WorldWideScience

Sample records for on-demand drug design

  1. On-demand microbicide products: design matters.

    Science.gov (United States)

    Patel, Sravan Kumar; Rohan, Lisa Cencia

    2017-12-01

    Sexual intercourse (vaginal and anal) is the predominant mode of human immunodeficiency virus (HIV) transmission. Topical microbicides used in an on-demand format (i.e., immediately before or after sex) can be part of an effective tool kit utilized to prevent sexual transmission of HIV. The effectiveness of prevention products is positively correlated with adherence, which is likely to depend on user acceptability of the product. The development of an efficacious and acceptable product is therefore paramount for the success of an on-demand product. Acceptability of on-demand products (e.g., gels, films, and tablets) and their attributes is influenced by a multitude of user-specific factors that span behavioral, lifestyle, socio-economic, and cultural aspects. In addition, physicochemical properties of the drug, anatomical and physiological aspects of anorectal and vaginal compartments, issues relating to large-scale production, and cost can impact product development. These factors together with user preferences determine the design space of an effective, acceptable, and feasible on-demand product. In this review, we summarize the interacting factors that together determine product choice and its target product profile.

  2. Magnetically induced localized on-demand drug delivery

    NARCIS (Netherlands)

    Rovers, S.A.

    2010-01-01

    Externally triggered on-demand drug release from an implant can significantly improve the efficiency of the drug therapy since it enables the patient or physician to control the dosing to the patient’s needs and releases the drug only at the required location in the human body. Therefore, patient

  3. Pharmacy on demand: New technologies to enable miniaturized and mobile drug manufacturing.

    Science.gov (United States)

    Lewin, John J; Choi, Eugene J; Ling, Geoffrey

    2016-01-15

    Developmental pharmaceutical manufacturing systems and techniques designed to overcome the shortcomings of traditional batch processing methods are described. Conventional pharmaceutical manufacturing processes do not adequately address the needs of military and civilian patient populations and healthcare providers. Recent advances within the Defense Advanced Research Projects Agency (DARPA) Battlefield Medicine program suggest that miniaturized, flexible platforms for end-to-end manufacturing of pharmaceuticals are possible. Advances in continuous-flow synthesis, chemistry, biological engineering, and downstream processing, coupled with online analytics, automation, and enhanced process control measures, pave the way for disruptive innovation to improve the pharmaceutical supply chain and drug manufacturing base. These new technologies, along with current and ongoing advances in regulatory science, have the future potential to (1) permit "on demand" drug manufacturing on the battlefield and in other austere environments, (2) enhance the level of preparedness for chemical, biological, radiological, and nuclear threats, (3) enhance health authorities' ability to respond to natural disasters and other catastrophic events, (4) minimize shortages of drugs, (5) address gaps in the orphan drug market, (6) support and enable the continued drive toward precision medicine, and (7) enhance access to needed medications in underserved areas across the globe. Modular platforms under development by DARPA's Battlefield Medicine program may one day improve the safety, efficiency, and timeliness of drug manufacturing. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  4. Knowledge acquisition and interface design for learning on demand systems

    Science.gov (United States)

    Nelson, Wayne A.

    1993-01-01

    The rapid changes in our world precipitated by technology have created new problems and new challenges for education and training. A knowledge 'explosion' is occurring as our society moves toward a service oriented economy that relies on information as the major resource. Complex computer systems are beginning to dominate the workplace, causing alarming growth and change in many fields. The rapidly changing nature of the workplace, especially in fields related to information technology, requires that our knowledge be updated constantly. This characteristic of modern society poses seemingly unsolvable instructional problems involving coverage and obsolescence. The sheer amount of information to be learned is rapidly increasing, while at the same time some information becomes obsolete in light of new information. Education, therefore, must become a lifelong process that features learning of new material and skills as needed in relation to the job to be done. Because of the problems cited above, the current model of learning in advance may no longer be feasible in our high-technology world. In many cases, learning in advance is impossible because there are simply too many things to learn. In addition, learning in advance can be time consuming, and often results in decontextualized knowledge that does not readily transfer to the work environment. The large and growing discrepancy between the amount of potentially relevant knowledge available and the amount a person can know and remember makes learning on demand an important alternative to current instructional practices. Learning on demand takes place whenever an individual must learn something new in order to perform a task or make a decision. Learning on demand is a promising approach for addressing the problems of coverage and obsolescence because learning is contextualized and integrated into the task environment rather than being relegated to a separate phase that precedes work. Learning on demand allows learners

  5. UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery.

    Science.gov (United States)

    Wang, Lei; Li, Baoqiang; Xu, Feng; Xu, Zheheng; Wei, Daqing; Feng, Yujie; Wang, Yaming; Jia, Dechang; Zhou, Yu

    2017-10-15

    Innovative drug delivery technologies based on smart hydrogels for localized on-demand drug delivery had aroused great interest. To acquire smart UV-crosslinkable chitosan hydrogel for NIR-triggered localized on-demanded drug release, a novel UV-crosslinkable and thermo-responsive chitosan was first designed and synthesized by grafting with poly N-isopropylacrylamide, acetylation of methacryloyl groups and embedding with photothermal carbon. The UV-crosslinkable unit (methacryloyl groups) endowed chitosan with gelation via UV irradiation. The thermo-responsive unit (poly N-isopropylacrylamide) endowed chitosan hydrogel with temperature-triggered volume shrinkage and reversible swelling/de-swelling behavior. The chitosan hybrid hydrogel embedded with photothermal carbon exhibited distinct NIR-triggered volume shrinkage (∼42% shrinkage) in response to temperature elevation as induced by NIR laser irradiation. As a demonstration, doxorubicin release rate was accelerated and approximately 40 times higher than that from non-irradiated hydrogels. The UV-crosslinkable and thermal-responsive hybrid hydrogel served as in situ forming hydrogel-based drug depot is developed for NIR-triggered localized on-demand release. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Ion channel electrophysiology via integrated planar patch-clamp chip with on-demand drug exchange.

    Science.gov (United States)

    Chen, Chang-Yu; Tu, Ting-Yuan; Jong, De-Shien; Wo, Andrew M

    2011-06-01

    Planar patch clamp has revolutionized characterization of ion channel behavior in drug discovery primarily via advancement in high throughput. Lab use of planar technology, however, addresses different requirements and suffers from inflexibility to enable wide range of interrogation via a single cell. This work presents integration of planar patch clamp with microfluidics, achieving multiple solution exchanges for tailor-specific measurement and allowing rapid replacement of the cell-contacting aperture. Studies via endogenously expressed ion channels in HEK 293T cells were commenced to characterize the device. Results reveal the microfluidic concentration generator produces distinct solution/drug combination/concentrations on-demand. Volume-regulated chloride channel and voltage-gated potassium channels in HEK 293T cells immersed in generated solutions under various osmolarities or drug concentrations show unique channel signature under specific condition. Excitation and blockage of ion channels in a single cell was demonstrated via serial solution exchange. Robustness of the reversible bonding and ease of glass substrate replacement were proven via repeated usage of the integrated device. The present approach reveals the capability and flexibility of integrated microfluidic planar patch-clamp system for ion channel assays. Copyright © 2011 Wiley Periodicals, Inc.

  7. Repetitive on-demand drug release from polymeric matrices containing a macroscopic spherical iron core.

    Science.gov (United States)

    Rovers, Stefan A; Kemmere, Maartje F; Keurentjes, Jos T F; Hoogenboom, Richard

    2017-09-15

    A system for multiple on-demand drug release has been prepared that can be activated with an alternating magnetic field as external trigger. The core/shell samples have been developed based on a macroscopic spherical iron core coated with a thermoresponsive polymer, poly(styrene-stat-butyl methacrylate), containing ibuprofen as a model drug. During exposure of the samples to the magnetic field (ON state), the release rate of ibuprofen is significantly increased, up to 35 times the release rate without the magnetic field (OFF state). Using one sample or two samples in line with the magnetic field does not influence the ON/OFF ratio of the system, showing the possibility of using multiple samples to increase and tune the drug dose. Increasing the concentration of ibuprofen in the polymer layer is shown to increase the release rate in both the ON and OFF states. Increasing the size of the iron core and, consequently, decreasing the polymer thickness, was found to only increase the release rate during exposure resulting in higher ON/OFF ratios. The developed on demand drug delivery systems represents a promising development towards on demand drug delivery implants. During my chemical engineering studies, it was only during my master thesis work that I decided to continue with PhD research as I really enjoyed doing original research. When coming to the end of my PhD research under supervision of Prof. Ulrich S. Schubert, I developed the ambition to pursue an academic career. Fortunately, I got the opportunity to stay with Prof. Schubert as project leader for the Dutch Polymer Institute (DPI). Within this position, I supervised ten researchers and was able to start developing my independent research lines. Despite that I now advise students to not stay in the same laboratory, this first position allowed me to gain some initial independence and to publish a large number of papers that has been a great benefit in my further career. After two and a half years I needed a new

  8. Efficacy of a Targeted Drug Delivery on-Demand Bolus Option for Chronic Pain.

    Science.gov (United States)

    Bolash, Robert B; Niazi, Tariq; Kumari, Meera; Azer, Gerges; Mekhail, Nagy

    2018-03-01

    Intrathecal targeted drug delivery systems historically required physician office visits for dose adjustment to manage fluctuating pain. A wireless device now enables patients to supplement their basal intrathecal infusion with a programmed on-demand bolus dose. We sought to quantify the change in oral breakthrough opioid need associated with the use of an intrathecal bolus in comparison to those treated with the basal infusion alone. Demographic, dosage, bolus usage and longevity data were extracted from the historical medical record of 69 patients (18/51 bolus/nonbolus) followed continuously at our center. Medication consumption and Pain Disability Index measures were obtained at baseline and most recent follow-up. Among patients with the bolus option, only 2 (11%; confidence interval [CI] 0% to 26%) continued to require oral opiates to manage breakthrough pain compared to 29 (57%; CI 43% to 71%) without the bolus option. The Pain Disability Index score decreased by 19% in patients with the bolus option and by 25% in those with the basal infusion. Total daily intrathecal opioid intake was 34% lower in the group with the bolus device. Utilizing an intrathecal bolus to treat incident pain was a safe way to manage unpredictable breakthrough pain and may represent a cost-saving opportunity by eliminating the need for oral analgesic medications. © 2017 World Institute of Pain.

