinogens and attendance at licensed venues past midnight and/or festivals in the past year (70% male; median age 23 years). A drug-checking service located at festivals or clubs would be used by 94%; a fixed-site service external to such events by 85%. Most (80%) were willing to wait an hour for their result. Almost all (94%) would not use a service if there was a possibility of arrest, and a majority (64%) would not use a service that did not provide individual feedback of results. Drug-checking results were only slightly more attractive if they provided comprehensive quantitative results compared with qualitative results of key ingredients. Most (93%) were willing to pay up to $5, and 68% up to $10, per test. One-third (33%) reported willingness to donate a whole dose for testing: they were more likely to be male, younger, less experienced, use drugs more frequently and attend venues/festivals less frequently. In this sample, festival- or club-based drug-checking services with low wait times and low cost appear broadly attractive under conditions of legal amnesty and individualised feedback. Quantitative analysis of ecstasy pills requiring surrender of a whole pill may appeal to a minority in Australia where pills are more expensive than elsewhere. [Barratt MJ, Bruno R, Ezard N, Ritter A. Pill testing or drug checking in Australia: Acceptability of service design features. Drug Alcohol Rev 2017;00:000-000]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

Continuous Drug Infusion for Diabetes Therapy: A Closed-Loop Control System Design

Directory of Open Access Journals (Sweden)

Jiming Chen

2008-03-01

Full Text Available While a typical way for diabetes therapy is discrete insulin infusion based on long-time interval measurement, in this paper, we design a closed-loop control system for continuous drug infusion to improve the traditional discrete methods and make diabetes therapy automatic in practice. By exploring the accumulative function of drug to insulin, a continuous injection model is proposed. Based on this model, proportional-integral-derivative (PID and fuzzy logic controllers are designed to tackle a control problem of the resulting highly nonlinear plant. Even with serious disturbance of glucose, such as nutrition absorption at meal time, the proposed scheme can perform well in simulation experiments.

Drug use trajectory patterns among older drug users

Directory of Open Access Journals (Sweden)

Tyndall B

2011-05-01

Full Text Available Miriam Boeri, Thor Whalen, Benjamin Tyndall, Ellen BallardKennesaw State University, Department of Sociology and Criminal Justice, Kennesaw GA, USAAbstract: To better understand patterns of drug use trajectories over time, it is essential to have standard measures of change. Our goal here is to introduce measures we developed to quantify change in drug use behaviors. A secondary goal is to provide effective visualizations of these trajectories for applied use. We analyzed data from a sample of 92 older drug users (ages 45 to 65 to identify transition patterns in drug use trajectories across the life course. Data were collected for every year since birth using a mixed methods design. The community-drawn sample of active and former users were 40% female, 50% African American, and 60% reporting some college or greater. Their life histories provided retrospective longitudinal data on the diversity of paths taken throughout the life course and changes in drug use patterns that occurred over time. Bayesian analysis was used to model drug trajectories displayed by innovative computer graphics. The mathematical techniques and visualizations presented here provide the foundation for future models using Bayesian analysis. In this paper we introduce the concepts of transition counts, transition rates and relapse/remission rates, and we describe how these measures can help us better understand drug use trajectories. Depicted through these visual tools, measurements of discontinuous patterns provide a succinct view of individual drug use trajectories. The measures we use on drug use data will be further developed to incorporate contextual influences on the drug trajectory and build predictive models that inform rehabilitation efforts for drug users. Although the measures developed here were conceived to better examine drug use trajectories, the applications of these measures can be used with other longitudinal datasets.Keywords: drug use, trajectory patterns

Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

Science.gov (United States)

Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

2009-01-30

In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

Molecular Thermodynamic Modeling and Design of Microencapsulation Systems for Drug Delivery

DEFF Research Database (Denmark)

Abildskov, Jens; O’Connell, John P.

2011-01-01

is based on fundamental thermodynamic relations and group contributions to properties of pure species (solvent, active ingredient and polymer) and their mixtures. The method is intended for pharmaceuticals with complex molecular structures, for which limited experimental information is known. Case studies......A systematic design strategy is given for computer-aided design of microparticle drug-delivery systems produced by solvent evaporation. In particular, design of solvents, polymer material, and external phase composition are considered for the case when the active ingredient is known. The procedure...... of solvent design are given....

Price Sensitivity of Demand for Prescription Drugs: Exploiting a Regression Kink Design

DEFF Research Database (Denmark)

Simonsen, Marianne; Skipper, Lars; Skipper, Niels

This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....... kink design. Thus, within a unifying framework we uncover price sensitivity for different subpopulations and types of drugs. The results suggest low average price responsiveness with corresponding price elasticities ranging from -0.08 to -0.25, implying that demand is inelastic. Individuals with lower...

Design and mechanistic study of a novel gold nanocluster-based drug delivery system.

Science.gov (United States)

Li, Qinzhen; Pan, Yiting; Chen, Tiankai; Du, Yuanxin; Ge, Honghua; Zhang, Buchang; Xie, Jianping; Yu, Haizhu; Zhu, Manzhou

2018-05-22

Chemically-triggered drug delivery systems (DDSs) have been extensively studied as they do not require specialized equipment to deliver the drug and can deeply penetrate human tissue. However, their syntheses are complicated and they tend to be cytotoxic, which restricts their clinical utility. In this work, the self-regulated drug loading and release capabilities of peptide-protected gold nanoclusters (Pep-Au NCs) are investigated using vancomycin (Van) as the model drug. Gold nanoclusters (Au NCs) coated with a custom-designed pentapeptide are synthesized as drug delivery nanocarriers and loaded with Van - a spontaneous process reliant on the specific binding between Van and the custom-designed peptide. The Van-loaded Au NCs show comparable antimicrobial activity with Van on its own, and the number of Van released by the Pep-Au NCs is found to be proportional to the amount of bacteria present. The controlled nature of the Van release is very encouraging, and predominantly due to the stronger binding affinity of Van with bacteria than that with Au NCs. In addition, these fluorescent Au NCs could also be used to construct temperature sensors, which enable the in vitro and in vivo bioimaging.

Radiant coolers - Theory, flight histories, design comparisons and future applications

Science.gov (United States)

Donohoe, M. J.; Sherman, A.; Hickman, D. E.

1975-01-01

Radiant coolers have been developed for application to the cooling of infrared detectors aboard NASA earth observation systems and as part of the Defense Meteorological Satellite Program. The prime design constraints for these coolers are the location of the cooler aboard the satellite and the satellite orbit. Flight data from several coolers indicates that, in general, design temperatures are achieved. However, potential problems relative to the contamination of cold surfaces are also revealed by the data. A comparison among the various cooler designs and flight performances indicates design improvements that can minimize the contamination problem in the future.

Future Perspective : Design Process of Perfume Packaging

OpenAIRE

Anderson, Duncan

2016-01-01

In a world where technology develops at a rapid speed a packaging designer should have the ability to adapt to the challenges in a world where the packaging landscape might look far more different from today. This thesis will look at possible future scenarios relating to resources, infrastructure and consumer behaviour in the year 2050. It will then go on to discuss the emergence of new packaging materials pitted to replace plastic, as well as take a look at printed electronics in packaging a...

Design, testing and modifications of the Pelletron accelerator and future uses

International Nuclear Information System (INIS)

Lopez V, H.; Valdovinos A, M.; Hernandez M, V.; Alba P, U.; Garcia R, R.; Rodriguez, R.; Alba P, R.; Ruiz M, J.

1989-01-01

Solutions to various problems in the design of high voltage generator and acceleration units of the Pelletron electron accelerator designed and constructed at ININ are presented. Information on the design of the control system of the electron beams, activities proposed for utilization of sulfur hexafluoride as an accelerator isolating gas as well as some future uses of the Pelletron. (Author). 7 refs, 3 figs

A proposed approach for enhancing design safety assurance of future plants

International Nuclear Information System (INIS)

Oh, Kyu Myeng; Ahn, Sang Kyu; Lee, Chang Ju; Kim, Inn Seock

2010-01-01

This paper provides various insights from a detailed review of deterministic approaches typically applied to ensure design safety of nuclear power plants (NPPs) and risk-informed approaches proposed to evaluate safety of advanced reactors such as Generation IV reactors. Also considered herein are the risk-informed safety analysis (RISA) methodology suggested by Westinghouse as a means to improve the conventional accident analysis, together with the Technology Neutral Framework recently suggested by the U.S. NRC for safety evaluation of future plants. These insights from the comparative review of deterministic and risk-informed approaches could be used in further enhancing the methodology for design safety assurance of future plants

Binding Mode and Induced Fit Predictions for Prospective Computational Drug Design.

Science.gov (United States)

Grebner, Christoph; Iegre, Jessica; Ulander, Johan; Edman, Karl; Hogner, Anders; Tyrchan, Christian

2016-04-25

Computer-aided drug design plays an important role in medicinal chemistry to obtain insights into molecular mechanisms and to prioritize design strategies. Although significant improvement has been made in structure based design, it still remains a key challenge to accurately model and predict induced fit mechanisms. Most of the current available techniques either do not provide sufficient protein conformational sampling or are too computationally demanding to fit an industrial setting. The current study presents a systematic and exhaustive investigation of predicting binding modes for a range of systems using PELE (Protein Energy Landscape Exploration), an efficient and fast protein-ligand sampling algorithm. The systems analyzed (cytochrome P, kinase, protease, and nuclear hormone receptor) exhibit different complexities of ligand induced fit mechanisms and protein dynamics. The results are compared with results from classical molecular dynamics simulations and (induced fit) docking. This study shows that ligand induced side chain rearrangements and smaller to medium backbone movements are captured well in PELE. Large secondary structure rearrangements, however, remain challenging for all employed techniques. Relevant binding modes (ligand heavy atom RMSD PELE method within a few hours of simulation, positioning PELE as a tool applicable for rapid drug design cycles.

Changing an automated drug inventory control system to a data base design.

Science.gov (United States)

Bradish, R A

1982-09-01

A pharmacy department's change from indexed sequential access files to a data base management system (DBMS) for purposes of automated inventory control is described. The DBMS has three main functional areas: (1) inventory ordering and accountability, (2) charging of interdepartmental and intradepartmental orders, and (3) data manipulation with report design for management control. There are seven files directly related to the inventory ordering and accountability area. Each record can be accessed directly or through another file. Information on the quantity of a drug on hand, drug(s) supplied by a specific vendor, status of a purchase order, or calculation of an estimated order quantity can be retrieved quickly. In the drug master file, two records contain a reorder point and safety-stock level that are determined by searching the entries in the order history file and vendor master file. The intradepartmental and interdepartmental orders section contains five files assigned to record and store information on drug distribution. All items removed from the stockroom and distributed are recorded, and reports can be generated for itemized bills, total cost by area, and as formatted files for the accounts payable department. The design, development, and implementation of the DBMS took approximately a year using a part-time pharmacist and minimal outside help, while the previous system required constant expensive help of a programmer/analyst. The DBMS has given the pharmacy department a flexible inventory management system with increased drug control, decreased operating expenses, increased use of department personnel, and the ability to develop and enhance other systems.

Spatio-temporal model based optimization framework to design future hydrogen infrastructure networks

International Nuclear Information System (INIS)

Konda, N.V.S.; Shah, N.; Brandon, N.P.

2009-01-01

A mixed integer programming (MIP) spatio-temporal model was used to design hydrogen infrastructure networks for the Netherlands. The detailed economic analysis was conducted using a multi-echelon model of the entire hydrogen supply chain, including feed, production, storage, and transmission-distribution systems. The study considered various near-future and commercially available technologies. A multi-period model was used to design evolutionary hydrogen supply networks in coherence with growing demand. A scenario-based analysis was conducted in order to account for uncertainties in future demand. The study showed that competitive hydrogen networks can be designed for any conceivable scenario. It was concluded that the multi-period model presented significant advantages in relation to decision-making over long time-horizons

Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs).

Science.gov (United States)

Shah, Utpal U; Roberts, Matthew; Orlu Gul, Mine; Tuleu, Catherine; Beresford, Michael W

2011-09-15

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied. Copyright © 2011 Elsevier B.V. All rights reserved.

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.…

Designing Decision Support System to Detect Drug Interactions Type 2 Diabetes.

Science.gov (United States)

Rasoolimoghadam, Mehdi; Safdari, Reza; Ghazisaeidi, Marjan; Maharanitehrani, MohammadReza; Tahmasebiyan, Shahram

2015-12-01

Type II Diabetes is the most common diseases of metabolic disorders and the treatment of oral anti-diabetic drug use takes place But The problem of using multi-drug and interactions at the same time is an issue that has always been a major challenge And diagnosis of drug interactions, particularly in Diabetic patients due to the problem with the disease is very important. The purpose of this studying is, to design a clinical assistant decided to use this approach to determine the type II diabetes drug interactions this makes it easy for those who are active in the field. Study is Developmental that to determine the content of the system a self-made checklist was used. Checklist Validity and reliability has been confirmed by four professors. The Research community to determine the content of the system was country endocrine that are 124 people. The sample size was calculated using Cochran that was 57 people. The Score of checklist was calculated in SPSS version 20 .finally, the checklist was approved by at least 70% points. The system by using Microsoft SQL server 2008 and visual Studio 2012 development environment was designed in C#.net. In the end, In order to evaluate the software to determine the level of satisfaction, usability and ease of use, designed systems sharing with all Medical Informatics students of Tehran University of Medical Sciences. For this purpose a self-made questionnaire was used. Questionnaire Validity has been confirmed by four professors and reliability was assessed by Cronbach method. The results of the survey are showing that the majority of students found out and believed the software is useful and easy to use and generally expressed their satisfaction software. The methodology provides a suitable approach for analysis and modeling of data in the medical field and the performance is good.

Design to learn: customizing services when the future matters

Directory of Open Access Journals (Sweden)

Dan Ariely

2013-04-01

Full Text Available Internet-based customization tools can be used to design service encounters that maximize customers' utility in the present or explore their tastes to provide more value in the future, where these two goals conflict with each other. Maximizing expected customer satisfaction in the present leads to slow rates of learning that may limit the ability to provide quality in the future. An emphasis on learning can lead to unsatisfied customers that will not only forego purchasing in the current period, but, more seriously, never return if they lose trust in the service provider's ability to meet their needs. This paper describes service design policies that balance the objectives of learning and selling by characterizing customer lifetime value as a function of knowledge. The analysis of the customization problem as a dynamic program yields three results. The first result is the characterization of customization policies that quantify the value of knowledge so as to adequately balance the expected revenue of present and future interactions. The second result is an analysis of the impact of operational decisions on loyalty, learning, and profitability over time. Finally, the quantification of the value of knowing the customer provides a connection between customer acquisition and retention policies, thus enhancing the current understanding of the mechanisms connecting service customization, value creation, and customer lifetime value.

Botulinum toxin drugs: brief history and outlook.

Science.gov (United States)

Dressler, D

2016-03-01

The global botulinum toxin (BT) market is currently undergoing rapid changes: this may be the time to review the history and the future of BT drug development. Since the early 1990s Botox(®) and Dysport(®) dominated the international BT market. Later, Myobloc(®)/NeuroBloc(®), a liquid BT type B drug, came out, but failed. Xeomin(®) is the latest major BT drug. It features removal of complexing proteins and improved neurotoxin purity. Several new BT drugs are coming out of Korea, China and Russia. Scientific challenges for BT drug development include modification of BT's duration of action, its transdermal transport and the design of BT hybrid drugs for specific target tissues. The increased competition will change the global BT market fundamentally and a re-organisation according to large indication groups, such as therapeutic and cosmetic applications, might occur.

Transdermal microneedles for drug delivery applications

International Nuclear Information System (INIS)

Teo, Ai Ling; Shearwood, Christopher; Ng, Kian Chye; Lu Jia; Moochhala, Shabbir

2006-01-01

Transdermal drug delivery (TDD) has many advantages, the main one being the ability to maintain the prolonged release of drugs to attain optimal blood concentrations. Unfortunately, nature has provided a very effective protective barrier, the stratum corneum (sc), which limits TDD to certain types of drugs with specific properties. In order to enhance TDD, the idea of using microneedles to painlessly penetrate the sc barrier has previously been proposed. In this paper, we will review the different microneedles that are currently being developed as well as our own efforts in this area. Based on our experiences, we will offer our view on the key parameters for effective transdermal microneedle design as well as future directions in this area

Transdermal microneedles for drug delivery applications

Energy Technology Data Exchange (ETDEWEB)

Teo, Ai Ling [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Shearwood, Christopher [School of Mechanical and Aerospace Engineering, 50 Nanyang Avenue, Singapore 639798 (Singapore); Ng, Kian Chye [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Lu Jia [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Moochhala, Shabbir [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore)]. E-mail: mshabbir@dso.org.sg

2006-07-25

Transdermal drug delivery (TDD) has many advantages, the main one being the ability to maintain the prolonged release of drugs to attain optimal blood concentrations. Unfortunately, nature has provided a very effective protective barrier, the stratum corneum (sc), which limits TDD to certain types of drugs with specific properties. In order to enhance TDD, the idea of using microneedles to painlessly penetrate the sc barrier has previously been proposed. In this paper, we will review the different microneedles that are currently being developed as well as our own efforts in this area. Based on our experiences, we will offer our view on the key parameters for effective transdermal microneedle design as well as future directions in this area.

Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

Science.gov (United States)

Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

2016-05-26

The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery.

Abbreviated New Drug Applications (ANDAS): Future trend in radiopharmaceuticals

International Nuclear Information System (INIS)

Kishore, R.

1990-01-01

The Drug Price Competition and Patent Term Restoration Act (commonly called Waxman Hatch Amendment) of 1984, to the Federal Food, Drug, and Cosmetic Act provided for abbreviated new drug applications (ANDAs) if the conditions specified in the Code of Federal Regulations (CFR) Title 21, subsection 312.55 are met. Under this subsection, reports of nonclinical laboratory studies and clinical investigations can be omitted. New drugs approved under these regulations are so called generic drugs as opposed to listed or pioneer (innovator) drugs. As the patents on more and more radiopharmaceuticals reach their expiration, the radiopharmaceutical industry is likely to produce more of these generic versions of innovator drugs. The ANDAs are required to contain information specified under subsections 314.50(a), (b), (d)(1) and (3), (e), and (g)

Design Pedagogy for an Unknown Future: A View from the Expanding Field of Design Scholarship and Professional Practice

Science.gov (United States)

Wilson, Stephanie Elizabeth; Zamberlan, Lisa

2017-01-01

This article draws on current research investigating the notion of design for an unknown future. It reflects on recent thinking about the role of creativity in design practice and discusses implications for the development and assessment of creativity in the design studio. It begins with a review of literature on the issues and challenges…

Current approaches and future directions in the treatment of leprosy

Directory of Open Access Journals (Sweden)

Worobec SM

2012-08-01

Full Text Available Sophie M WorobecDepartment of Dermatology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USAAbstract: This review surveys current treatments and future treatment trends in leprosy from a clinical perspective. The World Health Organization provides a multidrug treatment regimen that targets the Mycobacterium leprae bacillus which causes leprosy. Several investigational drugs are available for the treatment of drug-resistant M. leprae. Future directions in leprosy treatment will focus on: the molecular signaling mechanism M. leprae uses to avoid triggering an immune response; prospective studies of the side effects experienced during multiple-drug therapy; recognition of relapse rates post-completion of designated treatments; combating multidrug resistance; vaccine development; development of new diagnostic tests; and the implications of the recent discovery of a genetically distinct leprosy-causing bacillus, Mycobacterium lepromatosis.Keywords: epidemiology, leprosy, Hansen’s disease, multidrug resistance, multidrug therapy

Designers predict a bright future

International Nuclear Information System (INIS)

Statton, T.D.

1996-01-01

As power plant designers and builders, there is a bright future for the industry. The demand for electricity will continue to grow, and the need for new plants will increase accordingly. But companies that develop and supply these plants must adapt to new ways of doing business if they expect to see the dawn of this new age. Several factors will have a profound effect on the generation and use of electricity in future years. Instant communications now reach all corners of the globe, making people everywhere aspire to a higher standard of living. The economic surge needed to satisfy these appetites will, in turn, be fed by a network of suppliers who are themselves restructuring to serve global markets, unimpeded by past nationalistic barriers to trade. The strong correlation between economic progress and the growing demand for electricity is well recognized. A ready supply of affordable electricity is a necessary underpinning for any economic expansion. As economies advance and jobs increase, electric demand grows geometrically, fueled by an ever-improving quality of life. Coupled with increasing demand is the worldwide trend toward privatization of the generation industry. The reasons may vary in different parts of the world, but the effect is the same--companies are battling intensely for the right to build or purchase generating facilities. Those companies, like the industry they serve, are themselves in a period of transition. Once a closed, monopolistic group of owners in a predominantly services-based market, they are, thanks to competitive forces, being driven steadily toward a product-based structure

Development of safety principles for the design of future nuclear power plants

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-06-01

The main purpose of this TECDOC is to propose updates to existing safety principles which could be used as a basis for developing safety principles for the design of future NPPs. Accordingly, this document is intended to be useful to reactor designers, owners, operators, researchers and regulators. It is also expected that this document can contribute to international harmonization of safety approaches, and that it will help ensure that future reactors will be designed worldwide to a high standard of safety. As such, these proposed updates are intended to provide general guidance which, if carefully and properly implemented, will result in reactor designs with enhanced safety characteristics beyond those currently in operation. This enhancement results from the fact that the proposals are derived from the lessons learned from more recent operational experience, R and D, design, testing, and analysis developed over the past decade or so, as well as from attempts to reflect the current trends in reactor design, such as the introduction of new technologies. 8 refs, 3 figs.

Development of safety principles for the design of future nuclear power plants

International Nuclear Information System (INIS)

1995-06-01

The main purpose of this TECDOC is to propose updates to existing safety principles which could be used as a basis for developing safety principles for the design of future NPPs. Accordingly, this document is intended to be useful to reactor designers, owners, operators, researchers and regulators. It is also expected that this document can contribute to international harmonization of safety approaches, and that it will help ensure that future reactors will be designed worldwide to a high standard of safety. As such, these proposed updates are intended to provide general guidance which, if carefully and properly implemented, will result in reactor designs with enhanced safety characteristics beyond those currently in operation. This enhancement results from the fact that the proposals are derived from the lessons learned from more recent operational experience, R and D, design, testing, and analysis developed over the past decade or so, as well as from attempts to reflect the current trends in reactor design, such as the introduction of new technologies. 8 refs, 3 figs

What is past is prologue: future directions in Tokamak Power Reactor Design Research

International Nuclear Information System (INIS)

Conn, R.W.

1976-01-01

After reviewing the first generation of studies and the primary conclusions they produced, four current designs are discussed that are representative of present trends in this area of research. In particular, the trends towards reduced reactor size and higher neutron wall loadings are discussed. Moving in this direction requires new approaches to many subsystem designs. New approaches and future directions in first wall and blanket designs that can achieve reliable operation and reasonable lifetime, the use of cryogenic but normal aluminum magnets for the pulsed coils in a tokamak, blanket designs that allow elimination of the intermediate loop, and low activity shields and toroidal field magnets are described. A discussion is given of the future role of conceptual reactor design research and the need for close interactions with ongoing experiments in fusion technology

Commentary on ``Future directions: Building technologies and design tools``

Energy Technology Data Exchange (ETDEWEB)

Quadrel, R.W.

1992-08-10

This paper presents a number of interesting and thought-provoking scenarios about the future use of advanced technology in the design and operation of commercial buildings. I will express my reactions in the following series of short paragraphs. These thoughts will, I hope, raise some new questions and offer fruitful directions for further exploration.

Application of Quality by Design (QbD) Principles to Extractables/Leachables Assessment. Establishing a Design Space for Terminally Sterilized Aqueous Drug Products Stored in a Plastic Packaging System.

Science.gov (United States)

Jenke, Dennis

2010-01-01

The concept of quality by design (QbD) reflects the current global regulatory thinking related to pharmaceutical products. A cornerstone of the QbD paradigm is the concept of a design space, where the design space is a multidimensional combination of input variables and process parameters that have been demonstrated to provide the assurance of product quality. If a design space can be established for a pharmaceutical process or product, then operation within the design space confirms that the product or process output possesses the required quality attributes. This concept of design space can be applied to the safety (leachables) assessment of drug products manufactured and stored in packaging systems. Critical variables in such a design space would include those variables that affect the interaction of the drug product and its packaging, including (a) composition of the drug product, (b) composition of the packaging system, (c) configuration of the packaging system, and (d) the conditions of contact. This paper proposes and justifies such a leachables design space for aqueous drug products packaged in a specific plastic packaging system. Such a design space has the following boundaries:Aqueous drug products with a pH in the range of 2 to 8 and that contain no polarity-impacting agents such as organic solubilizers and stabilizers (addressing variable a). Packaging systems manufactured from materials that meet the system's existing material specifications (addressing variable b). Nominal fill volumes from 50 to 1000 mL (addressing variable c). Products subjected to terminal sterilization and then stored at room temperature for a period of up to 24 months (addressing variable d). The ramification of such a design space is that any drug product that falls within these boundaries is deemed to be compatible with the packaging system, from the perspective of safety, without the requirement of supporting drug product testing. When drug products are packaged in plastic

Transforming Future Teaching through ‘Carpe Diem’ Learning Design

Directory of Open Access Journals (Sweden)

Gilly Salmon

2014-01-01

Full Text Available Academic staff in Higher Education (HE need to transform their teaching practices to support more future-orientated, digital, student-centered learning. Promoting, enabling and implementing these changes urgently requires acceptable, meaningful and effective staff development for academics. We identify four key areas that are presenting as barriers to the implementation of successful staff development. We illuminate the Carpe Diem learning design workshop process and illustrate its impact on academic staff as a viable, constructive alternative to traditional staff development processes. The Carpe Diem model directly exposes and addresses the irony that educational institutions expect their academic staff to learn to design and deliver personalized, mobile and technology-enhanced learning to students, whilst wedded to ‘one size fits all’ face-to-face interventions…or worse, ‘page turning’ e-learning that masquerades as staff development. To avoid further frustrations and expensive, inappropriate initiatives, the spirit and practice of Carpe Diem could act as a ‘pathfinder beacon’, and be more widely adopted to enable fast, effective and fully embedded, learner-ready, future-proofed learning.

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.

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.

A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs: a retrospective analysis of replicate design trials.

Science.gov (United States)

Yu, Yang; Teerenstra, Steven; Neef, Cees; Burger, David; Maliepaard, Marc

2016-04-01

The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority. In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02-0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ). In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug. © 2015 The British Pharmacological Society.

Designing future products: what difficulties do designers encounter and how can their creative process be supported?

Science.gov (United States)

Bonnardel, Nathalie

2012-01-01

To remain competitive, companies must regularly offer new products to consumers. A major challenge for designers is therefore to come up with design solutions and define products that are both new and adapted to future users and usages. Although classic methods and ergonomic recommendations are useful in most run-of-the-mill design contexts, they are of limited benefit when the design situation requires greater creativity. This paper therefore addresses issues related to product design by pursuing a triple objective: (1) highlight the difficulties encountered by designers in imagining and conceiving new products, (2) find out which conditions could help designers come up with creative ideas for innovative products, and (3) suggest methods and tools to support designers' creative process and help them take other stakeholders' needs and expectations into consideration.

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.

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.

75 FR 8968 - Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability

Science.gov (United States)

2010-02-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0090] Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability... familiar and less familiar approaches. As more experience is obtained with the less familiar designs...

Drug knowledge bases and their applications in biomedical informatics research.

Science.gov (United States)

Zhu, Yongjun; Elemento, Olivier; Pathak, Jyotishman; Wang, Fei

2018-01-03

Recent advances in biomedical research have generated a large volume of drug-related data. To effectively handle this flood of data, many initiatives have been taken to help researchers make good use of them. As the results of these initiatives, many drug knowledge bases have been constructed. They range from simple ones with specific focuses to comprehensive ones that contain information on almost every aspect of a drug. These curated drug knowledge bases have made significant contributions to the development of efficient and effective health information technologies for better health-care service delivery. Understanding and comparing existing drug knowledge bases and how they are applied in various biomedical studies will help us recognize the state of the art and design better knowledge bases in the future. In addition, researchers can get insights on novel applications of the drug knowledge bases through a review of successful use cases. In this study, we provide a review of existing popular drug knowledge bases and their applications in drug-related studies. We discuss challenges in constructing and using drug knowledge bases as well as future research directions toward a better ecosystem of drug knowledge bases. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

77 FR 74195 - Draft Guidance for Industry and Food and Drug Administration Staff; Design Considerations for...

Science.gov (United States)

2012-12-13

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-1161] Draft Guidance for Industry and Food and Drug Administration Staff; Design Considerations for Devices Intended for Home Use; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The...

Drug Elucidation: Invertebrate Genetics Sheds New Light on the Molecular Targets of CNS Drugs

Directory of Open Access Journals (Sweden)

Donard S. Dwyer

2014-07-01

Full Text Available Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

Drug resistance in Mexico: results from the National Survey on Drug-Resistant Tuberculosis.

Science.gov (United States)

Bojorquez-Chapela, I; Bäcker, C E; Orejel, I; López, A; Díaz-Quiñonez, A; Hernández-Serrato, M I; Balandrano, S; Romero, M; Téllez-Rojo Solís, M M; Castellanos, M; Alpuche, C; Hernández-Ávila, M; López-Gatell, H

2013-04-01

To present estimations obtained from a population-level survey conducted in Mexico of prevalence rates of mono-, poly- and multidrug-resistant strains among newly diagnosed cases of pulmonary tuberculosis (TB), as well as the main factors associated with multidrug resistance (combined resistance to isoniazid and rifampicin). Study data came from the National Survey on TB Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. Samples were obtained for all newly diagnosed cases of pulmonary TB in selected sites. Drug susceptibility testing (DST) was performed for anti-tuberculosis drugs. DST results were obtained for 75% of the cases. Of these, 82.2% (95%CI 79.5-84.7) were susceptible to all drugs. The prevalence of multidrug-resistant TB (MDR-TB) was estimated at 2.8% (95%CI 1.9-4.0). MDR-TB was associated with previous treatment (OR 3.3, 95%CI 1.1-9.4). The prevalence of drug resistance is relatively low in Mexico. ENTB-2008 can be used as a baseline for future follow-up of drug resistance.

Design of diversity and focused combinatorial libraries in drug discovery.

Science.gov (United States)

Young, S Stanley; Ge, Nanxiang

2004-05-01

Using well-characterized chemical reactions and readily available monomers, chemists are able to create sets of compounds, termed libraries, which are useful in drug discovery processes. The design of combinatorial chemical libraries can be complex and there has been much information recently published offering suggestions on how the design process can be carried out. This review focuses on literature with the goal of organizing current thinking. At this point in time, it is clear that benchmarking of current suggested methods is required as opposed to further new methods.

Design of a RESTful web information system for drug prescription and administration.

Science.gov (United States)

Bianchi, Lorenzo; Paganelli, Federica; Pettenati, Maria Chiara; Turchi, Stefano; Ciofi, Lucia; Iadanza, Ernesto; Giuli, Dino

2014-05-01

Drug prescription and administration processes strongly impact on the occurrence of risks in medical settings for they can be sources of adverse drug events (ADEs). A properly engineered use of information and communication technologies has proven to be a promising approach to reduce these risks. In this study, we propose PHARMA, a web information system which supports healthcare staff in the secure cooperative execution of drug prescription, transcription and registration tasks. PHARMA allows the easy sharing and management of documents containing drug-related information (i.e., drug prescriptions, medical reports, screening), which is often inconsistent and scattered across different information systems and heterogeneous organization domains (e.g., departments, other hospital facilities). PHARMA enables users to access such information in a consistent and secure way, through the adoption of REST and web-oriented design paradigms and protocols. We describe the implementation of the PHARMA prototype, and we discuss the results of the usability evaluation that we carried out with the staff of a hospital in Florence, Italy.

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors.

Science.gov (United States)

Furlong, Michael; Seong, Jae Young

2017-01-01

Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.

Low energy nanoemulsification to design veterinary controlled drug delivery devices

Directory of Open Access Journals (Sweden)

Thierry F Vandamme

2010-10-01

Full Text Available Thierry F Vandamme, Nicolas Anton, University of Strasbourg, Faculty of Pharmacy, Illkirch Cedex, France; UMR CNRS 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, Illkirch Cedex, France,  This work is selected as Controlled Release Society Outstanding Veterinary Paper Award 2010Abstract: The unique properties of nanomaterials related to structural stability and quantum-scale reactive properties open up a world of possibilities that could be exploited to design and to target drug delivery or create truly microscale biological sensors for veterinary applications. We developed cost-saving and solvent-free nanoemulsions. Formulated with a low-energy method, these nanoemulsions can find application in the delivery of controlled amounts of drugs into the beverage of breeding animals (such as poultry, cattle, pigs or be used for the controlled release of injectable poorly water-soluble drugs.Keywords: nanoemulsion, nanomedicine, low-energy emulsification, veterinary, ketoprofen, sulfamethazine

Salicytamide: a New Anti-inflammatory Designed Drug Candidate.