  9. Design and control of precision drop-on-demand herbicide application in agricultural robotics

    OpenAIRE

    Urdal, Frode; Utstumo, Trygve; Vatne, Jan Kåre; Ellingsen, Simen Andreas Ådnøy; Gravdahl, Jan Tommy

    2014-01-01

    This is the author’s final, accepted and refereed manuscript to the article. Drop-on-demand weed control is a field of research within Precision Agriculture, where the herbicide application is controlled down to individual droplets. This paper focuses on the fluid dynamics and electronics design of the droplet dispensing. The droplets are formed through an array of nozzles, controlled by two-way solenoid valves. A much used control circuit for opening and closing a soleno...

  10. Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery.

    Science.gov (United States)

    Merino, Sonia; Martín, Cristina; Kostarelos, Kostas; Prato, Maurizio; Vázquez, Ester

    2015-05-26

    Considerable progress in the synthesis and technology of hydrogels makes these materials attractive structures for designing controlled-release drug delivery systems. In particular, this review highlights the latest advances in nanocomposite hydrogels as drug delivery vehicles. The inclusion/incorporation of nanoparticles in three-dimensional polymeric structures is an innovative means for obtaining multicomponent systems with diverse functionality within a hybrid hydrogel network. Nanoparticle-hydrogel combinations add synergistic benefits to the new 3D structures. Nanogels as carriers for cancer therapy and injectable gels with improved self-healing properties have also been described as new nanocomposite systems.

  11. Opportunistic Wireless Charging System Design for an On-Demand Shuttle Service

    Energy Technology Data Exchange (ETDEWEB)

    Meintz, Andrew; Doubleday, Kate; Markel, Tony

    2016-06-29

    System right-sizing is critical to the implementation of in-motion wireless power transfer (WPT) for electric vehicles. This study evaluates potential system designs for an on-demand employee shuttle by determining the required battery size based on the rated power at a variable number of charging locations. Vehicle power and state of charge are simulated over the drive cycle, based on position and velocity data at every second from the existing shuttle. Adding just one WPT location can halve the battery size. Many configurations are capable of self-sustaining with WPT, while others benefit from supplemental stationary charging.

  12. Can Pulsed Electromagnetic Fields Trigger On-Demand Drug Release from High-Tm Magnetoliposomes?

    Directory of Open Access Journals (Sweden)

    Martina Nardoni

    2018-03-01

    Full Text Available Recently, magnetic nanoparticles (MNPs have been used to trigger drug release from magnetoliposomes through a magneto-nanomechanical approach, where the mechanical actuation of the MNPs is used to enhance the membrane permeability. This result can be effectively achieved with low intensity non-thermal alternating magnetic field (AMF, which, however, found rare clinic application. Therefore, a different modality of generating non-thermal magnetic fields has now been investigated. Specifically, the ability of the intermittent signals generated by non-thermal pulsed electromagnetic fields (PEMFS were used to verify if, once applied to high-transition temperature magnetoliposomes (high-Tm MLs, they could be able to efficiently trigger the release of a hydrophilic model drug. To this end, hydrophilic MNPs were combined with hydrogenated soybean phosphatidylcholine and cholesterol to design high-Tm MLs. The release of a dye was evaluated under the effect of PEMFs for different times. The MNPs motions produced by PEMF could effectively increase the bilayer permeability, without affecting the liposomes integrity and resulted in nearly 20% of release after 3 h exposure. Therefore, the current contribution provides an exciting proof-of-concept for the ability of PEMFS to trigger drug release, considering that PEMFS find already application in therapy due to their anti-inflammatory effects.

  13. Can Pulsed Electromagnetic Fields Trigger On-Demand Drug Release from High-Tm Magnetoliposomes?

    Science.gov (United States)

    Nardoni, Martina; Della Valle, Elena; Liberti, Micaela; Relucenti, Michela; Casadei, Maria Antonietta; Paolicelli, Patrizia; Apollonio, Francesca; Petralito, Stefania

    2018-03-27

    Recently, magnetic nanoparticles (MNPs) have been used to trigger drug release from magnetoliposomes through a magneto-nanomechanical approach, where the mechanical actuation of the MNPs is used to enhance the membrane permeability. This result can be effectively achieved with low intensity non-thermal alternating magnetic field (AMF), which, however, found rare clinic application. Therefore, a different modality of generating non-thermal magnetic fields has now been investigated. Specifically, the ability of the intermittent signals generated by non-thermal pulsed electromagnetic fields (PEMFS) were used to verify if, once applied to high-transition temperature magnetoliposomes (high-Tm MLs), they could be able to efficiently trigger the release of a hydrophilic model drug. To this end, hydrophilic MNPs were combined with hydrogenated soybean phosphatidylcholine and cholesterol to design high-Tm MLs. The release of a dye was evaluated under the effect of PEMFs for different times. The MNPs motions produced by PEMF could effectively increase the bilayer permeability, without affecting the liposomes integrity and resulted in nearly 20% of release after 3 h exposure. Therefore, the current contribution provides an exciting proof-of-concept for the ability of PEMFS to trigger drug release, considering that PEMFS find already application in therapy due to their anti-inflammatory effects.

  14. An Opportunistic Wireless Charging System Design for an On-Demand Shuttle Service: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Doubleday, Kate; Meintz, Andrew; Markel, Tony

    2016-08-01

    System right-sizing is critical to implementation of in-motion wireless power transfer (WPT) for electric vehicles. This study introduces a modeling tool, WPTSim, which uses one-second speed, location, and road grade data from an on-demand employee shuttle in operation to simulate the incorporation of WPT at fine granularity. Vehicle power and state of charge are simulated over the drive cycle to evaluate potential system designs. The required battery capacity is determined based on the rated power at a variable number of charging locations. Adding just one WPT location can more than halve the battery capacity needed. Many configurations are capable of being self sustaining with WPT, while others benefit from supplemental stationary charging.

  15. Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers.

    Science.gov (United States)

    Nair, Madhavan; Guduru, Rakesh; Liang, Ping; Hong, Jeongmin; Sagar, Vidya; Khizroev, Sakhrat

    2013-01-01

    Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacy-targeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5'-triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe2O4@BaTiO3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

  16. Deep-Learning-Enabled On-Demand Design of Chiral Metamaterials.

    Science.gov (United States)

    Ma, Wei; Cheng, Feng; Liu, Yongmin

    2018-06-11

    Deep-learning framework has significantly impelled the development of modern machine learning technology by continuously pushing the limit of traditional recognition and processing of images, speech, and videos. In the meantime, it starts to penetrate other disciplines, such as biology, genetics, materials science, and physics. Here, we report a deep-learning-based model, comprising two bidirectional neural networks assembled by a partial stacking strategy, to automatically design and optimize three-dimensional chiral metamaterials with strong chiroptical responses at predesignated wavelengths. The model can help to discover the intricate, nonintuitive relationship between a metamaterial structure and its optical responses from a number of training examples, which circumvents the time-consuming, case-by-case numerical simulations in conventional metamaterial designs. This approach not only realizes the forward prediction of optical performance much more accurately and efficiently but also enables one to inversely retrieve designs from given requirements. Our results demonstrate that such a data-driven model can be applied as a very powerful tool in studying complicated light-matter interactions and accelerating the on-demand design of nanophotonic devices, systems, and architectures for real world applications.

  17. Near-infrared induced release for localized on-demand drug delivery

    NARCIS (Netherlands)

    Vertommen, M.A.M.E.

    2009-01-01

    By non-invasive external triggering of drug release from an implant, pulsewise administration can be realized according to the patient’s needs and at specific locations in the human body. In comparison to more traditional delivery forms (e.g. oral or by injection), externally triggered drug release

  18. Video-on-demand network design and maintenance using fuzzy optimization.

    Science.gov (United States)

    Abadpour, Arash; Alfa, Attahiru Sule; Diamond, Jeff

    2008-04-01

    Video-on-demand (VoD) is the entertainment source that, in the future, will likely overtake regular television in many aspects. Although many companies have deployed working VoD services, some aspects of the VoD should still undergo further improvement in order for it to reach to the foreseen potentials. An important aspect of a VoD system is the underlying network in which it operates. According to the huge number of customers in this network, it should be carefully designed to fulfill certain performance criteria. This process should be capable of finding optimal locations for the nodes of the network as well as determining the content that should be cached in each one. While this problem is categorized in the general group of network optimization problems, its specific characteristics demand a new solution to be sought for it. In this paper, which is inspired by the successful use of fuzzy optimization in similar problems in other fields, a fuzzy objective function that is heuristically shown to minimize the communication cost in a VoD network is derived while also controlling the storage cost. Then, an iterative algorithm is proposed to find a locally optimal solution to the proposed objective function. Capitalizing on the unrepeatable tendency of the proposed algorithm, a heuristic method for picking a good solution from a bundle of solutions produced by the proposed algorithm is also suggested. This paper includes a formal statement of the problem and its mathematical analysis. In addition, different scenarios in which the proposed algorithm can be utilized are discussed.