Science.gov (United States)

Guedes, Karen Marinho Maciel; Borges, Rosivaldo Santos; Fontes-Júnior, Enéas Andrade; Silva, Andressa Santa Brigida; Fernandes, Luanna Melo Pereira; Cartágenes, Sabrina Carvalho; Pinto, Ana Carla Godinho; Silva, Mallone Lopes; Queiroz, Luana Melo Diogo; Vieira, José Luís Fernandes; Sousa, Pergentino José Cunha; Maia, Cristiane Socorro Ferraz

2018-04-13

Salicytamide is a new drug developed through molecular modelling and rational drug design by the molecular association of paracetamol and salicylic acid. This study was conducted to assess the acute oral toxicity, antinociceptive, and antioedematogenic properties of salicytamide. Acute toxicity was based on the OECD 423 guidelines. Antinociceptive properties were investigated using the writhing, hot plate and formalin tests in Swiss mice. Antioedematogenic properties were evaluated using the carrageenan-induced paw oedema model and croton oil-induced dermatitis in Wistar rats. Salicytamide did not promote behavioural changes or animal deaths during acute oral toxicity evaluation. Furthermore, salicytamide exhibited peripheral antinociceptive activity as evidenced by the reduction in writhing behaviour (ED50 = 4.95 mg/kg) and licking time in the formalin test's inflammatory phase. Also, salicytamide elicited central antinociceptive activity on both hot plate test and formalin test's neurogenic phase. Additionally, salicytamide was effective in reducing carrageenan or croton oil-induced oedema formation. Overall, we have shown that salicytamide, proposed here as a new NSAID candidate, did not induce oral acute toxicity and elicited both peripheral antinociceptive effects (about 10-25 times more potent than its precursors in the writhing test) and antioedematogenic properties. Salicytamide also presented central antinociceptive activity, which seems to be mediated through opioid-independent mechanisms. These findings reveal salicytamide as a promising antinociceptive/antioedematogenic drug candidate.

Study on optimization design of superconducting magnet for magnetic force assisted drug delivery system

International Nuclear Information System (INIS)

Fukui, S.; Abe, R.; Ogawa, J.; Oka, T.; Yamaguchi, M.; Sato, T.; Imaizumi, H.

2007-01-01

Analytical study on the design of the superconducting magnet for the magnetic force assisted drug delivery system is presented in this paper. The necessary magnetic field condition to reside the magnetic drug particle in the blood vessels is determined by analyzing the particle motion in the blood vessel. The design procedure of the superconducting magnet for the M-DDS is presented and some case studies are conducted. The analytical results show that the superconducting magnet to satisfy the magnetic field conduction for the M-DDS is practically feasible

Licensing process for future applications of advanced-design nuclear reactors

International Nuclear Information System (INIS)

Miller, C.L.

1990-01-01

The existing 10CFR50 two-step licensing process in the Code of Federal Regulations can continue to be a viable licensing vehicle for future applications, at least for the near future. The US Nuclear Regulatory Commission (NRC) Commissioners and staff, the public, and the utilities (along with supporting architect/engineers and nuclear steam supply system vendors) have a vast body of experience and knowledge of the existing part 50 licensing process. All these participants are familiar with their respective roles in this process, and history shows this process to be a workable licensing vehicle. Nevertheless, the use of 10CFR52 should be encouraged for future applications. This proposed new rule is intended to achieve the early resolution of licensing issues, to reduce the complexity and uncertainty of the licensing process, and enhance the safety and reliability of nuclear power plants. Part 52's overall purpose is to improve reactor safety and streamline the licensing process by encouraging the use of standard reactor designs and by allowing the early resolution of site environmental and reactor safety issues. The public should be afforded an earlier entry into the licensing process as a result of design certification rulemaking process and combined construction permit/operating license hearings

Energy drink consumption and the perceived risk and disapproval of drugs: Monitoring the Future, 2010-2016.

Science.gov (United States)

Jackson, Dylan B; Leal, Wanda E

2018-07-01

Energy drinks have become quite popular in recent years among adolescents, prompting a wealth of recent research examining the potential deleterious consequences of energy drink consumption among youth. The present study adds to this body of work by exploring perceptions of risk and disapproval of soft and hard drugs among adolescents and whether such attitudes are predicted by patterns of energy drink/shot consumption. Data were derived from the seven most recent cohorts (2010-2016) of the Monitoring the Future (MTF) study, a nationally representative survey of U.S. youth. The significance of associations between energy drink/shot consumption and drug perceptions/attitudes was tested using logistic regression techniques employing adjustments for covariates and cohort-specific fixed effects. Energy drink/shot consumption was largely associated with significant increases in the odds of failing to perceive any risk of drug use and failing to disapprove of drug use among youths, regardless of whether attitudes concerning soft or hard drugs were examined. These associations were particularly robust in the case of habitual energy drink/shot consumers (relative to occasional consumers or abstainers). Additional efforts should be made to heighten awareness and education concerning the potential dangers of energy drink consumption among youth, particularly as it pertains to drug attitudes and diminished perceptions of substance use risk. Policies that minimize energy drink consumption among youth as well as programs that educate parents and teachers about the drug attitudes of youths who regularly consume energy drinks and promote active monitoring of these adolescents may be worthwhile. Copyright © 2018 Elsevier B.V. All rights reserved.

Design of biomedical devices and systems

CERN Document Server

King, Paul H

2008-01-01

Introduction to Biomedical Engineering Design. Fundamental Design Tools. Design Team Management, Reporting, and Documentation. Product Definition. Product Documentation. Product Development. Hardware Development Methods and Tools. Software Development Methods and Tools. Human Factors. Industrial Design. Biomaterials and Material Testing. Safety Engineering: Devices and Processes. Testing. Analysis of Test Data. Reliability and Liability. Food and Drug Administration. Regulations and Standards. Licensing, Patents, Copyrights, and Trade Secrets. Manufacturing and Quality Control. Miscellaneous Issues. Product Issues. Professional Issues. Design Case Studies. Future Design Issues.

Deep Learning for Drug Design: an Artificial Intelligence Paradigm for Drug Discovery in the Big Data Era.

Science.gov (United States)

Jing, Yankang; Bian, Yuemin; Hu, Ziheng; Wang, Lirong; Xie, Xiang-Qun Sean

2018-03-30

Over the last decade, deep learning (DL) methods have been extremely successful and widely used to develop artificial intelligence (AI) in almost every domain, especially after it achieved its proud record on computational Go. Compared to traditional machine learning (ML) algorithms, DL methods still have a long way to go to achieve recognition in small molecular drug discovery and development. And there is still lots of work to do for the popularization and application of DL for research purpose, e.g., for small molecule drug research and development. In this review, we mainly discussed several most powerful and mainstream architectures, including the convolutional neural network (CNN), recurrent neural network (RNN), and deep auto-encoder networks (DAENs), for supervised learning and nonsupervised learning; summarized most of the representative applications in small molecule drug design; and briefly introduced how DL methods were used in those applications. The discussion for the pros and cons of DL methods as well as the main challenges we need to tackle were also emphasized.

NRC policy on future reactor designs

International Nuclear Information System (INIS)

1985-07-01

On April 13, 1983, the US Nuclear Regulatory Commission issued for public comment a ''Proposed Commission Policy Statement on Severe Accidents and Related Views on Nuclear Reactor Regulation'' (48 FR 16014). This report presents and discusses the Commission's final version of that policy statement now entitled, ''Policy Statement on Severe Reactor Accidents Regarding Future Designs and Existing Plants.'' It provides an overview of comments received from the public and the Advisory Committee on Reactor Safeguards and the staff response to these. In addition to the Policy Statement, the report discusses how the policies of this statement relate to other NRC programs including the Severe Accident Research Program; the implementation of safety measures resulting from lessons learned in the accident at Three Mile Island; safety goal development; the resolution of Unresolved Safety Issues and other Generic Safety Issues; and possible revisions of rules or regulatory requirements resulting from the Severe Accident Source Term Program. Also discussed are the main features of a generic decision strategy for resolving Regulatory Questions and Technical Issues relating to severe accidents; the development and regulatory use of new safety information; the treatment of uncertainty in severe accident decision making; and the development and implementation of a Systems Reliability Program for both existing and future plants to ensure that the realized level of safety is commensurate with the safety analyses used in regulatory decisions

Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing

DEFF Research Database (Denmark)

Genina, Natalja; Boetker, Johan Peter; Colombo, Stefano

2017-01-01

for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion...... (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution...

Hard X-ray/soft gamma-ray telescope designs for future astrophysics missions

DEFF Research Database (Denmark)

Ferreira, Desiree Della Monica; Christensen, Finn Erland; Pivovaroff, Michael J.

2013-01-01

We present several concept designs of hard X-ray/soft λ-ray focusing telescopes for future astrophysics missions. The designs are based on depth graded multilayer coatings. These have been successfully employed on the NuSTAR mission for energies up to 80 keV. Recent advances in demonstrating...

Using Free Computational Resources to Illustrate the Drug Design Process in an Undergraduate Medicinal Chemistry Course

Science.gov (United States)

Rodrigues, Ricardo P.; Andrade, Saulo F.; Mantoani, Susimaire P.; Eifler-Lima, Vera L.; Silva, Vinicius B.; Kawano, Daniel F.

2015-01-01

Advances in, and dissemination of, computer technologies in the field of drug research now enable the use of molecular modeling tools to teach important concepts of drug design to chemistry and pharmacy students. A series of computer laboratories is described to introduce undergraduate students to commonly adopted "in silico" drug design…

Safety design and evaluation policy for future FBRs in Japan

International Nuclear Information System (INIS)

Aizawa, Kiyoto

1991-01-01

The safety policy for fast breeder reactors (FBRs) has gradually matured in accordance with the development of FBRs. The safety assessment of the Japanese prototype FBR, Monju during the licensing process accelerated the maturity and the integration of knowledge and databases. Results are expected to be reflected in the establishment of the safety design and evaluation policy for FBRs. Although the methodologies and safety policies developed for LWRs are applicable in principle to future FBRs, it is neither rational nor realistic to treat safety only with these policies. It is recommended that one should develop the methodologies and safety policies starting from understanding of the inherent safety characteristics of FBR's through safety research, plant operating experience and design work. In the last few years, some technical committees were organized in Japan and have discussed key safety issues which are specific to FBRs in order to provide preparatory reports and to establish safety standards and guidelines for future commercial FBRs. (author)

What is past is prologue: future directions in tokamak power reactor design research

International Nuclear Information System (INIS)

Conn, R.W.

1976-01-01

Conceptual tokamak power reactor designs over the last five years have provided us with many fundamental insights regarding tokamaks as fusion reactors. This first generation of studies has helped lay the groundwork upon which to build improvements in reactor design and begin a process of optimization. After reviewing the first generation of studies and the primary conclusions they produced, we discuss four current designs that are representative of present trends in this area of research. In particular, we discuss the trends towards reduced reactor size and higher neutron wall loadings. Moving in this direction requires new approaches to many subsystem designs. We describe new approaches and future directions in first wall and blanket designs that can achieve reliable operation and reasonable lifetime, the use of cryogenic but normal aluminum magnets for the pulsed coils in a tokamak, blanket designs that allow elimination of the intermediate loop, and low activity shields and toroidal field magnets. We close with a discussion of the future role of conceptual reactor design research and the need for close interaction with ongoing experiments in fusion technology

Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations.

Science.gov (United States)

Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj

2016-08-01

Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed.

Interventional procedures and future drug therapy for hypertension

Science.gov (United States)

Lobo, Melvin D.; Sobotka, Paul A.; Pathak, Atul

2017-01-01

Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care. PMID:27406184

From chemical graphs in computer-aided drug design to general Markov-Galvez indices of drug-target, proteome, drug-parasitic disease, technological, and social-legal networks.

Science.gov (United States)

Riera-Fernández, Pablo; Munteanu, Cristian R; Dorado, Julian; Martin-Romalde, Raquel; Duardo-Sanchez, Aliuska; González-Diaz, Humberto

2011-12-01

Complex Networks are useful in solving problems in drug research and industry, developing mathematical representations of different systems. These systems move in a wide range from relatively simple graph representations of drug molecular structures to large systems. We can cite for instance, drug-target protein interaction networks, drug policy legislation networks, or drug treatment in large geographical disease spreading networks. In any case, all these networks have essentially the same components: nodes (atoms, drugs, proteins, microorganisms and/or parasites, geographical areas, drug policy legislations, etc.) and edges (chemical bonds, drug-target interactions, drug-parasite treatment, drug use, etc.). Consequently, we can use the same type of numeric parameters called Topological Indices (TIs) to describe the connectivity patterns in all these kinds of Complex Networks despite the nature of the object they represent. The main reason for this success of TIs is the high flexibility of this theory to solve in a fast but rigorous way many apparently unrelated problems in all these disciplines. Another important reason for the success of TIs is that using these parameters as inputs we can find Quantitative Structure-Property Relationships (QSPR) models for different kind of problems in Computer-Aided Drug Design (CADD). Taking into account all the above-mentioned aspects, the present work is aimed at offering a common background to all the manuscripts presented in this special issue. In so doing, we make a review of the most common types of complex networks involving drugs or their targets. In addition, we review both classic TIs that have been used to describe the molecular structure of drugs and/or larger complex networks. Next, we use for the first time a Markov chain model to generalize Galvez TIs to higher order analogues coined here as the Markov-Galvez TIs of order k (MGk). Lastly, we illustrate the calculation of MGk values for different classes of

A future large-aperture UVOIR space observatory: reference designs

Science.gov (United States)

Rioux, Norman; Thronson, Harley; Feinberg, Lee; Stahl, H. Philip; Redding, Dave; Jones, Andrew; Sturm, James; Collins, Christine; Liu, Alice

2015-09-01

Our joint NASA GSFC/JPL/MSFC/STScI study team has used community-provided science goals to derive mission needs, requirements, and candidate mission architectures for a future large-aperture, non-cryogenic UVOIR space observatory. We describe the feasibility assessment of system thermal and dynamic stability for supporting coronagraphy. The observatory is in a Sun-Earth L2 orbit providing a stable thermal environment and excellent field of regard. Reference designs include a 36-segment 9.2 m aperture telescope that stows within a five meter diameter launch vehicle fairing. Performance needs developed under the study are traceable to a variety of reference designs including options for a monolithic primary mirror.

Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls

Directory of Open Access Journals (Sweden)

Hezekiel Mathambo Kumalo

2015-01-01

Full Text Available he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i covalent interactions in biomolecular systems; (ii the mathematical framework of covalent molecular docking; (iii implementation of covalent docking protocol in drug design workflows; (iv applications covalent docking: case studies and (v shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.

An adaptive drug delivery design using neural networks for effective treatment of infectious diseases: a simulation study.

Science.gov (United States)

Padhi, Radhakant; Bhardhwaj, Jayender R

2009-06-01

An adaptive drug delivery design is presented in this paper using neural networks for effective treatment of infectious diseases. The generic mathematical model used describes the coupled evolution of concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of a damaged organ due to the disease under the influence of external drugs. From a system theoretic point of view, the external drugs can be interpreted as control inputs, which can be designed based on control theoretic concepts. In this study, assuming a set of nominal parameters in the mathematical model, first a nonlinear controller (drug administration) is designed based on the principle of dynamic inversion. This nominal drug administration plan was found to be effective in curing "nominal model patients" (patients whose immunological dynamics conform to the mathematical model used for the control design exactly. However, it was found to be ineffective in curing "realistic model patients" (patients whose immunological dynamics may have off-nominal parameter values and possibly unwanted inputs) in general. Hence, to make the drug delivery dosage design more effective for realistic model patients, a model-following adaptive control design is carried out next by taking the help of neural networks, that are trained online. Simulation studies indicate that the adaptive controller proposed in this paper holds promise in killing the invading pathogens and healing the damaged organ even in the presence of parameter uncertainties and continued pathogen attack. Note that the computational requirements for computing the control are very minimal and all associated computations (including the training of neural networks) can be carried out online. However it assumes that the required diagnosis process can be carried out at a sufficient faster rate so that all the states are available for control computation.

Cyclodextrins in drug carrier systems.

Science.gov (United States)

Uekama, K; Otagiri, M

1987-01-01

One of the important characteristics of cyclodextrins is the formation of an inclusion complex with a variety of drug molecules in solution and in the solid state. As a consequence of intensive basic research, exhaustive toxic studies, and realization of industrial production during the past decade, there seem to be no more barriers for the practical application of natural cyclodextrins in the biomedical field. Recently, a number of cyclodextrin derivatives and cyclodextrin polymers have been prepared to obtain better inclusion abilities than parent cyclodextrins. The natural cyclodextrins and their synthetic derivatives have been successfully utilized to improve various drug properties, such as solubility, dissolution and release rates, stability, or bioavailability. In addition, the enhancement of drug activity, selective transfer, or the reduction of side effects has been achieved by means of inclusion complexation. The drug-cyclodextrin complex is generally formed outside of the body and, after administration, it dissociates, releasing the drug into the organism in a fast and nearly uniform manner. In the biomedical application of cyclodextrins, therefore, particular attention should be directed to the magnitude of the stability constant of the inclusion complex. In the case of parenteral application, a rather limited amount of work has been done because the cyclodextrins in the drug carrier systems have to be more effectively designed to compete with various biological components in the circulatory system. However, the works published thus far apparently indicate that the inclusion phenomena of cyclodextrin analogs may allow the rational design of drug formulation and that the combination of molecular encapsulation with other carrier systems will become a very effective and valuable method for the development of a new drug delivery system in the near future.

Current therapeutic molecules and targets in neurodegenerative diseases based on in silico drug design.

Science.gov (United States)

Sehgal, Sheikh Arslan; Hammad, Mirza A; Tahir, Rana Adnan; Akram, Hafiza Nisha; Ahmad, Faheem

2018-03-15

As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases. Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS, and Huntington's disease. Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis, and Huntington's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Analysis of Drug Design for a Selection of G Protein-Coupled Neuro-Receptors Using Neural Network Techniques

DEFF Research Database (Denmark)

Agerskov, Claus; Mortensen, Rasmus M.; Bohr, Henrik G.

2015-01-01

A study is presented on how well possible drug-molecules can be predicted with respect to their function and binding to a selection of neuro-receptors by the use of artificial neural networks. The ligands investigated in this study are chosen to be corresponding to the G protein-coupled receptors...... computational tools, able to aid in drug-design in a fast and cheap fashion, compared to conventional pharmacological techniques....... mu-opioid, serotonin 2B (5-HT2B) and metabotropic glutamate D5. They are selected due to the availability of pharmacological drug-molecule binding data for these receptors. Feedback and deep belief artificial neural network architectures (NNs) were chosen to perform the task of aiding drug-design.......925. The performance of 8 category networks (8 output classes for binding strength) obtained a prediction accuracy of above 60 %. After training the networks, tests were done on how well the systems could be used as an aid in designing candidate drug molecules. Specifically, it was shown how a selection of chemical...

21 CFR 516.30 - Annual reports for a MUMS-designated drug.

Science.gov (United States)

2010-04-01

... status or results of such studies; (b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and (c) A brief discussion of any changes that may affect the MUMS-designated drug status of the product. For example...

Evolutions in fragment-based drug design: the deconstruction–reconstruction approach

Science.gov (United States)

Chen, Haijun; Zhou, Xiaobin; Wang, Ailan; Zheng, Yunquan; Gao, Yu; Zhou, Jia

2014-01-01

Recent advances in the understanding of molecular recognition and protein–ligand interactions have facilitated rapid development of potent and selective ligands for therapeutically relevant targets. Over the past two decades, a variety of useful approaches and emerging techniques have been developed to promote the identification and optimization of leads that have high potential for generating new therapeutic agents. Intriguingly, the innovation of a fragment-based drug design (FBDD) approach has enabled rapid and efficient progress in drug discovery. In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries. We also highlight the deconstruction–reconstruction strategy by utilizing privileged fragments of reported ligands. PMID:25263697

PROJECT AND ACTON STAGE OD DESIGNING FUTURE MUSIC TEACHERS’ ETHNOCULTURAL TRAINING

Directory of Open Access Journals (Sweden)

Xu Jiayu

2017-04-01

Full Text Available In the article the issue of developing future music teachers’ ethnocultural training in the process of their professional training is revealed. The author emphasizes on the relevance of the issue as future music teachers’ ethnocultural training contributes to, on the one hand, completing mastering the national system of cultural values of native people by students of higher musical educational institutions and, on the other hand, involving perception and understanding of other nations’ cultural values, allowing future music teachers to transmit values expressed by the young generation to their professional activity. It is reported that the main feature of future music teachers’ ethnocultural training is a system of ethnic and cultural values which is the background of musical and psychological-pedagogical and art training; it is actively engaged as value tools musical folk art and national art. Value methods that are involved in the process of training are methods of traditional pedagogy, as well as the basis of pedagogical communication – people’s ethics. It is noted that developing future music teachers’ ethnocultural training requires designing the special methodology. The constant items of this methodology are thought to be the forms, methods, techniques and means of pedagogical and ethnopedagogical impacts as tools for developing students’ ethnopedagogical thinking in the process of musical and pedagogical activities; the system of controlling future music teachers’ ethnopedagogical, ethnological, ethnomusical knowledge and skills as a combination of methods that enables an opportunity to compare the level of mastering the knowledge and skills at different stages of educational process; to organize tuition using innovative technologies. The special attention is paid to professional and active component of this methodology. The diagnostic tests according to the criterion of “a degree of professional effectiveness in

Reconfigurable manufacturing systems: Principles, design, and future trends

Science.gov (United States)

Koren, Yoram; Gu, Xi; Guo, Weihong

2018-06-01

Reconfigurable manufacturing systems (RMSs), which possess the advantages of both dedicated serial lines and flexible manufacturing systems, were introduced in the mid-1990s to address the challenges initiated by globalization. The principal goal of an RMS is to enhance the responsiveness of manufacturing systems to unforeseen changes in product demand. RMSs are costeffective because they boost productivity, and increase the lifetime of the manufacturing system. Because of the many streams in which a product may be produced on an RMS, maintaining product precision in an RMS is a challenge. But the experience with RMS in the last 20 years indicates that product quality can be definitely maintained by inserting in-line inspection stations. In this paper, we formulate the design and operational principles for RMSs, and provide a state-of-the-art review of the design and operations methodologies of RMSs according to these principles. Finally, we propose future research directions, and deliberate on how recent intelligent manufacturing technologies may advance the design and operations of RMSs.

The semiempirical quantum mechanical scoring function for in-silico drug design

Czech Academy of Sciences Publication Activity Database

Fanfrlík, Jindřich; Lepšík, Martin; Řezáč, Jan; Kolář, Michal; Pecina, Adam; Nachtigallová, Dana; Hobza, Pavel

2015-01-01

Roč. 22, č. 1 (2015), s. 34 ISSN 1211-5894. [Discussions in Structural Molecular Biology. Annual Meeting of the Czech Society for Structural Biology /13./. 19.03.2015-21.03.2015, Nové Hrady] Institutional support: RVO:61388963 Keywords : drug design * SQM methods * binding Subject RIV: CF - Physical ; Theoretical Chemistry

[The use of saliva for exposure assessments on designer drugs among adolescents].

Science.gov (United States)

Napierała, Marta; Tezyk, Artur; Piznal, Małgorzata; Bogusiewicz, Joanna; Florek, Ewa

2015-01-01

Drug use is one of the fundamental problems of the contemporary world. Due to the debilitating effects on physical and mental health and the possibility of impaired social functions, it is extremely important to assess exposure to psychoactive substances among high-risk groups. Taking into account characteristics of adolescence, one of them includes young people. To assess the exposure of young people to drugs, survey research is the most commonly use. To establish reliability of the information indicated by the students, toxicological studies could be a good manner. High-performance liquid chromatography coupled with mass spectrometry (LC-MS) is currently one of the most common techniques use for the detection and determination of psychoactive substances in biological material. In practice, an important issue in toxicological studies is the selection of a suitable biological material. Taking into account economic considerations and the method of sampling, the saliva is an increasingly used alternative material. The aim of this study was to assess the exposure of junior high school students on psychoactive substances--designer drugs, through the analysis of surveys and qualitative analysis of saliva taken from teenagers. It has been shown that surveys are a relatively quick and easy form of assessing the exposure of young people to psychoactive substances, but require verification through toxicological analysis of biological material for the presence of psychoactive substances for their reliability. Poznan secondary school students experimented with designer drugs at a similar level as respondents of nationwide survey from 2013.

Design measures to facilitate implementation of safeguards at future water cooled nuclear power plants

International Nuclear Information System (INIS)

1999-01-01

The report is intended to present guidelines to the State authorities, designers and prospective purchasers of future water cooled power reactors which, if taken into account, will minimize the impact of IAEA safeguards on plant operation and ensure efficient and effective acquisition of safeguards data to the mutual benefit of the Member State, the plant operator and the IAEA. These guidelines incorporate the IAEA's experience in establishing and carrying out safeguards at currently operating nuclear power plants, the ongoing development of safeguards techniques and feedback of experience from plant operators and designers on the impact of IAEA safeguards on plant operation. The following main subjects are included: The IAEA's safeguards function for current and future nuclear power plants; summary of the political and legal foundations of the IAEA's safeguards system; the technical objective of safeguards and the supply and use of required design information; safeguards approaches for nuclear power plants; design implications of experience in safeguarding nuclear power plants and guidelines for future water cooled reactors to facilitate the implementation of safeguards

Personality, Drug Preference, Drug Use, and Drug Availability

Science.gov (United States)

Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

2011-01-01

This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

NMR screening in fragment-based drug design: a practical guide.

Science.gov (United States)

Kim, Hai-Young; Wyss, Daniel F

2015-01-01

Fragment-based drug design (FBDD) comprises both fragment-based screening (FBS) to find hits and elaboration of these hits to lead compounds. Typical fragment hits have lower molecular weight (FBDD since it identifies and localizes the binding site of weakly interacting hits on the target protein. Here we describe ligand-based NMR methods for hit identification from fragment libraries and for functional cross-validation of primary hits.

poolHiTS: A Shifted Transversal Design based pooling strategy for high-throughput drug screening

Directory of Open Access Journals (Sweden)

Woolf Peter J

2008-05-01

Full Text Available Abstract Background A key goal of drug discovery is to increase the throughput of small molecule screens without sacrificing screening accuracy. High-throughput screening (HTS in drug discovery involves testing a large number of compounds in a biological assay to identify active compounds. Normally, molecules from a large compound library are tested individually to identify the activity of each molecule. Usually a small number of compounds are found to be active, however the presence of false positive and negative testing errors suggests that this one-drug one-assay screening strategy can be significantly improved. Pooling designs are testing schemes that test mixtures of compounds in each assay, thereby generating a screen of the whole compound library in fewer tests. By repeatedly testing compounds in different combinations, pooling designs also allow for error-correction. These pooled designs, for specific experiment parameters, can be simply and efficiently created using the Shifted Transversal Design (STD pooling algorithm. However, drug screening contains a number of key constraints that require specific modifications if this pooling approach is to be useful for practical screen designs. Results In this paper, we introduce a pooling strategy called poolHiTS (Pooled High-Throughput Screening which is based on the STD algorithm. In poolHiTS, we implement a limit on the number of compounds that can be mixed in a single assay. In addition, we show that the STD-based pooling strategy is limited in the error-correction that it can achieve. Due to the mixing constraint, we show that it is more efficient to split a large library into smaller blocks of compounds, which are then tested using an optimized strategy repeated for each block. We package the optimal block selection algorithm into poolHiTS. The MATLAB codes for the poolHiTS algorithm and the corresponding decoding strategy are also provided. Conclusion We have produced a practical version

PWR design for low doses in the United Kingdom: The present and the future

Energy Technology Data Exchange (ETDEWEB)

Zodiates, A.M.; Willcock, A. [PWR Project Group, Knutsford, England (United Kingdom)

1995-03-01

The Pressurizer Water Reactor (PWR) design chosen for adoption by Nuclear Electric plc was based on the Westinghouse Standard Nuclear Unit Power Plant System (SNUPPS). This design was developed to meet the United Kingdom (UK) requirements and those improvements are embodied in the Sizewell B plant. Nuclear Electric plc is now looking to the design of the future PWRs to be built in the UK. These PWRs will be based as replicas of the Sizewell B design, but attention will be given to reducing operator doses further. This paper details the approach in operator protection improvements incorporated at Sizewall B, presents the estimated annual collective dose, and identifies the approach being adopted to reduce further operator doses in future plants.

Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks.

Science.gov (United States)

Zhang, Rui Xue; Ahmed, Taksim; Li, Lily Yi; Li, Jason; Abbasi, Azhar Z; Wu, Xiao Yu

2017-01-26

Polymer-lipid hybrid nanoparticles (PLN) are an emerging nanocarrier platform made from building blocks of polymers and lipids. PLN integrate the advantages of biomimetic lipid-based nanoparticles (i.e. solid lipid nanoparticles and liposomes) and biocompatible polymeric nanoparticles. PLN are constructed from diverse polymers and lipids and their numerous combinations, which imparts PLN with great versatility for delivering drugs of various properties to their nanoscale targets. PLN can be classified into two types based on their hybrid nanoscopic structure and assembly methods: Type-I monolithic matrix and Type-II core-shell systems. This article reviews the history of PLN development, types of PLN, lipid and polymer candidates, fabrication methods, and unique properties of PLN. The applications of PLN in delivery of therapeutic or imaging agents alone or in combination for cancer treatment are summarized and illustrated with examples. Important considerations for the rational design of PLN for advanced nanoscale drug delivery are discussed, including selection of excipients, synthesis processes governing formulation parameters, optimization of nanoparticle properties, improvement of particle surface functionality to overcome macroscopic, microscopic and cellular biological barriers. Future directions and potential clinical translation of PLN are also suggested.

[Designer drugs and caffeine - characteristics of psychoactive substances and their impact on the organism].

Science.gov (United States)

Wierzejska, Regina

2014-01-01

For many teenagers the time of growing up is a period of trying prohibited substances. Nowadays apart from alcohol and tobacco new designed, psychoactive substances known as "smart drugs" or "legal highs" are available. Intensive development of their market is taking place in the last few years which is difficult to overcome by regulations only. Toxicological tests used now are not able to detect the presence of many such substances in the body. Designer drugs cause the interest of young people even from small towns and many times taking them give effects requiring medical help. Caffeine is also a psychoactive substance but depending on the dose it can have positive or detrimental effect. Recently there are more and more products with caffeine, especially drinks and dietary supplements, what can cause the increase of consumption of caffeine. Children are particularly exposed to the adverse effect of high consumption of caffeine because of their small body weight and development of the central nervous system. This article presents actual data about the market of designer drugs, frequency of using them, consumption of caffeine by children and teenagers and about the impact of these substances on the organism.

Service design as an approach to new service development : reflections and futures studies

OpenAIRE

Yu, Eun; Sangiorgi, Daniela

2014-01-01

This paper illustrates how, although Service Design has been described as evolving from a narrow description of a phase in New Service Development (NSD) to an approach to Service Innovation, the current Service Design research is still focused on the initial stages of NSD. Comparing existing Service Design research with foundational knowledge on NSD, the authors have proposed two complementary directions for future Service Design studies: 1) the expansion of ‘service design as a phase’ to inv...

Ultrasound-Mediated Drug/Gene Delivery in Solid Tumor Treatment

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Yufeng Zhou

2013-01-01

Full Text Available Ultrasound is an emerging modality for drug delivery in chemotherapy. This paper reviews this novel technology by first introducing the designs and characteristics of three classes of drug/gene vehicles, microbubble (including nanoemulsion, liposomes, and micelles. In comparison to conventional free drug, the targeted drug-release and delivery through vessel wall and interstitial space to cancerous cells can be activated and enhanced under certain sonication conditions. In the acoustic field, there are several reactions of these drug vehicles, including hyperthermia, bubble cavitation, sonoporation, and sonodynamics, whose physical properties are illustrated for better understanding of this approach. In vitro and in vivo results are summarized, and future directions are discussed. Altogether, ultrasound-mediated drug/gene delivery under imaging guidance provides a promising option in cancer treatment with enhanced agent release and site specificity and reduced toxicity.

The next generation of CANDU: reactor design to meet future energy markets

International Nuclear Information System (INIS)

Hopwood, J.M.; Love, J.W.; Wren, D.J.

2001-01-01

Nuclear power plant designs for the future must respond to increasingly demanding market requirements. This means that value can be gained from substantial product development directed at these requirements. For the CANDU system, AECL has adopted the revolutionary approach, accommodating significant changes to design while retaining traditional CANDU strengths. The focus of the new design is to achieve a 40% reduction in capital cost, quicken construction time and higher efficiency. Key aspects of the new design include: light water coolant, smaller core, slightly enriched fuel, higher temperature and pressure coolant. Work is well advanced on the preliminary design

Ebola virus: A gap in drug design and discovery - experimental and computational perspective.

Science.gov (United States)

Balmith, Marissa; Faya, Mbuso; Soliman, Mahmoud E S

2017-03-01

The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the Ebola virus. © 2016 John Wiley & Sons A/S.

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- ...

Some thoughts on the future of probabilistic structural design of nuclear components

International Nuclear Information System (INIS)

Stancampiano, P.A.

1978-01-01

This paper presents some views on the future role of probabilistic methods in the structural design of nuclear components. The existing deterministic design approach is discussed and compared to the probabilistic approach. Some of the objections to both deterministic and probabilistic design are listed. Extensive research and development activities are required to mature the probabilistic approach suficiently to make it cost-effective and competitive with current deterministic design practices. The required research activities deal with probabilistic methods development, more realistic casual failure mode models development, and statistical data models development. A quasi-probabilistic structural design approach is recommended which accounts for the random error in the design models. (Auth.)

Media milling process optimization for manufacture of drug nanoparticles using design of experiments (DOE).

Science.gov (United States)

Nekkanti, Vijaykumar; Marwah, Ashwani; Pillai, Raviraj

2015-01-01

Design of experiments (DOE), a component of Quality by Design (QbD), is systematic and simultaneous evaluation of process variables to develop a product with predetermined quality attributes. This article presents a case study to understand the effects of process variables in a bead milling process used for manufacture of drug nanoparticles. Experiments were designed and results were computed according to a 3-factor, 3-level face-centered central composite design (CCD). The factors investigated were motor speed, pump speed and bead volume. Responses analyzed for evaluating these effects and interactions were milling time, particle size and process yield. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert® to evaluate both the repeatability and reproducibility of bead milling technique. Milling time was optimized to process variables by applying DOE resulted in considerable decrease in milling time to achieve the desired particle size. The study indicates the applicability of DOE approach to optimize critical process parameters in the manufacture of drug nanoparticles.