  19. The Design of Passive Optical Networking+Ethernet over Coaxial Cable Access Networking and Video-on-Demand Services Carrying

    Science.gov (United States)

    Ji, Wei

    2013-07-01

    Video on demand is a very attractive service used for entertainment, education, and other purposes. The design of passive optical networking+Ethernet over coaxial cable accessing and a home gateway system is proposed. The network integrates the passive optical networking and Ethernet over coaxial cable to provide high dedicated bandwidth for the metropolitan video-on-demand services. Using digital video broadcasting, IP television protocol, unicasting, and broadcasting mechanisms maximizes the system throughput. The home gateway finishes radio frequency signal receiving and provides three kinds of interfaces for high-definition video, voice, and data, which achieves triple-play and wire/wireless access synchronously.

  20. On Demand Internal Short Circuit Device Enables Verification of Safer, Higher Performing Battery Designs

    Energy Technology Data Exchange (ETDEWEB)

    Darcy, Eric; Keyser, Matthew

    2017-05-15

    The Internal Short Circuit (ISC) device enables critical battery safety verification. With the aluminum interstitial heat sink between the cells, normal trigger cells cannot be driven into thermal runaway without excessive temperature bias of adjacent cells. With an implantable, on-demand ISC device, thermal runaway tests show that the conductive heat sinks protected adjacent cells from propagation. High heat dissipation and structural support of Al heat sinks show high promise for safer, higher performing batteries.

  1. Hybrid Iron Oxide-Graphene Oxide-Polysaccharides Microcapsule: A Micro-Matryoshka for On-demand Drug Release and Antitumor Therapy In Vivo

    KAUST Repository

    Deng, Lin

    2016-02-25

    Premature drug release is a common drawback in stimuli responsive drug delivery systems (DDS) especially if it depends on internal triggers, that are hard to control, or a single external stimulus, that can only have one function. Thus, many DDS systems were reported combining different triggers, however limited success has been established in fine-tuning the release process mainly due to the poor bioavailability and complexity of the reported designs. This paper reports the design of a hybrid microcapsule (h-MC) by a simple layer-by-layer technique comprising polysaccharides (Alg, Chi, HA), iron oxide, and graphene oxide. Electrostatic assembly of the oppositely charged polysaccharides and graphene sheets provided a robust structure to load drugs through pH control. The polysaccharides component ensured high biocompatibility, bioavailability, and tumor cells targeting. Magnetic field and near infrared laser triggerable Fe3O4@GO component provided dual high energy and high penetration hyperthermia therapy. On-demand drug release from h-MC can be achieved by synchronizing these external triggers, making it highly controllable. The synergistic effect of hyperthermia and chemotherapy was successfully confirmed in vitro and in vivo.

  2. [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.

  3. Designing a scalable video-on-demand server with data sharing

    Science.gov (United States)

    Lim, Hyeran; Du, David H. C.

    2001-01-01

    As current disk space and transfer speed increase, the bandwidth between a server and its disks has become critical for video-on-demand (VOD) services. Our VOD server consists of several hosts sharing data on disks through a ring-based network. Data sharing provided by the spatial-reuse ring network between servers and disks not only increases the utilization towards full bandwidth but also improves the availability of videos. Striping and replication methods are introduced in order to improve the efficiency of our VOD server system as well as the availability of videos. We consider tow kinds of resources of a VOD server system. Given a representative access profile, our intention is to propose an algorithm to find an initial condition, place videos on disks in the system successfully. If any copy of a video cannot be placed due to lack of resources, more servers/disks are added. When all videos are place on the disks by our algorithm, the final configuration is determined with indicator of how tolerable it is against the fluctuation in demand of videos. Considering it is a NP-hard problem, our algorithm generates the final configuration with O(M log M) at best, where M is the number of movies.

  4. 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.

  5. 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.

  6. Drug Design and Emotion

    Science.gov (United States)

    Folkers, Gerd; Wittwer, Amrei

    2007-11-01

    "Geteiltes Leid ist halbes Leid." The old German proverb reflects the fact that sharing a bad emotion or feeling with someone else may lower the psychological strain of the person experiencing sorrow, mourning or anger. On the other hand the person showing empathy will take literally a load from its counterpart, up to physiological reaction of the peripheral and central nervous pain system. Though subjective, mental and physical states can be shared. Visual perception of suffering may be important but also narrative description plays a role, all our senses are mixing in. It is hypothetized that literature, art and humanities allow this overlap. A change of mental states can lead to empirically observable effects as it is the case for the effect of role identity or placebo on pain perception. Antidepressants and other therapeutics are another choice to change the mental and bodily states. Their development follows today's notion of "rationality" in the design of therapeutics and is characterized solely by an atomic resolution approach to understand drug activity. Since emotional states and physiological states are entangled, given the difficulty of a physical description of emotion, the future rational drug design should encompass mental states as well.

  7. Designing on-demand education for simultaneous development of domain-specific and self-directed learning skills

    NARCIS (Netherlands)

    Taminiau, E.M.C.; Kester, L.; Corbalan Perez, G.; Spector, J.M.; Kirschner, P.A.; Merriënboer, J.J.G. van

    2015-01-01

    On-demand education enables individual learners to choose their learning pathways according to their own learning needs. They must use self-directed learning (SDL) skills involving self-assessment and task selection to determine appropriate pathways for learning. Learners who lack these skills must

  8. Designing on-demand education for simultaneous development of domain-specific and self-directed learning skills

    NARCIS (Netherlands)

    Taminiau, Bettine; Kester, Liesbeth; Corbalan, Gemma; Spector, J. Michael; Kirschner, Paul A.; Van Merriënboer, Jeroen

    2016-01-01

    On-demand education enables individual learners to choose their learning pathways according to their own learning needs. They must use self-directed learning (SDL) skills involving self-assessment and task selection to determine appropriate pathways for learning. Learners who lack these skills must

  9. On-Demand Telemetry

    Data.gov (United States)

    National Aeronautics and Space Administration — AFRC has previously investigated the use of Network Based Telemetry. We will be building on that research to enable On-Demand Telemetry. On-Demand Telemetry is a way...

  10. 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.

  11. Rational drug design paradigms: the odyssey for designing better drugs.

    Science.gov (United States)

    Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

    2015-01-01

    Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.

  12. Composition-property relationships in multifunctional hollow mesoporous carbon nanosystems for PH-responsive magnetic resonance imaging and on-demand drug release

    Science.gov (United States)

    Zhang, Shengjian; Qian, Xiaoqing; Zhang, Linlin; Peng, Weijun; Chen, Yu

    2015-04-01

    The construction of intelligent stimuli-responsive nanosystems can substantially improve the sensitivity/resolution/specificity of diagnostic imaging and enhance the therapeutic efficiency of chemotherapy for cancer treatment. This work reports on a generic construction strategy to achieve a multiple stimuli-responsive theranostic system for cancer simply by optimizing the chemical compositions of inorganic nanoplatforms to avoid the tedious and complicated synthetic procedure for traditional organic or organic/inorganic nanosystems. Based on the ``breaking up'' nature of manganese oxides and specific features of the carbonaceous framework to interact with aromatic drug molecules, manganese oxide nanoparticles were elaborately integrated into hollow mesoporous carbon nanocapsules by a simple in situ framework redox strategy to realize concurrent pH-sensitive T1-weighted magnetic resonance imaging (MRI) and pH-/HIFU-responsive on-demand drug release. The ultrasensitive disease-triggered MRI performance has been successfully demonstrated by a 52.5-fold increase of longitudinal relaxivity (r1 = 10.5 mM-1 s-1) and on nude mice 4T1 xenograft. The pH- and HIFU-triggered doxorubicin release and enhanced therapeutic outcome against multidrug resistance of cancer cells were systematically confirmed. In particular, the fabricated inorganic composite nanocapsules were found to feature unique biological behaviours, such as antimetastasis effect, extremely low hemolysis against red blood cells and high in vivo histocompatibility. This report on the successful construction of a pure inorganic nanosystem with multiple stimuli-responsivenesses may pave the way to new methods for the development of intelligent nanofamilies for cancer therapy.The construction of intelligent stimuli-responsive nanosystems can substantially improve the sensitivity/resolution/specificity of diagnostic imaging and enhance the therapeutic efficiency of chemotherapy for cancer treatment. This work reports

  13. Education on Demand

    DEFF Research Database (Denmark)

    Boysen, Lis; Hende, Merete

    2015-01-01

    Dette notat beskriver nogle af resultaterne fra programmet "Education on Demand' i projektet Det erhvervsrettede Uddannelseslaboratorium. Programmet har haft fokus på udfordringer og forandringsbehov i uddannelsesinstitutioner og -systemet. Herunder har det beskæftiget sig særligt med de to temat......Dette notat beskriver nogle af resultaterne fra programmet "Education on Demand' i projektet Det erhvervsrettede Uddannelseslaboratorium. Programmet har haft fokus på udfordringer og forandringsbehov i uddannelsesinstitutioner og -systemet. Herunder har det beskæftiget sig særligt med de...