Hypothesis driven drug design: improving quality and effectiveness of the design-make-test-analyse cycle.

Science.gov (United States)

Plowright, Alleyn T; Johnstone, Craig; Kihlberg, Jan; Pettersson, Jonas; Robb, Graeme; Thompson, Richard A

2012-01-01

In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas. Key improvements include enhancing multi-disciplinary input into 'Design', increasing the use of knowledge and reducing cycle times in 'Make', providing parallel sets of relevant data within ten working days in 'Test' and maximising the learning in 'Analyse'. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

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.

Site Identification by Ligand Competitive Saturation (SILCS) Simulations for Fragment-Based Drug Design

OpenAIRE

Faller, Christina E.; Raman, E. Prabhu; MacKerell, Alexander D.; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules (“fragments”) that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind non-overlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR ...

Recreational drugs. Societal and professional issues.

Science.gov (United States)

Solari-Twadell, P A

1991-06-01

Recreational drug use presents a challenge to society and, in particular, the profession of nursing. Recreational drug use must be appreciated for the implications it presents for the episodes of abuse and development of chronic health problems. The effects and recreational use of volatile substances, cannabis, opioids, barbiturates, benzodiazepines, amphetamines, cocaine, psychedelics, and designer drugs as well as alcohol, caffeine, and nicotine must be acknowledged and understood if options for change are to be considered. The resultant cost of recreational drug use as well as health care implications, public safety, and prevention are significant issues society is faced with today. These issues will continue to be significant unless the current posture toward recreational drug use and abuse is addressed. The profession of nursing continues to be faced with the problems associated with recreational drug use not only through caring for clients, but immediately by the effects of recreational drug use on individual professional nurses. To respond effectively, nursing education and nursing research must be challenged to create an emphasis on this focus. Only through this type of multifocal approach will long-term substantial change be affected for the betterment of future generations.

Design and characterisation of matrix tablets of highly water soluble drug

Directory of Open Access Journals (Sweden)

Vijayalakshmi Prakya

2012-04-01

Full Text Available Tramadol HCL is a centrally acting opioid analgesic. Although the drug has a higher plasma half life, the steady state plasma concentration is not achieved with frequent dosing of q.i.d at 6 hour intervals. Therefore, the objective of the present work was to formulate a 100mg strength Tramadol matrix tablets to extend the drug release and thus decrease the dosing frequency and achieve steady state plasma concentration. Initially, preformulation studies were carried out to rule out any incompatibility between the drug and the chosen polymer(s after exposing physical mixtures of the drug and the polymer(s to 40 and deg;C/75% RH for three months. A suitable method was developed for drug estimation at 271nm by a UV double beam spectrophotometer. Next, various batches of tablets were designed using different polymers such as Ethylcellulose, Carnauba wax, HPMC-K100M, Carbopol-974P and Kollidon-SR. Direct compression technique was used except for the formulation containing carnauba wax for which melt granulation was done followed by compression. Formulations F-1 to F-15 contained single polymers in increasing concentrations in drug:polymer ratios of 1:1, 1:2 and 1:3 where it was observed that the drug release extended with increasing polymer concentrations. Carbopol-974P extended drug release better followed by HPMC-K100M and Carnauba wax compared to other polymers. A combination of these polymers was also used at various ratios to get formulations F-16 to F-20 and observed that the polymer combinations controlled drug release better. The type of fillers like lactose and microcrystalline cellulose had no effect on the physiochemical characters as well as on the drug release profiles. The in vitro release data from the best formulation fitted well in Higuchi as well as Peppas model, the and #8216;n and #8217; value, which confirmed that the release mechanism shifted from initial dissolution to later extended diffusion in which both diffusion and erosion

The impact of pharmacophore modeling in drug design.

Science.gov (United States)

Guner, Osman F

2005-07-01

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

Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

Science.gov (United States)

Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

2015-12-01

Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

Anticipating the use of future things: towards a framework for prospective use analysis in innovation design projects.

Science.gov (United States)

Nelson, Julien; Buisine, Stéphanie; Aoussat, Améziane

2013-11-01

Anticipation of future product use is a persistent issue in User-Centered Design. In this paper, we argue that one obstacle to early integration of use analysis in innovation design is overreliance on retrospective use analysis, i.e. that which is based on clear references to existing products or activities. In contrast, innovation design projects are full of uncertainty, leading to a need for prospective analysis. After having described some limitations of prospective use analysis, we contend that creativity tools may be used to assist the anticipation of future product use, by allowing designers to approach the variability of situations of future use in a structured manner rather than by "muddling through". We illustrate the expected benefits of this approach with two case studies, and describe some prospects for future research and practice in ergonomics. Copyright © 2013. Published by Elsevier Ltd.

Instrumentation and control of future sodium cooled fast reactors - Design improvements

International Nuclear Information System (INIS)

Madhusoodanan, K.; Sakthivel, M.; Chellapandi, P.

2013-06-01

India's fast reactor program started with the 40 MWt Fast Breeder Test Reactor. 500 MWe Prototype Fast Breeder Reactor (PFBR) is currently under construction at Kalpakkam. Safety of PFBR is enhanced by improved design features of I and C system. Since the design of Instrumentation and control (I and C) of PFBR, considerable improvements in terms of advancement in technology and indigenization has taken place. Further improvements in I and C is proposed for solving many of the difficulties faced during the design and construction phases of PFBR. Design improvements proposed are covered in this paper which will make the implementation and maintenance of I and C of future SFRs easier. (authors)

Possibilities of 50 years experience application of design activity of 'Energoprojekt-Warsaw' for nuclear energetics in future

International Nuclear Information System (INIS)

Roguska, M.; Grzebula, K.; Patrycy, A.

2000-01-01

The 50 year experience in design activity for energetics can be profitable for Polish nuclear energetics in the future. Especially previous works on nuclear power plant localization, design of nuclear technique objects and system of quality assurance certified (ISO 9001-1994) can give the solid base for design of future nuclear power plant in Poland when needed

Drug delivery interfaces in the 21st century: from science fiction ideas to viable technologies.

Science.gov (United States)

Chertok, Beata; Webber, Matthew J; Succi, Marc D; Langer, Robert

2013-10-07

Early science fiction envisioned the future of drug delivery as targeted micrometer-scale submarines and "cyborg" body parts. Here we describe the progression of the field toward technologies that are now beginning to capture aspects of this early vision. Specifically, we focus on the two most prominent types of systems in drug delivery: the intravascular micro/nano drug carriers for delivery to the site of pathology and drug-loaded implantable devices that facilitate release with the predefined kinetics or in response to a specific cue. We discuss the unmet clinical needs that inspire these designs, the physiological factors that pose difficult challenges for their realization, and viable technologies that promise robust solutions. We also offer a perspective on where drug delivery may be in the next 50 years based on expected advances in material engineering and in the context of future diagnostics.

Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

Science.gov (United States)

Rodrigues, Tiago

2017-11-15

Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

Drugged Driving

Science.gov (United States)

... Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College-Age Adults in 2016 Monitoring the Future 2016 Survey Results Drug and Alcohol Use in College-Age Adults in 2015 View All NIDA Home ...

Troubling Futures: Can Participatory Design Research provide a Constitutive Anthropology for the 21st Century?

Directory of Open Access Journals (Sweden)

Ann Light

2015-10-01

Full Text Available This paper argues there is value in considering participatory design as a form of anthropology at a time when we recognise that we need not only to understand cultures but to change them towards sustainable living. Holding up the democratically-oriented practices of some participatory design research to definitions of anthropology allows the essay to explore the role of intervention in social process. And, challenging definitional boundaries, it examines design as a participatory tool for cultural change, creating and interrogating futures (and the idea of futures. In analysing how designing moves towards change in the world, the paper brings together design research and anthropological concepts to help us better understand and operationalise our interventions and pursue them in a fair and sustainable manner.

Telomerase – future drug target enzyme?

Directory of Open Access Journals (Sweden)

Tomaž Langerholc

2012-06-01

Full Text Available Eucaryotic chromosome endings (telomeres replication problem was solved in the 1980’s by discovery of the telomerase enzyme. The Nobel Prize in Physiology or Medicine was awarded in 2009 for the discovery of telomerase. Altered telomerase expression in cancer, and human dream of eternal youth have accelerated the development of pharmacological telomerase inhibitors and activators. However, after 15 years of development they are still not available on the market. In the present article we reviewed pharmacological agents that target telomerase activity, which have entered clinical trials. Current drugs in development are mostly not intended to be used alone, as telomerase inhibitors under clinical trials are used in combination with the existing chemotherapeutics and anti-telomerase vaccines in combination with immuno-stimulants. Apart from cancer and aging, there are other diseases linked to deregulated activity of telomerase/telomeres and we also discuss technical and legal problems that researchers encounter in developing anti-telomerase therapy. Given the pace of development, first anti-telomerase drugs might appear on the market in the next 5 years.

NMR in structure-based drug design.

Science.gov (United States)

Carneiro, Marta G; Ab, Eiso; Theisgen, Stephan; Siegal, Gregg

2017-11-08

NMR spectroscopy is a powerful technique that can provide valuable structural information for drug discovery endeavors. Here, we discuss the strengths (and limitations) of NMR applications to structure-based drug discovery, highlighting the different levels of resolution and throughput obtainable. Additionally, the emerging field of paramagnetic NMR in drug discovery and recent developments in approaches to speed up and automate protein-observed NMR data collection and analysis are discussed. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Resolution V fractional factorial Design for Screening of factors affecting weakly basic drugs liposomal systems.

Science.gov (United States)

El-Helaly, Sara Nageeb; Habib, Basant A; Abd El-Rahman, Mohamed K

2018-04-21

This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies. Copyright © 2017. Published by Elsevier B.V.

Core-shell designed scaffolds for drug delivery and tissue engineering.

Science.gov (United States)

Perez, Roman A; Kim, Hae-Won

2015-07-01

Scaffolds that secure and deliver therapeutic ingredients like signaling molecules and stem cells hold great promise for drug delivery and tissue engineering. Employing a core-shell design for scaffolds provides a promising solution. Some unique methods, such as co-concentric nozzle extrusion, microfluidics generation, and chemical confinement reactions, have been successful in producing core-shelled nano/microfibers and nano/microspheres. Signaling molecules and drugs, spatially allocated to the core and/or shell part, can be delivered in a controllable and sequential manner for optimal therapeutic effects. Stem cells can be loaded within the core part on-demand, safely protected from the environments, which ultimately affords ex vivo culture and in vivo tissue engineering. The encapsulated cells experience three-dimensional tissue-mimic microenvironments in which therapeutic molecules are secreted to the surrounding tissues through the semi-permeable shell. Tuning the material properties of the core and shell, changing the geometrical parameters, and shaping them into proper forms significantly influence the release behaviors of biomolecules and the fate of the cells. This topical issue highlights the immense usefulness of core-shell designs for the therapeutic actions of scaffolds in the delivery of signaling molecules and stem cells for tissue regeneration and disease treatment. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

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.

Unblocking Blockbusters: Using Boolean Text-Mining to Optimise Clinical Trial Design and Timeline for Novel Anticancer Drugs

Directory of Open Access Journals (Sweden)

Richard J. Epstein

2009-08-01

Full Text Available Two problems now threaten the future of anticancer drug development: (i the information explosion has made research into new target-specific drugs more duplication-prone, and hence less cost-efficient; and (ii high-throughput genomic technologies have failed to deliver the anticipated early windfall of novel first-in-class drugs. Here it is argued that the resulting crisis of blockbuster drug development may be remedied in part by innovative exploitation of informatic power. Using scenarios relating to oncology, it is shown that rapid data-mining of the scientific literature can refine therapeutic hypotheses and thus reduce empirical reliance on preclinical model development and early-phase clinical trials. Moreover, as personalised medicine evolves, this approach may inform biomarker-guided phase III trial strategies for noncytotoxic (antimetastatic drugs that prolong patient survival without necessarily inducing tumor shrinkage. Though not replacing conventional gold standards, these findings suggest that this computational research approach could reduce costly ‘blue skies’ R&D investment and time to market for new biological drugs, thereby helping to reverse unsustainable drug price inflation.

Unblocking Blockbusters: Using Boolean Text-Mining to Optimise Clinical Trial Design and Timeline for Novel Anticancer Drugs

Directory of Open Access Journals (Sweden)

Richard J. Epstein

2009-01-01

Full Text Available Two problems now threaten the future of anticancer drug development: (i the information explosion has made research into new target-specific drugs more duplication-prone, and hence less cost-efficient; and (ii high-throughput genomic technologies have failed to deliver the anticipated early windfall of novel first-in-class drugs. Here it is argued that the resulting crisis of blockbuster drug development may be remedied in part by innovative exploitation of informatic power. Using scenarios relating to oncology, it is shown that rapid data-mining of the scientific literature can refine therapeutic hypotheses and thus reduce empirical reliance on preclinical model development and early-phase clinical trials. Moreover, as personalised medicine evolves, this approach may inform biomarker-guided phase III trial strategies for noncytotoxic (antimetastatic drugs that prolong patient survival without necessarily inducing tumor shrinkage. Though not replacing conventional gold standards, these findings suggest that this computational research approach could reduce costly ‘blue skies’ R&D investment and time to market for new biological drugs, thereby helping to reverse unsustainable drug price inflation.

Skin Permeation Enhancers and their Effects on Narcotic Transdermal Drug Delivery Systems through Response Surface Experimental Design

Directory of Open Access Journals (Sweden)

A. Moghimi

2014-02-01

Full Text Available Drug delivery through skin is often obstructed by low permeability of skin towards most drugs; however, such problem would be solved by application of skin penetration enhancers in the formulations. In the present study, a drug in adhesive patch with buprenorphine as active ingredient was prepared. Drug-in-adhesive transdermal drug delivery systems with different chemical penetration enhancers were designed. For this purpose a response-surface experimental design was used. Response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects of dependent variables such as: the rate of skin permeation and adhesion properties including peel strength and tack value. The parameters such as drug release and adhesion were used as independent variables. Levulinic acid, lauryl alcohol and Tween 80 were used as penetration enhancers. In order to prepare samples, buprenorphine with constant concentration was incorporated into acrylic pressure sensitive adhesive with carboxylic functionality and this mixture was added to chemical penetration enhancer with different concentrations. The results show that the cumulative amount of drug release in presence of Tween 80 is 462.9 ± 0.006 μg so it is higher than cumulative amount of drug release in presence of levulinic acid (357.9 ± 0.005 μg and lauryl alcohol (269.5 ± 0.001 μg. Results of adhesion properties such as peel strength and tack reveal that using levulinic acid and lauryl alcohol will increase peel strength while Tween 80 will decrease it. Besides, the results show that all these permeation enhancers have increased tack values.

Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

Science.gov (United States)

Sun, Qihang

Nanocarriers can minimize the side effects and improve therapeutic efficacy of anticancer drugs. Although some success has been achieved via active or passive drug delivery to tumor cells, the known nanocarriers are far from satisfying therapeutic efficacy expectations. This is because they usually fail in one of the four crucial requirements, that is, to retain drug in blood circulation but release it reliably in tumor cells and to be stealthy in transport in circulation and tumor tissue but sticky upon arrival at the tumor cell. Therefore, the goal of this work is to fabricate nanoassemblies of dendrimers and lipids to address all these challenges. Particularly, nanoassemblies designed and prepared in this work are illustrated to improve the tumor tissue penetration. Examples of dendrimers synthesized in this work are water-insoluble, pH-dependent water-insoluble and water-soluble biodegradable polyester dendrimers. These dendrimers are shown to be encapsulated by commonly used fusogenic and long-circulating lipids to form reliable nanoassemblies. The dendrimer/lipid nanocarriers are used to demonstrate a cascade drug delivery. They are expected to be stable in circulation, due to their appropriately large size, but to release the drug-loaded dendrimers in tumor tissue. The released dendrimers carrying drugs are much smaller and hence expected to have a much deeper penetration throughout the tumor tissue.

Design status of the NLC beam-delivery system and possible future studies

International Nuclear Information System (INIS)

Zimmermann, F.; Bowden, G.; Burke, D.

1996-10-01

The authors outline some highlights in the present design of the beam-delivery and removal system for the Next Linear Collider (NLC), and present a long list of possible or desirable future studies. On several of the listed items work has already been started since the Snowmass workshop. Other studies could be conducted, for example, in the framework of a conceptual design report (CDR)

Crystallography and Drug Design

Indian Academy of Sciences (India)

IAS Admin

is of immense help in developing drugs for specific diseases by targeting molecules ... tions, or selected from a large pool of available libraries and the binding strengths can ... was identified to be caused by a virus named later as the human.

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.

Principal component analysis as a tool for library design: a case study investigating natural products, brand-name drugs, natural product-like libraries, and drug-like libraries.

Science.gov (United States)

Wenderski, Todd A; Stratton, Christopher F; Bauer, Renato A; Kopp, Felix; Tan, Derek S

2015-01-01

Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design.

3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online.

Science.gov (United States)

Coppola, M; Mondola, R

2012-01-05

The illicit marketplace of substances of abuse continually offers for sale legal alternatives to controlled drugs to a large public. In recent years, a new group of designer drugs, the synthetic cathinones, has emerged as a new trend, particularly among young people. The 3,4-methylenedioxypyrovalerone (MDPV), one of this synthetic compounds, caused an international alert for its cardiovascular and neurological toxicity. This substance, sold as bath salts, has caused many serious intoxications and some deaths in several countries. The aim of this paper is summarise the clinical, pharmacological and toxicological information about this new designer drug. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Meningococcal disease and future drug targets

DEFF Research Database (Denmark)

Gammelgaard, L K; Colding, H; Hartzen, S H

2011-01-01

recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets...... for novel neuroprotective adjuvants, which are needed in order to improve the clinical management of meningoencephalitis and patient prognosis....

A Structural View on Medicinal Chemistry Strategies against Drug Resistance.

Science.gov (United States)

Agnello, Stefano; Brand, Michael; Chellat, Mathieu F; Gazzola, Silvia; Riedl, Rainer

2018-05-30

The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibiotic drug design.

Science.gov (United States)

Uda, Narasimha Rao; Upert, Grégory; Angelici, Gaetano; Nicolet, Stefan; Schmidt, Tobias; Schwede, Torsten; Creus, Marc

2014-01-01

The development of resistance to virtually all current antibiotics makes the discovery of new antimicrobial compounds with novel protein targets an urgent challenge. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is an essential metallo-enzyme for growth and proliferation in many bacteria, acting in the desuccinylation of N-succinyl-L,L-diaminopimelic acid (SDAP) in a late stage of the anabolic pathway towards both lysine and a crucial building block of the peptidoglycan cell wall. L-Captopril, which has been shown to exhibit very promising inhibitory activity in vitro against DapE and has attractive drug-like properties, nevertheless does not target DapE in bacteria effectively. Here we show that L-captopril targets only the Zn(2+)-metallo-isoform of the enzyme, whereas the Mn(2+)-enzyme, which is also a physiologically relevant isoform in bacteria, is not inhibited. Our finding provides a rationale for the failure of this promising lead-compound to exhibit any significant antibiotic activity in bacteria and underlines the importance of addressing metallo-isoform heterogeneity in future drug design. Moreover, to our knowledge, this is the first example of metallo-isoform heterogeneity in vivo that provides an evolutionary advantage to bacteria upon drug-challenge.

Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance

Energy Technology Data Exchange (ETDEWEB)

Ghosh,A.; Sridhar, P.; Leshchenko, S.; Hussain, A.; Li, J.; Kovalevsky, A.; Walters, D.; Wedelind, J.; Grum-Tokars, V.; et al.

2006-01-01

Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Angstroms resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development.

Science.gov (United States)

Mátyus, Péter; Chai, Christina L L

2016-06-20

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties.

Science.gov (United States)

Huang, Yuh-Tyng; Tsai, Tong-Rong; Cheng, Chun-Jen; Cham, Thau-Ming; Lai, Tsun-Fwu; Chuo, Wen-Ho

2007-11-01

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2(3) full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T(max) was prolonged (from 0.65 +/- 0.082 hr to 4.83 +/- 1.60 hr) and AUC(0-t) (from 734.88 +/- 230.68 ng/ml.hr to 1153.34 +/- 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.

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.

A New Framework to Evaluate Urban Design Using Urban Microclimatic Modeling in Future Climatic Conditions

Directory of Open Access Journals (Sweden)

Dasaraden Mauree

2018-04-01

Full Text Available Building more energy-efficient and sustainable urban areas that will both mitigate the effects of climate change and anticipate living conditions in future climate scenarios requires the development of new tools and methods that can help urban planners, architects and communities achieve this goal. In the current study, we designed a workflow that links different methodologies developed separately, to derive the energy consumption of a university school campus for the future. Three different scenarios for typical future years (2039, 2069, 2099 were run, as well as a renovation scenario (Minergie-P. We analyzed the impact of climate change on the heating and cooling demand of buildings and determined the relevance of taking into account the local climate in this particular context. The results from the simulations confirmed that in the future, there will be a constant decrease in the heating demand, while the cooling demand will substantially increase. Significantly, it was further demonstrated that when the local urban climate was taken into account, there was an even higher rise in the cooling demand, but also that a set of proposed Minergie-P renovations were not sufficient to achieve resilient buildings. We discuss the implication of this work for the simulation of building energy consumption at the neighborhood scale and the impact of future local climate on energy system design. We finally give a few perspectives regarding improved urban design and possible pathways for future urban areas.

Collaborative Behavioral Management for Drug-Involved Parolees: Rationale and Design of the Step'n Out Study

Science.gov (United States)

Friedmann, Peter D.; Katz, Elizabeth C.; Rhodes, Anne G.; Taxman, Faye S.; O'Connell, Daniel J.; Frisman, Linda K.; Burdon, William M.; Fletcher, Bennett W.; Litt, Mark D.; Clarke, Jennifer; Martin, Steven S.

2008-01-01

This article describes the rationale, study design, and implementation for the Step'n Out study of the Criminal Justice Drug Abuse Treatment Studies. Step'n Out tests the relative effectiveness of collaborative behavioral management of drug-involved parolees. Collaborative behavioral management integrates the roles of parole officers and treatment…

Will growth in cryptomarket drug buying increase the harms of illicit drugs?

Science.gov (United States)

Aldridge, Judith; Stevens, Alex; Barratt, Monica J

2018-05-01

Cryptomarkets-on-line, anonymous market-places for illicit goods and services that specialize mainly in drugs-account for a small but rapidly growing share of the illicit drug market in many countries. Policy responses so far are based generally on the assumption that their rise will only increase drug harms. In this contribution for debate, we question this assumption. We provide a narrative review of the emerging literature connected to drug cryptomarkets. We use MacCoun & Reuter's formula to understand the effect of population-level increases in use on total harm as depending on the level of harm associated with each unit of use. We then consider the potential for cryptomarkets to increase or decrease the harms and benefits related to each unit of drug use, with specific attention to the quality of drugs sold and the non-drug-related harms and benefits for customers. It is likely that cryptomarkets will increase both the amount and the range of substances that are sold. However, we argue that the effects on harms will depend upon whether cryptomarkets also increase the quality and safety of products that are sold, provide harm-reducing information to consumers and reduce transactional conflict involved in drug purchasing. There is an emerging and rapidly growing evidence base connected to the macro and micro harms and benefits of cryptomarkets for drug users. Future researchers should use appropriately matched comparative designs to establish more firmly the differential harms and benefits of sourcing drugs both on- and off-line. While it is unlikely that the on-line drug trade can be eradicated completely, cryptomarkets will respond to regulation and enforcement in ways that have complex, and sometimes unanticipated, effects on both harms and benefits. © 2017 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Projecting the Future for Design Science Research: An Action‐Case Based Analysis

DEFF Research Database (Denmark)

Baskerville, Richard; Pries-Heje, Jan

2015-01-01

and theories appears to be a key challenge. In this paper we commence with a DESRIST paper from 2012 that instantiated design principles in an artifact for a bank. That paper included plans and techniques for future use of its principles (propagation), including prescriptions for a five-phase adoption process...... or theories have stimulated many actual projections. We demonstrate these concepts in a case study of propagation: a chemical manufacturer and service provider that adopted the design principles arising from that 2012 DESRIST banking-based design science research. We conclude that generalizability is too well...

Future product design

DEFF Research Database (Denmark)

Andreasen, Mogens Myrup

1997-01-01

This paper (in form of overheads) formulate new challenges and possibilities for engineering design, utilizing rationalization effect from modularisation, re-use and transparaency.......This paper (in form of overheads) formulate new challenges and possibilities for engineering design, utilizing rationalization effect from modularisation, re-use and transparaency....

Demographic Subgroup Trends among Adolescents in the Use of Various Licit and Illicit Drugs, 1975-2016. Monitoring the Future Occasional Paper Series. Paper 88

Science.gov (United States)

Johnston, Lloyd D.; O'Malley, Patrick M.; Miech, Richard A.; Bachman, Jerald G.; Schulenberg, John E.

2017-01-01

This occasional paper presents national demographic subgroup data for the 1975-2016 Monitoring the Future (MTF) national survey results on 8th , 10th, and 12th graders' use of drugs, alcohol, and tobacco. MTF is funded by the National Institute on Drug Abuse at the National Institutes of Health under a series of investigator-initiated, competitive…

Demographic Subgroup Trends among Adolescents in the Use of Various Licit and Illicit Drugs, 1975-2015. Monitoring the Future Occasional Paper Series. Paper 86

Science.gov (United States)

Johnston, Lloyd D.; O'Malley, Patrick M.; Miech, Richard A.; Bachman, Jerald G.; Schulenberg, John E.

2016-01-01

This occasional paper presents national demographic subgroup data for the 1975-2015 Monitoring the Future (MTF) national survey results on 8th, 10th, and 12th graders' use of drugs, alcohol, and tobacco. MTF is funded by the National Institute on Drug Abuse at the National Institutes of Health under a series of investigator-initiated, competitive…

Demographic Subgroup Trends among Adolescents in the Use of Various Licit and Illicit Drugs, 1975-2014. Monitoring the Future Occasional Paper Series. Paper 83

Science.gov (United States)

Johnston, Lloyd D.; O'Malley, Patrick M.; Miech, Richard A.; Bachman, Jerald G.; Schulenberg, John E.

2015-01-01

This occasional paper presents national demographic subgroup data for the 1975-2014 Monitoring the Future (MTF) national survey results on 8th, 10th, and 12th graders' use of drugs, alcohol, and tobacco. MTF is funded by the National Institute on Drug Abuse at the National Institutes of Health under a series of investigator-initiated, competitive…

Elucidating Concepts in Drug Design through Taste with Natural and Artificial Sweeteners

Science.gov (United States)

Lipchock, James M.; Lipchock, Sarah V.

2016-01-01

Fundamental concepts in biochemistry important for drug design often lack connection to the macroscopic world and can be difficult for students to grasp, particularly those in introductory science courses at the high school and college level. Educational research has shown that multisensory teaching facilitates learning, but teaching at the high…

Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

Science.gov (United States)

Courtney, Colleen; Chatterjee, Anushree

2014-03-01

``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

Design Innovations and Implementation Challenges - A Case of Smart Textiles in Future Hospital Interiors

DEFF Research Database (Denmark)

Mogensen, Jeppe; Jørgensen, Poul-Erik; Poulsen, Søren Bolvig

2014-01-01

Concerned with the overall challenges of implementing design innovations, this paper relates to the specific case of applying smart textiles in future hospital interiors. The methodological approach is inspired by design thinking and implementation processes, and through the scope of a developed ...

Design and fabrication of a magnetically actuated non-invasive reusable drug delivery device.

Science.gov (United States)

Dsa, Joyline; Goswami, Manish; Singh, B R; Bhatt, Nidhi; Sharma, Pankaj; Chauhan, Meenakshi K

2018-07-01

We present a novel approach of designing and fabricating a noninvasive drug delivery device which is capable of delivering the drug to the target site in a controlled manner. The device utilizes a reservoir which can be reused once the drug has completely diffused from it. This micro-reservoir based fabricated device has been successfully tested using niosomes of insulin drug filled in, which was then sealed with a magnetic membrane of 20 µm thick and was actuated by applying magnetic field. The deflection of the membrane on application of magnetic field results in the drug release from the reservoir. The discharge of the drug solution and the release rates was controlled by external magnetic field. The simulation of the membrane deflection using COMSOL software was carried out to optimize the concentration of the ferrous nanopowder in PDMS matrix. The characterization of the devices was implemented in-vitro on water and in-vivo on Wistar rats. It was also validated using high-performance liquid chromatography (HPLC) by observing characteristic peak of insulin. The blood samples showed the retention time of 2.79 min at λ max of 280 nm which further authenticated the effectiveness of the proposed work. This noninvasive fabricated device provides reusability, precise control and can enable the patient or a physician to actively administrate the drug when required.

The national drug abuse treatment clinical trials network data share project: website design, usage, challenges, and future directions.

Science.gov (United States)

Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; Wu, Li-Tzy; Vanveldhuisen, Paul

2013-01-01

There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the 'gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website

Drug design based on x-ray diffraction and steered molecular dynamics

Czech Academy of Sciences Publication Activity Database

Hašek, Jindřich; Skálová, Tereza; Dohnálek, Jan; Dušková, Jarmila; Petroková, Hana; Vondráčková, Eva; Zimmermann, K.

2005-01-01

Roč. 12, č. 3 (2005), s. 208-210 ISSN 1211-5894. [VUFB Conference on Modern Methods in Synthesis and Analysis of Active Pharmaceutical Substances /5./. Praha, 23.11.2005-24.11.2005] R&D Projects: GA AV ČR KJB4050312 Institutional research plan: CEZ:AV0Z40500505 Keywords : drug design * X-ray diffraction * steered molecular dynamics Subject RIV: CF - Physical ; Theoretical Chemistry

Abuse liability of novel 'legal high' designer stimulants: evidence from animal models.

Science.gov (United States)

Watterson, Lucas R; Watterson, Elizabeth; Olive, Michael Foster

2013-09-01

In the last few years, the variety and recreational use of 'legal high' designer stimulants has increased to unprecedented levels. Since their rapid emergence in drug markets, numerous adverse physical and psychological effects have been extensively reported. However, less is understood about the potential for compulsive use of and addiction to these drugs. Recently, a small collection of scientific studies assessing the abuse liability of these drugs has emerged. This new knowledge has been derived primarily from animal studies using behaviorally based procedures which include intravenous self-administration, conditioned place preference, intracranial self-stimulation, and drug discrimination. In this review we present a brief history of the recent rise in designer stimulant use followed by a short methodological description of the aforementioned procedures. We then review neurochemical and abuse liability studies on designer stimulants that have been examined to date. Finally, we conclude with a discussion of these collective findings, our current understanding of the abuse liability of these drugs in relation to each other and the illicit drugs they are designed to mimic, and recommend future research directions.

Attributions, future time perspective and career maturity in nursing undergraduates: correlational study design.

Science.gov (United States)

Cheng, Cheng; Yang, Liu; Chen, Yuxia; Zou, Huijing; Su, Yonggang; Fan, Xiuzhen

2016-01-25

Career maturity is an important parameter as nursing undergraduates prepare for their future careers. However, little is known regarding the relationships between attributions, future time perspective and career maturity among nursing undergraduates. The purpose of this study was to investigate the degree of career maturity and its relationship with attributions and future time perspective. A cross-sectional survey was designed. This survey was administered to 431 Chinese nursing undergraduates. Independent-sample t-tests and one-way ANOVA were performed to examine the mean differences between categories of binary and categorical demographic characteristics, respectively. Pearson correlations and multiple linear regressions were used to test the relationships between attributions, future time perspective and career maturity. The degree of career maturity was moderate among nursing undergraduates and that internal attributions of academic achievement, future efficacy and future purpose consciousness were positively associated with career maturity (all p time perspective and to facilitate their transition from school to clinical practice.

The Future of Organization Design: An Interpretative Synthesis in Three Themes

Directory of Open Access Journals (Sweden)

Richard M. Burton

2013-04-01

Full Text Available In the inaugural issue of the Journal of Organization Design (Vol. 1, #1, 2012, noted scholars and experienced practitioners presented their views on the future of organization design. The seven wise and provocative statements were subsequently discussed by members of the Organizational Design Community at a conference held at Harvard University on August 3, 2012. I was asked by JOD to monitor the discussion and identify the broad organization design themes that emerged. Although the discussion was wide ranging, three themes were noticeable. The first theme is that there are fundamentals of organization design, and all agreed that design involves creating a cohesive socio-technical system from a number of constituent elements. The second theme is that the boundaries of many newer organizational forms extend beyond that of the single firm, so the scope of organization design needs to expand to include ecosystems, collaborative communities, industries, and other supra-firm architectures. The third theme involves time and change, requiring a shift in focus from how organizations become stable and predictable to how they can become more agile.

Commentary on Future directions: Building technologies and design tools''

Energy Technology Data Exchange (ETDEWEB)

Quadrel, R.W.

1992-08-10

This paper presents a number of interesting and thought-provoking scenarios about the future use of advanced technology in the design and operation of commercial buildings. I will express my reactions in the following series of short paragraphs. These thoughts will, I hope, raise some new questions and offer fruitful directions for further exploration.

Designing Online Instruction for Success: Future Oriented Motivation and Self-Regulation

Science.gov (United States)

Schmidt, Joel T.; Werner, Christian H.

2007-01-01

Given the high rate of student drop-out and withdrawal from courses and programs using an online learning format, it is important to consider innovative ways to foster and encourage student success in online environments. One such way is to incorporate aspects of student future orientation into the design of online instruction. This paper presents…

Designing Futures in Indonesia

OpenAIRE

Alexandra Crosby

2016-01-01

Design is a wide reaching and unruly idea, often associated with seamless global mobility, ubiquitous consumerism, elite urban tastes, and fast paced economic growth. But design is also increasingly understood to be operating at edges, as a necessary response to the ethical and political challenges of advanced global capitalism. Design is both the problem and the solution, and effects everything. As Tony Fry writes ‘Design–the designer and designed objects, images, systems and things–shapes t...