  14. 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...

  15. Electro-Active Polymers (EAPs: A Promising Route to Design Bio-Organic/Bioinspired Platforms with on Demand Functionalities

    Directory of Open Access Journals (Sweden)

    Vincenzo Guarino

    2016-05-01

    Full Text Available Through recent discoveries and new knowledge among correlations between molecular biology and materials science, it is a growing interest to design new biomaterials able to interact—i.e., to influence, to guide or to detect—with cells and their surrounding microenvironments, in order to better control biological phenomena. In this context, electro-active polymers (EAPs are showing great promise as biomaterials acting as an interface between electronics and biology. This is ascribable to the highly tunability of chemical/physical properties which confer them different conductive properties for various applicative uses (i.e., molecular targeting, biosensors, biocompatible scaffolds. This review article is divided into three parts: the first one is an overview on EAPs to introduce basic conductivity mechanisms and their classification. The second one is focused on the description of most common processes used to manipulate EAPs in the form of two-dimensional (2D and three-dimensional (3D materials. The last part addresses their use in current applications in different biomedical research areas including tissue engineering, biosensors and molecular delivery.

  16. Development of self-assembled molecular structures on polymeric surfaces and their applications as ultrasonically responsive barrier coatings for on-demand, pulsatile drug delivery

    Science.gov (United States)

    Kwok, Connie Sau-Kuen

    Nature in the form of DNA, proteins, and cells has the remarkable ability to interact with its environment by processing biological information through specific molecular recognition at the interface. As such, materials that are capable of triggering an appropriate biological response need to be engineered at the biomaterial surface. Chemically and structurally well-defined self-assembled monolayers (SAMs), biomimetics of the lipid bilayer in cell membranes, have been created and studied mostly on rigid metallic surfaces. This dissertation is motivated by the lack of methods to generate a molecularly designed surface for biomedical polymers and thus provides an enabling technology to engineer a polymeric surface precisely at a molecular and cellular level. To take this innovation one step further, we demonstrated that such self-assembled molecular structure coated on drug-containing polymeric devices could act as a stimulus-responsive barrier for controlled drug delivery. A simple, one-step procedure for generating ordered, crystalline methylene chains on polymeric surfaces via urethane linkages was successfully developed. The self-assemblies and molecular structures of these crystalline methylene chains are comparable to the SAM model surfaces, as evidenced by various surface characterization techniques (XPS, TOF-SIMS, and FTIR-ATR). For the first time, these self-assembled molecular structures are shown to function collectively as an ultrasound-responsive barrier membrane for pulsatile drug delivery, including delivery of low-molecular-weight ciprofloxacin and high-molecular-weight insulin. Encouraging results, based on the insulin-activated deoxyglucose uptakes in adipocytes, indicate that the released insulin remained biologically active. Both chemical and acoustic analyses suggest that the ultrasound-assisted release mechanism is primarily induced by transient cavitation, which causes temporary disruption of the self-assembled overlayer, and thus allows

  17. 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.

  18. Design and fabrication of a PET/PTFE-based piezoelectric squeeze mode drop-on-demand inkjet printhead with interchangeable nozzle

    KAUST Repository

    Li, Erqiang

    2010-09-01

    A PET/PTFE-based piezoelectric squeeze mode drop-on-demand inkjet printhead with interchangeable nozzles is designed and fabricated. The printhead chamber is comprised of PET (polyethylene terephthalate) tubing or PTFE (polytetrafluoroethylene, or Teflon) tubing, which of a much softer material, than the conventionally used glass tubing. Applying the same electrical voltage, PET/PTFE-based printhead will generate a larger volume change in the material to be dispensed. The novel printhead fabricated herein has successfully dispensed liquids with viscosities up to 100 cps, as compared to 20 cps for the commercial printheads. Furthermore, PTFE-based printhead provides excellent anti-corrosive property when strongly corrosive inks are involved. The interchangeable nozzle design enables the same printhead to be fitted with nozzles of different orifice size, thus a clogged nozzle can be easily removed for cleaning or replacement. The characteristics of this novel printhead are also studied by dispensing glycerin-water solutions. © 2010 Elsevier B.V. All rights reserved.

  19. PROOF on Demand

    International Nuclear Information System (INIS)

    Malzacher, Peter; Manafov, Anar

    2010-01-01

    PROOF on Demand (PoD) is a set of utilities, which allows starting a PROOF cluster at user request, on any resource management system. It provides a plug-in based system, which allows to use different job submission frontends, such as LSF or gLite WMS. Main components of PoD are the PROOFAgent and the PAConsole. PROOFAgent provides the communication layer between the PROOF master on the local machine and the PROOF workers on the remote resources, possibly behind a firewall. PAConsole provides a user-friendly GUI, which is used to setup, manage, and shutdown the dynamic PROOF cluster. Installation is simple and doesn't require administrator privileges, and all the processes run in user space. PoD gives users, who don't have a centrally-administrated static PROOF cluster at their institute, the possibility to enjoy the full power of interactive analysis with PROOF.

  20. Hybrid Iron Oxide-Graphene Oxide-Polysaccharides Microcapsule: A Micro-Matryoshka for On-demand Drug Release and Antitumor Therapy In Vivo

    KAUST Repository

    Deng, Lin; Li, Qiujin; Al-Rehili, Safa'a; Omar, Haneen; Almalik, Abdulaziz; Alshamsan, Aws; Zhang, Jianfei; Khashab, Niveen M.

    2016-01-01

    microcapsule (h-MC) by a simple layer-by-layer technique comprising polysaccharides (Alg, Chi, HA), iron oxide, and graphene oxide. Electrostatic assembly of the oppositely charged polysaccharides and graphene sheets provided a robust structure to load drugs

  1. 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.

  2. "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...

  3. Drug plan design incentives among Medicare prescription drug plans.

    Science.gov (United States)

    Huskamp, Haiden A; Keating, Nancy L; Dalton, Jesse B; Chernew, Michael E; Newhouse, Joseph P

    2014-07-01

    Medicare Advantage prescription drug plans (MA-PDs) and standalone prescription drug plans (PDPs) face different incentives for plan design resulting from the scope of covered benefits (only outpatient drugs for PDPs versus all drug and nondrug services for Medicare Advantage [MA]/MA-PDs). The objective is to begin to explore how MA-PDs and PDPs may be responding to their different incentives related to benefit design. We compared 2012 PDP and MA-PD average formulary coverage, prior authorization (PA) or step therapy use, and copayment requirements for drugs in 6 classes used commonly among Medicare beneficiaries. We primarily used 2012 Prescription Drug Plan Formulary and Pharmacy Network Files and MA enrollment data. 2011 Truven Health MarketScan claims were used to estimate drug prices and to compute drug market share. Average coverage and PA/step rates, and average copayment requirements, were weighted by plan enrollment and drug market share. MA-PDs are generally more likely to cover and less likely to require PA/step for brand name drugs with generic alternatives than PDPs, and MA-PDs often have lower copayment requirements for these drugs. For brands without generics, we generally found no differences in average rates of coverage or PA/step, but MA-PDs were more likely to cover all brands without generics in a class. We found modest, confirmatory evidence suggesting that PDPs and MA-PDs respond to different incentives for plan design. Future research is needed to understand the factors that influence Medicare drug plan design decisions.

  4. BATMAN: MOS Spectroscopy on Demand

    Science.gov (United States)

    Molinari, E.; Zamkotsian, F.; Moschetti, M.; Spano, P.; Boschin, W.; Cosentino, R.; Ghedina, A.; González, M.; Pérez, H.; Lanzoni, P.; Ramarijaona, H.; Riva, M.; Zerbi, F.; Nicastro, L.; Valenziano, L.; Di Marcantonio, P.; Coretti, I.; Cirami, R.

    2016-10-01

    Multi-Object Spectrographs (MOS) are the major instruments for studying primary galaxies and remote and faint objects. Current object selection systems are limited and/or difficult to implement in next generation MOS for space and ground-based telescopes. A promising solution is the use of MOEMS devices such as micromirror arrays, which allow the remote control of the multi-slit configuration in real time. TNG is hosting a novelty project for real-time, on-demand MOS masks based on MOEMS programmable slits. We are developing a 2048×1080 Digital-Micromirror-Device-based (DMD) MOS instrument to be mounted on the Galileo telescope, called BATMAN. It is a two-arm instrument designed for providing in parallel imaging and spectroscopic capabilities. With a field of view of 6.8×3.6 arcmin and a plate scale of 0.2 arcsec per micromirror, this astronomical setup can be used to investigate the formation and evolution of galaxies. The wavelength range is in the visible and the spectral resolution is R=560 for a 1 arcsec object, and the two arms will have 2k × 4k CCD detectors. ROBIN, a BATMAN demonstrator, has been designed, realized and integrated. We plan to have BATMAN first light by mid-2016.

  5. 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

  6. 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.

  7. 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.

  8. Computer-Aided Drug Design in Epigenetics

    Directory of Open Access Journals (Sweden)

    Wenchao Lu

    2018-03-01

    Full Text Available Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  9. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-01-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field. PMID:29594101

  10. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-03-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  11. 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.…

  12. 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.

  13. LEGO-inspired drug design

    DEFF Research Database (Denmark)

    Thanh Tung, Truong; Dao, Trong Tuan; Grifell Junyent, Marta

    2018-01-01

    The fungal plasma membrane H+-ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure-activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for design...

  14. 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.

  15. 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)

  16. Fabricate-On-Demand Vacuum Insulating Glazings

    Energy Technology Data Exchange (ETDEWEB)

    McCamy, James W. [PPG Industries, Inc., Pittsburgh, PA (United States)

    2017-09-19

    PPG proposed to design a fabricate-on-demand manufacturing process to overcome the cost and supply chain issues preventing widespread adoption of vacuum insulated glazing (VIG) units. To do so, we focused on improving three areas of VIG manufacturing that drive high costs and limit the ability for smaller manufacturers to enter the market: edge sealing, pillar design/placement, and evacuating the VIG.

  17. 21 CFR 316.23 - Timing of requests for orphan-drug designation; designation of already approved drugs.

    Science.gov (United States)

    2010-04-01

    ...) A sponsor may request orphan-drug designation at any time in the drug development process prior to... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Timing of requests for orphan-drug designation..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan...

  18. 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.

  19. In silico fragment-based drug design.

    Science.gov (United States)

    Konteatis, Zenon D

    2010-11-01

    In silico fragment-based drug design (FBDD) is a relatively new approach inspired by the success of the biophysical fragment-based drug discovery field. Here, we review the progress made by this approach in the last decade and showcase how it complements and expands the capabilities of biophysical FBDD and structure-based drug design to generate diverse, efficient drug candidates. Advancements in several areas of research that have enabled the development of in silico FBDD and some applications in drug discovery projects are reviewed. The reader is introduced to various computational methods that are used for in silico FBDD, the fragment library composition for this technique, special applications used to identify binding sites on the surface of proteins and how to assess the druggability of these sites. In addition, the reader will gain insight into the proper application of this approach from examples of successful programs. In silico FBDD captures a much larger chemical space than high-throughput screening and biophysical FBDD increasing the probability of developing more diverse, patentable and efficient molecules that can become oral drugs. The application of in silico FBDD holds great promise for historically challenging targets such as protein-protein interactions. Future advances in force fields, scoring functions and automated methods for determining synthetic accessibility will all aid in delivering more successes with in silico FBDD.

  20. 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

  1. 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.

  2. DataBase on Demand

    International Nuclear Information System (INIS)

    Aparicio, R Gaspar; Gomez, D; Wojcik, D; Coz, I Coterillo

    2012-01-01

    At CERN a number of key database applications are running on user-managed MySQL database services. The database on demand project was born out of an idea to provide the CERN user community with an environment to develop and run database services outside of the actual centralised Oracle based database services. The Database on Demand (DBoD) empowers the user to perform certain actions that had been traditionally done by database administrators, DBA's, providing an enterprise platform for database applications. It also allows the CERN user community to run different database engines, e.g. presently open community version of MySQL and single instance Oracle database server. This article describes a technology approach to face this challenge, a service level agreement, the SLA that the project provides, and an evolution of possible scenarios.

  3. 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.

  4. 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.

  5. 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.

  6. On-Demand Special Use Airspace, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — We design and develope a Decision Support Tool (DST) that supports On-Demand Special Use Airspace (SUA) scheduling and flight plan optimization around SUA between...

  7. On-Demand Special Use Airspace, Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — We design and develop a Decision Support Tool (DST) that supports On-Demand Special Use Airspace (SUA) scheduling and flight plan optimization around SUA between...

  8. 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.

  9. 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

  10. 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.

  11. The Integron: Adaptation On Demand.

    Science.gov (United States)

    Escudero, José Antonio; Loot, Céline; Nivina, Aleksandra; Mazel, Didier

    2015-04-01

    The integron is a powerful system which, by capturing, stockpiling, and rearranging new functions carried by gene encoding cassettes, confers upon bacteria a rapid adaptation capability in changing environments. Chromosomally located integrons (CI) have been identified in a large number of environmental Gram-negative bacteria. Integron evolutionary history suggests that these sedentary CIs acquired mobility among bacterial species through their association with transposable elements and conjugative plasmids. As a result of massive antibiotic use, these so-called mobile integrons are now widespread in clinically relevant bacteria and are considered to be the principal agent in the emergence and rise of antibiotic multiresistance in Gram-negative bacteria. Cassette rearrangements are catalyzed by the integron integrase, a site-specific tyrosine recombinase. Central to these reactions is the single-stranded DNA nature of one of the recombination partners, the attC site. This makes the integron a unique recombination system. This review describes the current knowledge on this atypical recombination mechanism, its implications in the reactions involving the different types of sites, attC and attI, and focuses on the tight regulation exerted by the host on integron activity through the control of attC site folding. Furthermore, cassette and integrase expression are also highly controlled by host regulatory networks and the bacterial stress (SOS) response. These intimate connections to the host make the integron a genetically stable and efficient system, granting the bacteria a low cost, highly adaptive evolution potential "on demand".

  12. Evaluate the interactive and reusable service in adaptive on demand applications

    OpenAIRE

    Hwang , Chyi-Wen

    2007-01-01

    In this paper, the researcher based on the open platforms and tools for personalized learning idea, with the “ Interactive & reusable” function in UI design model, directly dealing with Knowledge on demand (KOD) service from the aspect-oriented and object-oriented issue. Moreover, to propose the KOD combine with VOD (Video on Demand); AOD (Audio on Demand); COD (Course on Demand) and IOD (Information on Demand in Global index searching) in diversity of hypermedia metadata.

  13. On-Demand Urine Analyzer

    Science.gov (United States)

    Farquharson, Stuart; Inscore, Frank; Shende, Chetan

    2010-01-01

    A lab-on-a-chip was developed that is capable of extracting biochemical indicators from urine samples and generating their surface-enhanced Raman spectra (SERS) so that the indicators can be quantified and identified. The development was motivated by the need to monitor and assess the effects of extended weightlessness, which include space motion sickness and loss of bone and muscle mass. The results may lead to developments of effective exercise programs and drug regimes that would maintain astronaut health. The analyzer containing the lab-on-a- chip includes materials to extract 3- methylhistidine (a muscle-loss indicator) and Risedronate (a bone-loss indicator) from the urine sample and detect them at the required concentrations using a Raman analyzer. The lab-on- a-chip has both an extractive material and a SERS-active material. The analyzer could be used to monitor the onset of diseases, such as osteoporosis.

  14. Achieving a Launch on Demand Capability

    Science.gov (United States)

    Greenberg, Joel S.

    2002-01-01

    -orbit availability. Results of an analysis are presented. The implications of launch on demand are addressed for each of the above three situations and related architecture performance metrics and computer simulation models are described that may be used to evaluate the implications of architecture and policy changes in terms of LOD requirements. The models and metrics are aimed at providing answers to such questions as: How well does a specified space transportation architecture respond to satellite launch demand and changes thereto? How well does a normally functioning and apparently architecture respond to unanticipated needs? What is the effect of a modification to the architecture on its ability to respond to satellite launch demand, including responding to unanticipated needs? What is the cost of the architecture [including facilities, operations, inventory, and satellites]? What is the sensitivity of overall architecture effectiveness and cost to various transportation system delays? What is the effect of adding [or eliminating] a launch vehicle or family of vehicles to [from] the architecture on its effectiveness and cost? What is the value of improving launch vehicle and satellite compatibility and what are the effects on probability of delay statistics and cost of designing for multi-launch vehicle compatibility

  15. 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

  16. 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)

  17. 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)

  18. 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.

  19. 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.

  20. A multifunctional multimaterial system for on-demand protein release.

    Science.gov (United States)

    Tuncaboylu, Deniz Ceylan; Friess, Fabian; Wischke, Christian; Lendlein, Andreas

    2018-06-15

    In order to provide best control of the regeneration process for each individual patient, the release of protein drugs administered during surgery may need to be timely adapted and/or delayed according to the progress of healing/regeneration. This study aims to establish a multifunctional implant system for a local on-demand release, which is applicable for various types of proteins. It was hypothesized that a tubular multimaterial container kit, which hosts the protein of interest as a solution or gel formulation, would enable on-demand release if equipped with the capacity of diameter reduction upon external stimulation. Using devices from poly(ɛ-caprolactone) networks, it could be demonstrated that a shape-memory effect activated by heat or NIR light enabled on-demand tube shrinkage. The decrease of diameter of these shape-memory tubes (SMT) allowed expelling the payload as demonstrated for several proteins including SDF-1α, a therapeutically relevant chemotactic protein, to achieve e.g. continuous release with a triggered add-on dosing (open tube) or an on-demand onset of bolus or sustained release (sealed tube). Considering the clinical relevance of protein factors in (stem) cell attraction to lesions and the progress in monitoring biomarkers in body fluids, such on-demand release systems may be further explored e.g. in heart, nerve, or bone regeneration in the future. Copyright © 2018. Published by Elsevier B.V.

  1. 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.

  2. Optimized mine ventilation on demand (OMVOD)

    International Nuclear Information System (INIS)

    Anderson, M.

    2009-01-01

    This paper provided an overview of the Optimized Mine Ventilation on Demand (OMVOD) system that is being installed at Xstrata Nickel Rim South Project and at Vale Inco's Totten Mine in Sudbury. The OMVOD system is designed to dynamically monitor and control air quality and quantity in real time and dilute and remove hazardous substances including diesel particulate matter (DPM), carbon monoxide (CO) and nitrous oxide (NO 2 ). It is also designed to control the thermal environment and provide ventilation for humans as well as mobile equipment engine combustion according to regulatory standards. The paper highlighted the OMVOD system optimization of energy, air quality measurement and control and production management of the mines through real time dynamic automation. Topics of discussion included real-time tracking and monitoring of diesel equipment; real-time tracking of underground miners; real-time evaluation of mine ventilation networks; and real-time control and optimization of ventilation equipment. ABB and Simsmart Technologies have joined forces to provide underground mining customers with a ventilation optimization solution. Simsmart's OMVOD provides proven real time/dynamic automation technology to significantly reduce energy costs, provide health and safety benefits as well as major capital cost savings while realizing an increase in production.