Economic Evaluation of the Juvenile Drug Court/Reclaiming Futures (JDC/RF) Model.

Science.gov (United States)

McCollister, Kathryn; Baumer, Pamela; Davis, Monica; Greene, Alison; Stevens, Sally; Dennis, Michael

2018-07-01

Juvenile drug court (JDC) programs are an increasingly popular option for rehabilitating juvenile offenders with substance problems, but research has found inconsistent evidence regarding their effectiveness and economic impact. While assessing client outcomes such as reduced substance use and delinquency is necessary to gauge program effectiveness, a more comprehensive understanding of program success and sustainability can be attained by examining program costs and economic benefits. As part of the National Cross-Site Evaluation of JDC and Reclaiming Futures (RF), an economic analysis of five JDC/RF programs was conducted from a multisystem and multiagency perspective. The study highlights the direct and indirect costs of JDC/RF and the savings generated from reduced health problems, illegal activity, and missed school days. Results include the average (per participant) cost of JDC/RF, the total economic benefits per JDC/RF participant, and the net savings of JDC/RF relative to standard JDC.

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

Science.gov (United States)

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

2016-01-01

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

DNA nanomaterials for preclinical imaging and drug delivery.

Science.gov (United States)

Jiang, Dawei; England, Christopher G; Cai, Weibo

2016-10-10

Besides being the carrier of genetic information, DNA is also an excellent biological organizer to establish well-designed nanostructures in the fields of material engineering, nanotechnology, and biomedicine. DNA-based materials represent a diverse nanoscale system primarily due to their predictable base pairing and highly regulated conformations, which greatly facilitate the construction of DNA nanostructures with distinct shapes and sizes. Integrating the emerging advancements in bioconjugation techniques, DNA nanostructures can be readily functionalized with high precision for many purposes ranging from biosensors to imaging to drug delivery. Recent progress in the field of DNA nanotechnology has exhibited collective efforts to employ DNA nanostructures as smart imaging agents or delivery platforms within living organisms. Despite significant improvements in the development of DNA nanostructures, there is limited knowledge regarding the in vivo biological fate of these intriguing nanomaterials. In this review, we summarize the current strategies for designing and purifying highly-versatile DNA nanostructures for biological applications, including molecular imaging and drug delivery. Since DNA nanostructures may elicit an immune response in vivo, we also present a short discussion of their potential toxicities in biomedical applications. Lastly, we discuss future perspectives and potential challenges that may limit the effective preclinical and clinical employment of DNA nanostructures. Due to their unique properties, we predict that DNA nanomaterials will make excellent agents for effective diagnostic imaging and drug delivery, improving patient outcome in cancer and other related diseases in the near future. Copyright © 2016 Elsevier B.V. All rights reserved.

Consequences for designer and manufacturer of mechanical components due to future requirements in Europe

International Nuclear Information System (INIS)

Hans-Joachim, Frank

2001-01-01

In the frame of European harmonization, a lot of changes on requirements for designer and manufacturer of mechanical components have been performed. Differed organizations are involved in preparing future requirements for nuclear application. On one side the French German cooperation on the development of EPR. At the origin of this project was the common decision in 1989 of Framatome and Siemens to cooperate through NPI, to design the Nuclear Island, which meets the future needs of utilities. EDF and a group of the main German Utilities joined this cooperation in 1991 and since then they have been totally involved to the progress of the work. In addition, all the process was backed up to the end by the strong cooperation between the French and the German. Safety Authorities, which have a long lasting cooperation to define common requirements, which have to be applied to future Nuclear Power Plants. Furthermore an organization has been set up to elaborate common codes related to the EPR design, at the level of the French design and construction rules (RCC) or the German KTA safety standards, the so-called EPR technical codes (ETC). On the other side, the European utilities co-operate on a much broader basis for the establishment of European Utilities Requirements (EUR). These requirements are prepared by a group of European utilities that represent the major European electricity generating companies that are determined to keep the nuclear option open. The technical requirements specified in the EUR document define the boundaries in which future plants need to be designed in order to be acceptable for the needs of the utilities and in order to fulfill the basic requirements of competitive power generation costs and licensability in all countries represented in the EUR group. All the new requirements have to be applied by designer and manufacturer. Siemens /SNP act as a designer of a lot of various vessels and tanks, heat exchangers and other items of process

Current status and future prospects of Korean standardized nuclear power plant design

International Nuclear Information System (INIS)

Rieh, C.-H.; Park, S.-K.; Lee, B.-R.

1992-01-01

The authors reviewed a brief history of Korean nuclear industry since the first Kori-1 plant operation in 1978 with special emphasis on the NSSS and BOP design and engineering, and the design approaches for nuclear power plants in the future. Continued effort to enhance plant economy and operational safety has been made by increasing plant size, and improving safety features, systems and component reliability in various design aspects. Korean nuclear industry is now trying to be one of the major contributors to the world nuclear field in sharing nuclear technology gained from past experience and developed through internation technical cooperation programs

Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

International Nuclear Information System (INIS)

Makin, Guy; Dive, Caroline

2001-01-01

Drug resistance is a fundamental problem in the treatment of most common human cancers. Our understanding of the cellular mechanisms underlying death and survival has allowed the development of rational approaches to overcoming drug resistance. The mitogen activated protein kinase family of protein serine/threonine kinases has been implicated in this complex web of signalling, with some members acting to enhance death and other members to prevent it. A recent publication by MacKeigan et al is the first to demonstrate an enhancement of drug-induced cell death by simultaneous blockade of MEK-mediated survival signalling, and offers the potential for targeted adjuvant therapy as a means of overcoming drug resistance

Nanomedicine of synergistic drug combinations for cancer therapy - Strategies and perspectives.

Science.gov (United States)

Zhang, Rui Xue; Wong, Ho Lun; Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

2016-10-28

Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

The Semiempirical Quantum Mechanical Scoring Function for In Silico Drug Design

Czech Academy of Sciences Publication Activity Database

Lepšík, Martin; Řezáč, Jan; Kolář, Michal; Pecina, Adam; Hobza, Pavel; Fanfrlík, Jindřich

2013-01-01

Roč. 78, č. 9 (2013), s. 921-931 ISSN 2192-6506 R&D Projects: GA ČR GBP208/12/G016 Grant - others:Operational Program Research and Development for Innovations(XE) CZ 1.05/2.1.00/03/0058 Institutional support: RVO:61388963 Keywords : computational chemistry * drug design * noncovalent interactions * quantum chemistry * semiempirical calculations Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.242, year: 2013

Technical Meeting on Impact of Fukushima Event on Current and Future Fast Reactor Designs. Presentations

International Nuclear Information System (INIS)

2012-01-01

The overall purpose of the Technical Meeting was to recognize and analyse the implications of the accident occurred at the Fukushima Dai-ichi Nuclear Power Station on current and future fast neutron systems design and operation. The aim was to provide a global forum for discussing the principal lessons learned from this event, and thus to review safety principles and characteristics of existing and future fast neutron concepts, especially in relation with extreme natural events which potentially may lead to severe accident scenarios. The participants also presented and discussed innovative technical solutions, design features and countermeasures for design extension conditions - including earthquakes, tsunami and other extreme natural hazards - which can enhance the safety level of existing and future fast neutron systems. Furthermore, the meeting gave the opportunity to present advanced methods for the evaluation of the robustness of plants against design extension conditions. Another important goal of this TM was to discuss how to harmonize safety approaches and goals for next generation’s fast reactors. Finally, the meeting was intended to identify areas where further research and development in nuclear safety, technology and engineering in the light of the Fukushima accident are needed. In the frame of the implementation of its Nuclear Safety Action Plan endorsed by all Member States, the IAEA will consider these areas as potential technical topics for new Coordinated Research Projects, to be launched in the near future

Electricity market design of the future

International Nuclear Information System (INIS)

Peek, Markus; Diels, Robert

2016-01-01

The transformation of the power generation system, to one in which renewable energies will form a cornerstone, will change the requirements for all market actors. To achieve the goals of the German Energiewende ('energy transition'), greater flexibility in production and consumption is of particular importance. Flexibility enables the cost-effective integration of the fluctuating actual feed-in of renewable energies. On the one hand, the technical options for reducing existing technical inflexibilities are given to a considerable extent. On the other hand, analyses of the transnational compensation effects of load and renewable energy supply (RES) feed-in show that flexibility requirements can be reduced significantly in a common electricity market. Electricity markets in which there is open technological competition are an appropriate instrument for the flexibilization of the power supply system. In the short term, the mechanisms of competitive electricity markets ensure an efficient synchronization of supply and demand. Over the medium and long term, the market creates efficient incentives to adapt the generation system and the behavior of consumers to future needs, resulting from the changes in the residual load structure. But at the same time, in recent years the occurrence of negative electricity prices in situations with significantly positive residual loads show that flexibility restraints exist. The causes of these restraints are at least partly due to the market design or the regulatory framework. On the one hand, there are barriers to market entry and, on the other hand, price signals from the electricity markets do not reach all market actors or reach them distortedly. To enable the cost effective development of the different flexibility options in an open technology competition, restraints resulting from market design and the regulatory framework (e. g. in the framework of grid charges, the market and product design of control power markets

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

Directory of Open Access Journals (Sweden)

Helen B. Stone

2016-02-01

Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Design of a Push-Broom Multi-Beam Radiometer for Future Ocean Observations

DEFF Research Database (Denmark)

Cappellin, C.; Pontoppidan, K.; Nielsen, P. H.

2015-01-01

The design of a push-broom multi-beam radiometer for future ocean observations is described. The radiometer provides a sensitivity one order of magnitude higher than a traditional conical scanning radiometer, and has the big advantage of being fully stationary relative to the satellite platform...

Missing Fragments: Detecting Cooperative Binding in Fragment-Based Drug Design

Science.gov (United States)

2012-01-01

The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind to alternate subsites within a given binding pocket leading to cooperative binding when linked. In this study, the binding of fragments to human phenylethanolamine N-methyltransferase is used to illustrate how (a) current protocols may fail to detect fragments that bind cooperatively, (b) theoretical approaches can be used to validate potential hits, and (c) apparent false positives obtained when screening against cocktails of fragments may in fact indicate promising leads. PMID:24900472

New design procedure development of future reactor critical power estimation. (1) Practical design-by-analysis method for BWR critical power design correlation

International Nuclear Information System (INIS)

Yamamoto, Yasushi; Mitsutake, Toru

2007-01-01

For present BWR fuels, the full mock-up thermal-hydraulic test, such as the critical power measurement test, pressure drop measurement test and so on, has been needed. However, the full mock-up test required the high costs and large-scale test facility. At present, there are only a few test facilities to perform the full mock-up thermal-hydraulic test in the world. Moreover, for future BWR, the bundle size tends to be larger, because of reducing the plant construction costs and minimizing the routine check period. For instance, AB1600, improved ABWR, was proposed from Toshiba, whose bundle size was 1.2 times larger than the conventional BWR fuel size. It is too expensive and far from realistic to perform the full mock-up thermal-hydraulic test for such a large size fuel bundle. The new design procedure is required to realize the large scale bundle design development, especially for the future reactor. Therefore, the new design procedure, Practical Design-by-Analysis (PDBA) method, has been developed. This new procedure consists of the partial mock-up test and numerical analysis. At present, the subchannel analysis method based on three-fluid two-phase flow model only is a realistic choice. Firstly, the partial mock-up test is performed, for instance, the 1/4 partial mock-up bundle. Then, the first-step critical power correlation coefficients are evaluated with the measured data. The input data, such as the spacer effect model coefficient, on the subchannel analysis are also estimated with the data. Next, the radial power effect on the critical power of the full-bundle size was estimated with the subchannel analysis. Finally, the critical power correlation is modified by the subchannel analysis results. In the present study, the critical power correlation of the conventional 8x8 BWR fuel was developed with the PDBA method by 4x4 partial mock-up tests and the subchannel analysis code. The accuracy of the estimated critical power was 3.8%. The several themes remain to

The role of water molecules in computational drug design.

Science.gov (United States)

de Beer, Stephanie B A; Vermeulen, Nico P E; Oostenbrink, Chris

2010-01-01

Although water molecules are small and only consist of two different atom types, they play various roles in cellular systems. This review discusses their influence on the binding process between biomacromolecular targets and small molecule ligands and how this influence can be modeled in computational drug design approaches. Both the structure and the thermodynamics of active site waters will be discussed as these influence the binding process significantly. Structurally conserved waters cannot always be determined experimentally and if observed, it is not clear if they will be replaced upon ligand binding, even if sufficient space is available. Methods to predict the presence of water in protein-ligand complexes will be reviewed. Subsequently, we will discuss methods to include water in computational drug research. Either as an additional factor in automated docking experiments, or explicitly in detailed molecular dynamics simulations, the effect of water on the quality of the simulations is significant, but not easily predicted. The most detailed calculations involve estimates of the free energy contribution of water molecules to protein-ligand complexes. These calculations are computationally demanding, but give insight in the versatility and importance of water in ligand binding.

Oral transmucosal drug delivery--current status and future prospects.

Science.gov (United States)

Sattar, Mohammed; Sayed, Ossama M; Lane, Majella E

2014-08-25

Oral transmucosal drug delivery (OTDD) dosage forms have been available since the 1980s. In contrast to the number of actives currently delivered locally to the oral cavity, the number delivered as buccal or sublingual formulations remains relatively low. This is surprising in view of the advantages associated with OTDD, compared with conventional oral drug delivery. This review examines a number of aspects related to OTDD including the anatomy of the oral cavity, models currently used to study OTDD, as well as commercially available formulations and emerging technologies. The limitations of current methodologies to study OTDD are considered as well as recent publications and new approaches which have advanced our understanding of this route of drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

Quality by design case study: an integrated multivariate approach to drug product and process development.

Science.gov (United States)

Huang, Jun; Kaul, Goldi; Cai, Chunsheng; Chatlapalli, Ramarao; Hernandez-Abad, Pedro; Ghosh, Krishnendu; Nagi, Arwinder

2009-12-01

To facilitate an in-depth process understanding, and offer opportunities for developing control strategies to ensure product quality, a combination of experimental design, optimization and multivariate techniques was integrated into the process development of a drug product. A process DOE was used to evaluate effects of the design factors on manufacturability and final product CQAs, and establish design space to ensure desired CQAs. Two types of analyses were performed to extract maximal information, DOE effect & response surface analysis and multivariate analysis (PCA and PLS). The DOE effect analysis was used to evaluate the interactions and effects of three design factors (water amount, wet massing time and lubrication time), on response variables (blend flow, compressibility and tablet dissolution). The design space was established by the combined use of DOE, optimization and multivariate analysis to ensure desired CQAs. Multivariate analysis of all variables from the DOE batches was conducted to study relationships between the variables and to evaluate the impact of material attributes/process parameters on manufacturability and final product CQAs. The integrated multivariate approach exemplifies application of QbD principles and tools to drug product and process development.

Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles.

Science.gov (United States)

Shin, Sangmun; Choi, Du Hyung; Truong, Nguyen Khoa Viet; Kim, Nam Ah; Chu, Kyung Rok; Jeong, Seong Hoon

2011-04-04

A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet. Copyright © 2011 Elsevier B.V. All rights reserved.

Crystals of Human Serum Albumin for Use in Genetic Engineering and Rational Drug Design

Science.gov (United States)

Carter, Daniel C. (Inventor)

1994-01-01

This invention pertains to crystals of serum albumin and processes for growing them. The purpose of the invention is to provide crystals of serum albumin which can be studied to determine binding sites for drugs. Form 2 crystals grow in the monoclinic space P2(sub 1), and possesses the following unit cell constraints: a = 58.9 +/- 7, b = 88.3 +/- 7, c = 60.7 +/- 7, Beta = 101.0 +/- 2 degrees. One advantage of the invention is that it will allow rational drug design

Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs.

Science.gov (United States)

Löscher, Wolfgang

2017-07-01

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function

DEFF Research Database (Denmark)

Holm, R.; Jensen, I.H.M.; Sonnergaard, Jørn

2006-01-01

with the hard gelatin capsule. Three formulation variables, PEG200, a surfactant mixture, and an oil mixture, were included in the experimental design. The results of the mathematical analysis of the data demonstrated significant interactions among the formulation variables, and the desirability function......D-optimal design and the desirability function were applied to optimize a self-microemulsifying drug delivery system (SMEDDS). The optimized key parameters were the following: 1) particle size of the dispersed emulsion, 2) solubility of the drug in the vehicle, and 3) the vehicle compatibility...

Future Technology Workshop: A Collaborative Method for the Design of New Learning Technologies and Activities

Science.gov (United States)

Vavoula, Giasemi N.; Sharples, Mike

2007-01-01

We describe the future technology workshop (FTW), a method whereby people with everyday knowledge or experience in a specific area of technology use (such as using digital cameras) envision and design the interactions between current and future technology and activity. Through a series of structured workshop sessions, participants collaborate to…

Bioinformatics in cancer therapy and drug design

International Nuclear Information System (INIS)

Horbach, D.Y.; Usanov, S.A.