  3. "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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-02-17

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

  5. 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.

  6. 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

  7. Design and Synthesis of Epigenetic Drugs

    DEFF Research Database (Denmark)

    Leurs, Ulrike

    2014-01-01

    of histone- and DNA-modifying enzymes can lead to the development of diseases such as cancer. The histone demethylases of the KDM4 family have been implicated in a wide range of diseases, and are hence important drug targets. KDM4s belong to the bigger family of 2-OG oxygenases, an enzyme class sharing high...

  8. Mobility on Demand Operational Concept Report.

    Science.gov (United States)

    2017-09-10

    This operational concept report provides an overview of the Mobility on Demand (MOD) concept and its evolution, description of the MOD ecosystem in a supply and demand framework, and its stakeholders and enablers. Leveraging the MOD ecosystem framewo...

  9. 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.

  10. Designer Drugs: A Review of Literature Abdulsallam Bakdash

    Directory of Open Access Journals (Sweden)

    Abdulsallam Bakdash

    2015-05-01

    Full Text Available A new phenomenon in the drug market has appeared in recent years: there has been an increase in the number and types of designer drugs. A massive influx of these structural and/or functional analogs of controlled substances has resulted in an increase in their marketing and abuse. At present, these drugs are significantly more widely available compared to previous years because they are relatively inexpensive and marketed as being safer than classic drugs of abuse. The most important factor in the spread of designer drugs is that the majority of these substances are undetectable as drugs or illegal drugs in standard drug testing procedures. The biological effects of these substances are largely unknown to both users and medical scientists. However, most known cases of abuse have shown serious and dangerous physical and psychological reactions in users. The manufacturing and marketing of designer drugs presents a major challenge for specialist sectors, especially laboratories that have to test these substances. This highlights the important role of drugcontrol institutions and regulatory and legislative bodies to determine the legal status of these drugs, which are designed and marketed - mostly through the internet - as being legal. All of these factors make it incumbent upon these sectors to form a unified goal and strategy to control these substances and prevent their spread. This review provides fundamental information about designer drugs. This will provide an accurate overview of their status, and will aid future work to develop a regulatory and legislative strategy to combat their manufacture, marketing, and use.

  11. Microcrystalline identification of selected designer drugs.

    Science.gov (United States)

    Elie, Leonie; Baron, Mark; Croxton, Ruth; Elie, Mathieu

    2012-01-10

    A microcrystalline test for the detection of 4-methylmethcathinone (mephedrone), benzylpiperazine (BZP) and 5,6-methylenedioxy-2-aminoindane (MDAI) using aqueous solutions of mercury chloride is described. Each of the compounds investigated formed specific drug-reagent crystals within minutes. The uniqueness of the test was confirmed by comparison of the microcrystalline response to that of other psychoactive stimulants and a common cutting agent. The limit of detection and cut-off levels for reference standards were established to 3 g/L and 5 g/L for mephedrone, 0.5 g/L for MDAI and 0.2 g/L and 0.3 g/L for BZP, respectively. Various mixtures of standards of either mephedrone, BZP or MDAI combined with caffeine were investigated for their microcrystalline response. Results showed that simultaneous detection of drug and cutting agent was possible with the concentrations tested but were dependant on the ratio of drug to cutting agent. BZP could be detected alongside caffeine from as low as 20% (v/v), MDAI from 40% (v/v) and mephedrone from 50% (v/v) and higher. Finally, seven samples of online purchased 'legal highs' were analysed using the developed test and the findings were compared to FTIR and GC-MS results. It was shown that 6 out of 7 samples did not contain the advertised active ingredient. Five samples consisted of BZP, caffeine and 1-[3-(trifluoromethyl)phenyl]piperazine (3-TFMPP). The microcrystalline tests carried out on these samples showed positive results for both BZP and caffeine without interference from other substances present. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Emergency Physicians' Knowledge of Cannabinoid Designer Drugs

    Directory of Open Access Journals (Sweden)

    Patrick M Lank

    2013-09-01

    Full Text Available Introduction: The use of synthetic drugs of abuse in the United States has grown in the last few years, with little information available on how much physicians know about these drugs and how they are treating patients using them. The objective of this study was to assess emergency physician (EP knowledge of synthetic cannabinoids (SC.Methods: A self-administered internet-based survey of resident and attending EPs at a large urban emergency department (ED was administered to assess familiarity with the terms Spice or K2 and basic knowledge of SC, and to describe some practice patterns when managing SC intoxication in the ED.Results: Of the 83 physicians invited to participate, 73 (88% completed surveys. The terms “Spice” and “K2” for SC were known to 25/73 (34% and 36/73 (49% of respondents. Knowledge of SC came most commonly (72% from non-medical sources, with lay publications and the internet providing most respondents with information. Among those with previous knowledge of synthetic cannabinoids, 25% were not aware that SC are synthetic drugs, and 17% did not know they are chemically most similar to marijuana. Among all participants, 80% felt unprepared caring for a patient in the ED who had used synthetic cannabinoids.Conclusion: Clinically active EPs are unfamiliar with synthetic cannabinoids. Even those who stated they had heard of synthetic cannabinoids answered poorly on basic knowledge questions. More education is needed among EPs of all ages and levels of training on synthetic cannabinoids. [West J Emerg Med. 2013;14(5:467–470.

  13. 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

  14. 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.

  15. 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.

  16. The design of drugs for HIV and HCV.

    Science.gov (United States)

    De Clercq, Erik

    2007-12-01

    Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antiviral drugs, and future treatment strategies for chronic HCV might involve combination regimens that are analogous to those currently used for HIV. By considering the drug targets in the different stages of the life cycle of these two viruses, this article presents aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV, and highlights general lessons learned from anti-HIV-drug design that could be applied to HCV.

  17. Aviation Frontiers: On-Demand Aircraft

    Science.gov (United States)

    Moore, Mark D.

    2010-01-01

    Throughout the 20th Century, NASA has defined the forefront of aeronautical technology, and the aviation industry owes much of its prosperity to this knowledge and technology. In recent decades, centralized aeronautics has become a mature discipline, which raises questions concerning the future aviation innovation frontiers. Three transformational aviation capabilities, bounded together by the development of a Free Flight airspace management system, have the potential to transform 21st Century society as profoundly as civil aviation transformed the 20th Century. These mobility breakthroughs will re-establish environmental sustainable centralized aviation, while opening up latent markets for civil distributed sensing and on-demand rural and regional transportation. Of these three transformations, on-demand aviation has the potential to have the largest market and productivity improvement to society. The information system revolution over the past 20 years shows that vehicles lead, and the interconnecting infrastructure to make them more effective follows; that is, unless on-demand aircraft are pioneered, a distributed Air Traffic Control system will likely never be established. There is no single technology long-pole that will enable on-demand vehicle solutions. However, fully digital aircraft that include electric propulsion has the potential to be a multi-disciplinary initiator of solid state technologies that can provide order of magnitude improvements in the ease of use, safety/reliability, community and environmental friendliness, and affordability.

  18. Bandwidth-on-demand motion control

    NARCIS (Netherlands)

    Van Loon, S.J.L.M.; Hunnekens, B.G.B.; Simon, A.S.; van de Wouw, N.; Heemels, W.P.M.H.

    2018-01-01

    In this brief, we introduce a 'bandwidth-on-demand' variable-gain control (VGC) strategy that allows for a varying bandwidth of the feedback controller. The proposed VGC can achieve improved performance given time-varying, reference-dependent performance requirements compared with linear

  19. Design of an Implantable Device for Ocular Drug Delivery

    Directory of Open Access Journals (Sweden)

    Jae-Hwan Lee

    2012-01-01

    Full Text Available Ocular diseases, such as, glaucoma, age-related macular degeneration (AMD, diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting million of adults in USA and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This study focuses on the design, simulation, and development of an implantable ocular drug delivery device consisting of micro-/nanochannels embedded between top and bottom covers with a drug reservoir made from polydimethylsiloxane (PDMS which is silicon-based organic and biodegradable polymer. Several simulations were carried out with six different micro-channel configurations in order to see the feasibility for ocular drug delivery applications. Based on the results obtained, channel design of osmotic I and osmotic II satisfied the diffusion rates required for ocular drug delivery. Finally, a prototype illustrating the three components of the drug delivery design is presented. In the future, the device will be tested for its functionality and diffusion characteristics.

  20. 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.

  1. 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 .

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.…

  7. 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)…

  8. 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.

  9. New Product Development Based on Demand

    OpenAIRE

    Davis-Krook, Shelby

    2015-01-01

    The purpose of this thesis was to determine how to develop a new product based on demand within a target market for an international company. Specifically looking at developing a new product line in an already developed brand, Alpha Performance. The research I have conducted in the following topics may help Alpha Performance if they choose to use my findings to create a one of a kind woman’s clothing line based on the demands of the Finnish market: target market research, product demand rese...

  10. 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.

  11. 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.

  12. [Effects of the new comprehensive system for designating illegal drug components on the abuse of designer drugs and future problems based on an online questionnaire].

    Science.gov (United States)

    Morino, Taichi; Okazaki, Mitsuhiro; Toda, Takaki; Yokoyama, Takashi

    2015-12-01

    Recently, the abuse of designer drugs has become a social problem. Designer drugs are created by modifying part of the chemical structure of drugs that have already been categorized as illegal, thereby creating a different chemical compound in order to evade Pharmaceutical Affairs Law regulations. The new comprehensive system for designating illegal drug components has been in effect since March 2013, and many designer drugs can now be regulated. We conducted an online questionnaire survey of people with a history of designer drug use to elucidate the effects of the new system on the abuse of designer drugs and to identify potential future problems. Over half the subjects obtained designer drugs only before the new system was implemented. Awareness of the system was significantly lower among subjects who obtained designer drugs for the first time after its introduction than those who obtained the drugs only before its implementation. Due to the new system, all methods of acquiring designer drugs saw decreases in activity. However, the ratio of the acquisition of designer drugs via the Internet increased. Since over 50% of the subjects never obtained designer drugs after the new system was introduced, goals that aimed to make drug procurement more difficult were achieved. However, awareness of the new system among subjects who obtained designer drugs after the new system was introduced was significantly low. Therefore, fostering greater public awareness of the new system is necessary. The results of the questionnaire also suggested that acquiring designer drugs through the Internet has hardly been affected by the new system. We strongly hope that there will be a greater push to restrict the sale of designer drugs on the Internet in the near future.

  13. 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.

  14. 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.

  15. 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...

  16. 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.

  17. 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.

  18. Building a print on demand web service

    Science.gov (United States)

    Reddy, Prakash; Rozario, Benedict; Dudekula, Shariff; V, Anil Dev

    2011-03-01

    There is considerable effort underway to digitize all books that have ever been printed. There is need for a service that can take raw book scans and convert them into Print on Demand (POD) books. Such a service definitely augments the digitization effort and enables broader access to a wider audience. To make this service practical we have identified three key challenges that needed to be addressed. These are: a) produce high quality image images by eliminating artifacts that exist due to the age of the document or those that are introduced during the scanning process b) develop an efficient automated system to process book scans with minimum human intervention; and c) build an eco system which allows us the target audience to discover these books.

  19. 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.

  20. 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...

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Service on demand for ISS users

    Science.gov (United States)

    Hüser, Detlev; Berg, Marco; Körtge, Nicole; Mildner, Wolfgang; Salmen, Frank; Strauch, Karsten

    2002-07-01

    Since the ISS started its operational phase, the need of logistics scenarios and solutions, supporting the utilisation of the station and its facilities, becomes increasingly important. Our contribution to this challenge is a SERVICE On DEMAND for ISS users, which offers a business friendly engineering and logistics support for the resupply of the station. Especially the utilisation by commercial and industrial users is supported and simplified by this service. Our industrial team, consisting of OHB-System and BEOS, provides experience and development support for space dedicated hard- and software elements, their transportation and operation. Furthermore, we operate as the interface between customer and the envisaged space authorities. Due to a variety of tailored service elements and the ongoing servicing, customers can concentrate on their payload content or mission objectives and don't have to deal with space-specific techniques and regulations. The SERVICE On DEMAND includes the following elements: ITR is our in-orbit platform service. ITR is a transport rack, used in the SPACEHAB logistics double module, for active and passive payloads on subrack- and drawer level of different standards. Due to its unique late access and early retrieval capability, ITR increases the flexibility concerning transport capabilities to and from the ISS. RIST is our multi-functional test facility for ISPR-based experiment drawer and locker payloads. The test program concentrates on physical and functional interface and performance testing at the payload developers site prior to the shipment to the integration and launch. The RIST service program comprises consulting, planning and engineering as well. The RIST test suitcase is planned to be available for lease or rent to users, too. AMTSS is an advanced multimedia terminal consulting service for communication with the space station scientific facilities, as part of the user home-base. This unique ISS multimedia kit combines

  6. 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.

  7. 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.

  8. 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.

  9. 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...

  10. 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...

  11. 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.

  12. 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

  13. 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.

  14. On-Demand Cell Internal Short Circuit Device

    Science.gov (United States)

    Darcy, Eric; Keyser, Matthew

    2014-01-01

    A device implantable in Li-ion cells that can generate a hard internal short circuit on-demand by exposing the cell to 60?C has been demonstrated to be valuable for expanding our understanding of cell responses. The device provides a negligible impact to cell performance and enables the instigation of the 4 general categories of cell internal shorts to determine relative severity and cell design susceptibility. Tests with a 18650 cell design indicates that the anode active material short to the aluminum cathode current collector tends to be more catastrophic than the 3 other types of internal shorts. Advanced safety features (such as shutdown separators) to prevent or mitigate the severity of cell internal shorts can be verified with this device. The hard short success rate achieved to date in 18650 cells is about 80%, which is sufficient for using these cells in battery assemblies for field-failure-relevant, cell-cell thermal runaway propagation verification tests

  15. 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.

  16. First drop dissimilarity in drop-on-demand inkjet devices

    International Nuclear Information System (INIS)

    Famili, Amin; Palkar, Saurabh A.; Baldy, William J. Jr.

    2011-01-01

    As inkjet printing technology is increasingly applied in a broader array of applications, careful characterization of its method of use is critical due to its inherent sensitivity. A common operational mode in inkjet technology known as drop-on-demand ejection is used as a way to deliver a controlled quantity of material to a precise location on a target. This method of operation allows ejection of individual or a sequence (burst) of drops based on a timed trigger event. This work presents an examination of sequences of drops as they are ejected, indicating a number of phenomena that must be considered when designing a drop-on-demand inkjet system. These phenomena appear to be driven by differences between the first ejected drop in a burst and those that follow it and result in a break-down of the linear relationship expected between driving amplitude and drop mass. This first drop, as quantified by high-speed videography and subsequent image analysis, can be different in morphology, trajectory, velocity, and volume from subsequent drops within a burst. These findings were confirmed orthogonally by both volume and mass measurement techniques which allowed quantitation down to single drops.

  17. 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.

  18. 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.

  19. 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.

  20. Adjusting process count on demand for petascale global optimization

    KAUST Repository

    Sosonkina, Masha; Watson, Layne T.; Radcliffe, Nicholas R.; Haftka, Rafael T.; Trosset, Michael W.

    2013-01-01

    There are many challenges that need to be met before efficient and reliable computation at the petascale is possible. Many scientific and engineering codes running at the petascale are likely to be memory intensive, which makes thrashing a serious problem for many petascale applications. One way to overcome this challenge is to use a dynamic number of processes, so that the total amount of memory available for the computation can be increased on demand. This paper describes modifications made to the massively parallel global optimization code pVTdirect in order to allow for a dynamic number of processes. In particular, the modified version of the code monitors memory use and spawns new processes if the amount of available memory is determined to be insufficient. The primary design challenges are discussed, and performance results are presented and analyzed.

  1. Optimized ventilation-on-demand (VOD)

    Energy Technology Data Exchange (ETDEWEB)

    Masse, M. [Simsmart Technologies Inc., Brossard, PQ (Canada); Cervinka, A. [Newtrax Technologies Inc., Montreal, PQ (Canada)

    2008-07-01

    This presentation described how the combination of 2 innovative technologies can help optimize mine ventilation. Newtrax Technologies has developed a self-contained battery-powered wireless electronic system designed to operate in harsh industrial environments, including underground mines. Simsmart Technologies has created an advanced process and control simulation based design tool used in industrial applications, including mine ventilation systems. This presentation described the system components and how they work. These included the wireless mesh network designed for dynamic diesel machinery tracking and operating status monitoring; the real-time ventilation model and fan speed optimizer; the OPC server for information interchange; the OPC linkage to existing control infrastructure; a human machine interface that provide data archiving capability; live MS-Excel to interrogate the simulation, controls and optimizer; and, the battery-powered network mesh that provides SCADA functionality to route optimized setpoints. Details of the user interface were also provided. 1 tab., 20 figs.

  2. Biomedical data integration in computational drug design and bioinformatics.

    Science.gov (United States)

    Seoane, Jose A; Aguiar-Pulido, Vanessa; Munteanu, Cristian R; Rivero, Daniel; Rabunal, Juan R; Dorado, Julian; Pazos, Alejandro

    2013-03-01

    In recent years, in the post genomic era, more and more data is being generated by biological high throughput technologies, such as proteomics and transcriptomics. This omics data can be very useful, but the real challenge is to analyze all this data, as a whole, after integrating it. Biomedical data integration enables making queries to different, heterogeneous and distributed biomedical data sources. Data integration solutions can be very useful not only in the context of drug design, but also in biomedical information retrieval, clinical diagnosis, system biology, etc. In this review, we analyze the most common approaches to biomedical data integration, such as federated databases, data warehousing, multi-agent systems and semantic technology, as well as the solutions developed using these approaches in the past few years.