2005-01-01

One of the mechanisms of external signal transduction (ionizing radiation, toxicants, stress) to the target cell is the existence of membrane and intracellular proteins with intrinsic tyrosine kinase activity. No wonder that etiology of malignant growth links to abnormalities in signal transduction through tyrosine kinases. The epidermal growth factor receptor (EGFR) tyrosine kinases play fundamental roles in development, proliferation and differentiation of tissues of epithelial, mesenchymal and neuronal origin. There are four types of EGFR: EGF receptor (ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. Abnormal expression of EGFR, appearance of receptor mutants with changed ability to protein-protein interactions or increased tyrosine kinase activity have been implicated in the malignancy of different types of human tumors. Bioinformatics is currently using in investigation on design and selection of drugs that can make alterations in structure or competitively bind with receptors and so display antagonistic characteristics. (authors)

Bioinformatics in cancer therapy and drug design

Energy Technology Data Exchange (ETDEWEB)

Horbach, D Y [International A. Sakharov environmental univ., Minsk (Belarus); Usanov, S A [Inst. of bioorganic chemistry, National academy of sciences of Belarus, Minsk (Belarus)

2005-05-15

One of the mechanisms of external signal transduction (ionizing radiation, toxicants, stress) to the target cell is the existence of membrane and intracellular proteins with intrinsic tyrosine kinase activity. No wonder that etiology of malignant growth links to abnormalities in signal transduction through tyrosine kinases. The epidermal growth factor receptor (EGFR) tyrosine kinases play fundamental roles in development, proliferation and differentiation of tissues of epithelial, mesenchymal and neuronal origin. There are four types of EGFR: EGF receptor (ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. Abnormal expression of EGFR, appearance of receptor mutants with changed ability to protein-protein interactions or increased tyrosine kinase activity have been implicated in the malignancy of different types of human tumors. Bioinformatics is currently using in investigation on design and selection of drugs that can make alterations in structure or competitively bind with receptors and so display antagonistic characteristics. (authors)

HIV protease drug resistance and its impact on inhibitor design.

Science.gov (United States)

Ala, P J; Rodgers, J D; Chang, C H

1999-07-01

The primary cause of resistance to the currently available HIV protease inhibitors is the accumulation of multiple mutations in the viral protease. So far more than 20 substitutions have been observed in the active site, dimer interface, surface loops and flaps of the homodimer. While many mutations reduce the protease's affinity for inhibitors, others appear to enhance its catalytic efficiency. This high degree of genetic flexibility has made the protease an elusive drug target. The design of the next generation of HIV protease inhibitors will be discussed in light of the current structural information.

Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery

Science.gov (United States)

Logie, Jennifer

Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery has emerged as a strategy to more effectively deliver chemotherapeutics to the tumour site. Specifically, polymeric micelles enable the solubilization of hydrophobic small molecule drugs within the core and mitigate the necessity of excipients. Notwithstanding the significant progress made in polymeric micelle delivery, translation is limited by poor stability and low drug loading. In this work, a rational design approach is used to chemically modify poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG) in order to overcome these limitations and effectively deliver drug to tumours. The PEG density of the polymer system was optimized to enhance the stability of our polymeric micelles. Higher PEG densities permitted the lyophilization of micelles and enhanced the serum stability of the system. To increase the drug loading of our system, we facilitated specific intermolecular interactions within the micelle core. For drugs that form colloidal aggregates, such as pentyl-PABC doxazolidine, polymers were used to stabilize the colloidal core against aggregation and protein adsorption. For more challenging molecules, where self-assembly cannot be controlled, such as docetaxel, we modified the polymeric backbone with a peptide from the binding site of the drug to achieve loadings five times higher than those achieved in conventional micelle systems. This novel docetaxel nanoparticle was assessed in vivo in an orthotopic mouse model of breast cancer, where it showed a wider therapeutic index than the conventional ethanolic polysorbate 80 formulation. The improved tolerability of this formulation enabled higher dosing regimens and led to heightened efficacy and survival in this mouse model. Combined, these studies validated P

An Optimization Model for Expired Drug Recycling Logistics Networks and Government Subsidy Policy Design Based on Tri-level Programming

OpenAIRE

Huang, Hui; Li, Yuyu; Huang, Bo; Pi, Xing

2015-01-01

In order to recycle and dispose of all people’s expired drugs, the government should design a subsidy policy to stimulate users to return their expired drugs, and drug-stores should take the responsibility of recycling expired drugs, in other words, to be recycling stations. For this purpose it is necessary for the government to select the right recycling stations and treatment stations to optimize the expired drug recycling logistics network and minimize the total costs of recycling and disp...

Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations

Science.gov (United States)

Yakovenko, Oleksandr; Jones, Steven J. M.

2018-01-01

We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource (https://drugdesigndata.org/). The challenge was focused on the ligands of the farnesoid X receptor (FXR), a highly flexible nuclear receptor of the cholesterol derivative chenodeoxycholic acid. FXR is considered an important therapeutic target for metabolic, inflammatory, bowel and obesity related diseases (Expert Opin Drug Metab Toxicol 4:523-532, 2015), but in the context of this competition it is also interesting due to the significant ligand-induced conformational changes displayed by the protein. To deal with these conformational changes we employed multiple simulations of molecular dynamics (MD). Our MD-based protocols were top-ranked in estimating the free energy of binding of the ligands and FXR protein. Our approach was ranked second in the prediction of the binding poses where we also combined MD with molecular docking and artificial neural networks. Our approach showed mediocre results for high-throughput scoring of interactions.

Raman spectroscopy in pharmaceutical product design

DEFF Research Database (Denmark)

Paudel, Amrit; Raijada, Dhara; Rantanen, Jukka

2015-01-01

Almost 100 years after the discovery of the Raman scattering phenomenon, related analytical techniques have emerged as important tools in biomedical sciences. Raman spectroscopy and microscopy are frontier, non-invasive analytical techniques amenable for diverse biomedical areas, ranging from...... molecular-based drug discovery, design of innovative drug delivery systems and quality control of finished products. This review presents concise accounts of various conventional and emerging Raman instrumentations including associated hyphenated tools of pharmaceutical interest. Moreover, relevant...... application cases of Raman spectroscopy in early and late phase pharmaceutical development, process analysis and micro-structural analysis of drug delivery systems are introduced. Finally, potential areas of future advancement and application of Raman spectroscopic techniques are discussed....

Terrorism, Drug Trafficking, and the Globalization of Supply

Directory of Open Access Journals (Sweden)

Joel Hernández

2013-08-01

Full Text Available This case study analyzes the diversification of both terrorist groups and drug traffickers and the convergence between the two types of organizations in recent decades. As financial markets have become globalized, so have opportunities for illicit groups to transact with each other. The article builds on the collapse of Lebanese Canadian Bank in 2011 after its designation by the U.S. Treasury Department as a money-laundering financial institution tied to global drug trafficking and to Hezbollah. It follows the trajectory of two Hezbollah-associated drug kingpins: Ayman Joumaa, who facilitated trade between Hezbollah and the Zetas, and Maroun Saade, who was apprehended attempting to connect Hezbollah to the Taliban. In its analysis of the histories, motivations, and relationships among these three groups, the article reflects on relationships currently in existence between terrorist and drug-trafficking organizations, and on the implications of the possible directions these relationships might take in the future.

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure.

Science.gov (United States)

Staud, Frantisek; Cerveny, Lukas; Ceckova, Martina

2012-11-01

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

Future aircraft cabins and design thinking: optimisation vs. win-win scenarios

Directory of Open Access Journals (Sweden)

A. Hall

2013-06-01

Full Text Available With projections indicating an increase in mobility over the next few decades and annual flight departures expected to rise to over 16 billion by 2050, there is a demand for the aviation industry and associated stakeholders to consider new forms of aircraft and technology. Customer requirements are recognized as a key driver in business. The airline is the principal customer for the aircraft manufacture. The passenger is, in turn, the airline's principal customer but they are just one of several stakeholders that include aviation authorities, airport operators, air-traffic control and security agencies. The passenger experience is a key differentiator used by airlines to attract and retain custom and the fuselage that defines the cabin envelope for the in-flight passenger experience and cabin design therefore receives significant attention for new aircraft, service updates and refurbishments. Decision making in design is crucial to arriving at viable and worthwhile cabin formats. Too little innovation will result in an aircraft manufacturer and airlines using its products falling behind its competitors. Too much may result in an over-extension with, for example, use of immature technologies that do not have the necessary reliability for a safety critical industry or sufficient value to justify the development effort. The multiple requirements associated with cabin design, can be viewed as an area for optimisation, accepting trade-offs between the various parameters. Good design, however, is often defined as developing a concept that resolves the contradictions and takes the solution towards a win-win scenario. Indeed our understanding and practice of design allows for behaviors that enhance design thinking through divergence and convergence, the use of abductive reasoning, experimentation and systems thinking. This paper explores and defines the challenges of designing the aircraft cabin of the future that will deliver on the multiple

Frequency and structure of stimulant designer drug consumption among suspected drug users in Budapest and South-East Hungary in 2012-2013.

Science.gov (United States)

Institóris, László; Árok, Zsófia; Seprenyi, Katalin; Varga, Tibor; Sára-Klausz, Gabriella; Keller, Éva; Tóth, Réka A; Sala, Leonardo; Kereszty, Éva; Róna, Kálmán

2015-03-01

Identification of abuse and frequency patterns of stimulant designer drugs (SDDs) provides important information for their risk assessment and legislative control. In the present study urine and/or blood samples of suspected drug users in criminal cases were analysed by GC-MS for 38 SDDs, and for the most frequent illicit and psychoactive licit drugs in Hungary. Between July 2012 and June 2013, 2744 suspected drug users were sampled in Budapest and during 2012 and 2013, 774 persons were sampled in South-East Hungary (Csongrád County - neighbour the Romanian and Serbian borders). In Budapest 71.4% of cases, and in South-East Hungary 61% of cases were positive for at least one substance. Pentedrone was the most frequent SDD in both regions; however, the frequency distribution of the remaining drugs was highly diverse. SDDs were frequently present in combination with other drugs - generally with amphetamine or other stimulants, cannabis and/or benzodiazepines. The quarterly distribution of positive samples indicated remarkable seasonal changes in the frequency and pattern of consumption. Substances placed on the list of illicit drugs (mephedrone, 4-fluoro-amphetamine, MDPV, methylone, 4-MEC) showed a subsequent drop in frequency and were replaced by other SDDs (pentedrone, 3-MMC, methiopropamine, etc.). Newly identified compounds from seized materials were added to the list of new psychoactive substances ("Schedule C"). While the risk assessment of substances listed in Schedule C has to be performed within 2 years after scheduling, continuous monitoring of their presence and frequency among drug users is essential. In summary, our results suggest which substances should be dropped from the list of SDDs measured in biological samples; while the appearance of new substances from seized materials indicate the need for developing adequate standard analytical methods. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Future developments in biliary stenting

Science.gov (United States)

Hair, Clark D; Sejpal, Divyesh V

2013-01-01

Biliary stenting has evolved dramatically over the past 30 years. Advancements in stent design have led to prolonged patency and improved efficacy. However, biliary stenting is still affected by occlusion, migration, anatomical difficulties, and the need for repeat procedures. Multiple novel plastic biliary stent designs have recently been introduced with the primary goals of reduced migration and improved ease of placement. Self-expandable bioabsorbable stents are currently being investigated in animal models. Although not US Food and Drug Administration approved for benign disease, fully covered self-expandable metal stents are increasingly being used in a variety of benign biliary conditions. In malignant disease, developments are being made to improve ease of placement and stent patency for both hilar and distal biliary strictures. The purpose of this review is to describe recent developments and future directions of biliary stenting. PMID:23837001

Magnetically responsive microparticles for targeted drug and radionuclide delivery

International Nuclear Information System (INIS)

Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

2004-01-01

We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 (micro)m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 (micro)m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 (micro)m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

Making the future palpable: Notes from a major incident Future Laboratory

DEFF Research Database (Denmark)

Büscher, Monika; Kristensen, Margit; Mogensen, Preben Holst

2008-01-01

In this paper we describe experiences from a Future Laboratory. Future laboratories allow users to experiment with prototypes of future technologies in as realistic as possible conditions. We have devised this method because, to realize the potential of advanced ubiquitous computing technologies...... it is essential to anticipate and design for future practices, but for prospective users it is often difficult to imagine and articulate future practices and provide design specifications. However, they readily invent new ways of working in engagement with new technologies and, by facilitating realistic use...... of prototype technologies in Future Laboratories, designers and users can define and study both opportunities and constraints for design. We present 11 scenes from a Major Incidents Future Laboratory held in September 2005. Many raise tough questions rather than provide quick answers. In addition, many also...

A basic design of alarm system for the future nuclear power plants in Korea

International Nuclear Information System (INIS)

Lee, Cheol-Kwon; Hur, Seop; Shin, Jae-Hwal; Koo, In-Soo; Park, Jong-Kyun

1997-01-01

The design of an advanced alarm system is under way to apply to the new MMIS for the future nuclear power plants in Korea. Based on the alarm system design bases we established the design requirements and are now refining them with the results of evaluation through the prototype. To realize the advanced system new algorithms for alarm processing and display are implemented and various new devices are examined. The evaluation for the design is performed in accordance with the verification and validation plans and through the prototype. (author). 7 refs, 2 figs

Application of mixture experimental design in formulation and characterization of solid self-nanoemulsifying drug delivery systems containing carbamazepine

OpenAIRE

Krstić Marko Z.; Ibrić Svetlana R.

2016-01-01

One of the problems with orally used drugs is their poor solubility, which can be overcame by creating solid self-nanoemulsifying drug delivery systems (SNEDDS). Aim is choosing appropriate SNEDDS using mixture design and adsorption of SNEDDS on a solid carrier to improve the dissolution rate of carbamazepine. Self-emulsifying drug delivery systems (SEDDS) consisting of oil phase (caprilic-capric triglycerides), a surfactant (Polisorbat 80 and Labrasol® (1:...

Design and construction of a DNA origami drug delivery system based on MPT64 antibody aptamer for tuberculosis treatment.

Science.gov (United States)

Ranjbar, Reza; Hafezi-Moghadam, Mohammad Sadegh

2016-02-01

With all of the developments on infectious diseases, tuberculosis (TB) remains a cause of death among people. One of the most promising assembly techniques in nano-technology is "scaffolded DNA origami" to design and construct a nano-scale drug delivery system. Because of the global health problems of tuberculosis, the development of potent new anti-tuberculosis drug delivery system without cross-resistance with known anti-mycobacterial agents is urgently needed. The aim of this study was to design a nano-scale drug delivery system for TB treatment using the DNA origami method. In this study, we presented an experimental research on a DNA drug delivery system for treating Tuberculosis. TEM images were visualized with an FEI Tecnai T12 BioTWIN at 120 kV. The model was designed by caDNAno software and computational prediction of the 3D solution shape and its flexibility was calculated with a CanDo server. Synthesizing the product was imaged using transmission electron microscopy after negative-staining by uranyl formate. We constructed a multilayer 3D DNA nanostructure system by designing square lattice geometry with the scaffolded-DNA-origami method. With changes in the lock and key sequences, we recommend that this system be used for other infectious diseases to target the pathogenic bacteria.

A role for fragment-based drug design in developing novel lead compounds for central nervous system targets

Directory of Open Access Journals (Sweden)

Michael J. Wasko

2015-09-01

Full Text Available Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacologic screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening, which employs computer models of the target protein to narrow the search for possible leads. A variant of virtual screening is fragment-based drug design, an emerging in silico lead discovery method that introduces low molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for growing the lead candidate. Current efforts in virtual fragment-based drug design within central nervous system (CNS targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor binding pocket using the fragment as a scaffold. This process places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies.

Future developments in biliary stenting

Directory of Open Access Journals (Sweden)

Hair CD

2013-06-01

Full Text Available Clark D Hair,1 Divyesh V Sejpal21Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA; 2Department of Medicine, Section of Gastroenterology, Hofstra North Shore-LIJ School of Medicine, North Shore University Hospital, Manhasset, NY, USAAbstract: Biliary stenting has evolved dramatically over the past 30 years. Advancements in stent design have led to prolonged patency and improved efficacy. However, biliary stenting is still affected by occlusion, migration, anatomical difficulties, and the need for repeat procedures. Multiple novel plastic biliary stent designs have recently been introduced with the primary goals of reduced migration and improved ease of placement. Self-expandable bioabsorbable stents are currently being investigated in animal models. Although not US Food and Drug Administration approved for benign disease, fully covered self-expandable metal stents are increasingly being used in a variety of benign biliary conditions. In malignant disease, developments are being made to improve ease of placement and stent patency for both hilar and distal biliary strictures. The purpose of this review is to describe recent developments and future directions of biliary stenting.Keywords: plastic stents, self-expandable metal stents, drug eluting stents, bioabsorbable stents, malignant biliary strictures, benign biliary strictures