  3. Intrinsic motivation and organizational identification among on-demand workers.

    Science.gov (United States)

    Rockmann, Kevin W; Ballinger, Gary A

    2017-09-01

    On-demand firms provide services for clients through a network of on-demand workers ready to complete specific tasks for a set contractual price. Given such on-demand work is defined by payment on short-term contracts with no obligation for continued employment, there is little reason to believe on-demand workers experience more than extrinsic motivation and a transactional relationship with the on-demand firm. However, using self-determination theory, we argue that to the degree that on-demand work fulfills innate psychological needs individual on-demand workers will develop intrinsic motivation, which further leads to organizational identification with the on-demand firm. Across 2 survey-based studies we find support for this path to organizational identification. This adds to the literature on motivation and identification by strengthening the link between individual needs and the individual-organizational relationship. Implications for theory and for the management of on-demand workers are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  4. Efficient network resource management for multimedia-on-demand services

    Science.gov (United States)

    Kuo, Chinhwa; Chiu, Jui-Hwa; Wu, Jong-Jyh; Chen, Dxo-Shin

    1998-08-01

    A Multimedia Instruction on Demand (MID) serves the purpose of providing an environment for lecture design, lecture annotation, and lecture review over networks. In order to support real-time multimedia interactive playback for such an application, the underlying networks are required to provide network resource management mechanism to enforce the reservation policy. In our design, the MID server and MID gateway consist of the following mechanisms, namely, resource management agent, admission control agent, packet classifier, and packet scheduler. We make use of the framework of the ReSerVation Protocol to devise and implement a network resource management mechanism, which control end-to-end packet delays and bandwidth allocation for the designed MID system. In the present paper, our contributions are as follows: (1) a network resource management scheme is designed to support real-time multimedia over the Internet and (2) an experimental test bed is established to measure the system performance. The developed scheme is currently being implemented in the Multimedia Information Networking laboratory at Tamkang University.

  5. 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…

  6. 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.

  7. Advanced drug delivery systems: Nanotechnology of health design A review

    Directory of Open Access Journals (Sweden)

    Javad Safari

    2014-04-01

    Full Text Available Nanotechnology has finally and firmly entered the realm of drug delivery. Performances of intelligent drug delivery systems are continuously improved with the purpose to maximize therapeutic activity and to minimize undesirable side-effects. This review describes the advanced drug delivery systems based on micelles, polymeric nanoparticles, and dendrimers. Polymeric carbon nanotubes and many others demonstrate a broad variety of useful properties. This review emphasizes the main requirements for developing new nanotech-nology-based drug delivery systems.

  8. Virtual fragment preparation for computational fragment-based drug design.

    Science.gov (United States)

    Ludington, Jennifer L

    2015-01-01

    Fragment-based drug design (FBDD) has become an important component of the drug discovery process. The use of fragments can accelerate both the search for a hit molecule and the development of that hit into a lead molecule for clinical testing. In addition to experimental methodologies for FBDD such as NMR and X-ray Crystallography screens, computational techniques are playing an increasingly important role. The success of the computational simulations is due in large part to how the database of virtual fragments is prepared. In order to prepare the fragments appropriately it is necessary to understand how FBDD differs from other approaches and the issues inherent in building up molecules from smaller fragment pieces. The ultimate goal of these calculations is to link two or more simulated fragments into a molecule that has an experimental binding affinity consistent with the additive predicted binding affinities of the virtual fragments. Computationally predicting binding affinities is a complex process, with many opportunities for introducing error. Therefore, care should be taken with the fragment preparation procedure to avoid introducing additional inaccuracies.This chapter is focused on the preparation process used to create a virtual fragment database. Several key issues of fragment preparation which affect the accuracy of binding affinity predictions are discussed. The first issue is the selection of the two-dimensional atomic structure of the virtual fragment. Although the particular usage of the fragment can affect this choice (i.e., whether the fragment will be used for calibration, binding site characterization, hit identification, or lead optimization), general factors such as synthetic accessibility, size, and flexibility are major considerations in selecting the 2D structure. Other aspects of preparing the virtual fragments for simulation are the generation of three-dimensional conformations and the assignment of the associated atomic point charges.

  9. 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

  10. 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.

  11. Drop-on-Demand System for Manufacturing of Melt-based Solid Oral Dosage: Effect of Critical Process Parameters on Product Quality.

    Science.gov (United States)

    Içten, Elçin; Giridhar, Arun; Nagy, Zoltan K; Reklaitis, Gintaras V

    2016-04-01

    The features of a drop-on-demand-based system developed for the manufacture of melt-based pharmaceuticals have been previously reported. In this paper, a supervisory control system, which is designed to ensure reproducible production of high quality of melt-based solid oral dosages, is presented. This control system enables the production of individual dosage forms with the desired critical quality attributes: amount of active ingredient and drug morphology by monitoring and controlling critical process parameters, such as drop size and product and process temperatures. The effects of these process parameters on the final product quality are investigated, and the properties of the produced dosage forms characterized using various techniques, such as Raman spectroscopy, optical microscopy, and dissolution testing. A crystallization temperature control strategy, including controlled temperature cycles, is presented to tailor the crystallization behavior of drug deposits and to achieve consistent drug morphology. This control strategy can be used to achieve the desired bioavailability of the drug by mitigating variations in the dissolution profiles. The supervisor control strategy enables the application of the drop-on-demand system to the production of individualized dosage required for personalized drug regimens.

  12. 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.

  13. Heuristic lipophilicity potential for computer-aided rational drug design

    Science.gov (United States)

    Du, Qishi; Arteca, Gustavo A.; Mezey, Paul G.

    1997-09-01

    In this contribution we suggest a heuristic molecular lipophilicitypotential (HMLP), which is a structure-based technique requiring noempirical indices of atomic lipophilicity. The input data used in thisapproach are molecular geometries and molecular surfaces. The HMLP is amodified electrostatic potential, combined with the averaged influences fromthe molecular environment. Quantum mechanics is used to calculate theelectron density function ρ(r) and the electrostatic potential V(r), andfrom this information a lipophilicity potential L(r) is generated. The HMLPis a unified lipophilicity and hydrophilicity potential. The interactions ofdipole and multipole moments, hydrogen bonds, and charged atoms in amolecule are included in the hydrophilic interactions in this model. TheHMLP is used to study hydrogen bonds and water-octanol partitioncoefficients in several examples. The calculated results show that the HMLPgives qualitatively and quantitatively correct, as well as chemicallyreasonable, results in cases where comparisons are available. Thesecomparisons indicate that the HMLP has advantages over the empiricallipophilicity potential in many aspects. The HMLP is a three-dimensional andeasily visualizable representation of molecular lipophilicity, suggested asa potential tool in computer-aided three-dimensional drug design.

  14. The ways and means of fragment-based drug design.

    Science.gov (United States)

    Doak, Bradley C; Norton, Raymond S; Scanlon, Martin J

    2016-11-01

    Fragment-based drug design (FBDD) has emerged as a mainstream approach for the rapid and efficient identification of building blocks that can be used to develop high-affinity ligands against protein targets. One of the strengths of FBDD is the relative ease and low cost of the primary screen to identify fragments that bind. However, the fragments that emerge from primary screens often have low affinities, with K D values in the high μM to mM range, and a significant challenge for FBDD is to develop the initial fragments into more potent ligands. Successful fragment elaboration often requires co-structures of the fragments bound to their target proteins, as well as a range of biophysical and biochemical assays to track potency and efficacy. These challenges have led to the development of specific chemical strategies for the elaboration of weakly-binding fragments into more potent "hits" and lead compounds. In this article we review different approaches that have been employed to meet these challenges and describe some of the strategies that have resulted in several fragment-derived compounds entering clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Peptide-based proteasome inhibitors in anticancer drug design.

    Science.gov (United States)

    Micale, Nicola; Scarbaci, Kety; Troiano, Valeria; Ettari, Roberta; Grasso, Silvana; Zappalà, Maria

    2014-09-01

    The identification of the key role of the eukaryotic 26S proteasome in regulated intracellular proteolysis and its importance as a target in many pathological conditions wherein the proteasomal activity is defective (e.g., malignancies, autoimmune diseases, neurodegenerative diseases, etc.) prompted several research groups to the development of specific inhibitors of this multicatalytic complex with the aim of obtaining valid drug candidates. In regard to the anticancer therapy, the peptide boronate bortezomib (Velcade®) represents the first molecule approved by FDA for the treatment of multiple myeloma in 2003 and mantle cell lymphoma in 2006. Since then, a plethora of molecules targeting the proteasome have been identified as potential anticancer agents and a few of them reached clinical trials or are already in the market (i.e., carfilzomib; Kyprolis®). In most cases, the design of new proteasome inhibitors (PIs) takes into account a proven peptide or pseudopeptide motif as a base structure and places other chemical entities throughout the peptide skeleton in such a way to create an efficacious network of interactions within the catalytic sites. The purpose of this review is to provide an in-depth look at the current state of the research in the field of peptide-based PIs, specifically those ones that might find an application as anticancer agents. © 2014 Wiley Periodicals, Inc.

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

    NARCIS (Netherlands)

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

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

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

    African Journals Online (AJOL)

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

  18. 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…

  19. 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...

  20. 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.

  1. 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...

  2. 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.

  3. Access control for on-demand provisioned cloud infrastructure services

    NARCIS (Netherlands)

    Ngo, C.T.

    2016-01-01

    The evolution of Cloud Computing brings advantages to both customers and service providers to utilize and manage computing and network resources more efficiently with virtualization, service-oriented architecture technologies, and automated on-demand resource provisioning. However, these advantages

  4. Vaccines 'on demand': science fiction or a future reality.

    Science.gov (United States)

    Ulmer, Jeffrey B; Mansoura, Monique K; Geall, Andrew J

    2015-02-01

    Self-amplifying mRNA vaccines are being developed as a platform technology with potential to be used for a broad range of targets. The synthetic production methods for their manufacture, combined with the modern tools of bioinformatics and synthetic biology, enable these vaccines to be produced rapidly from an electronic gene sequence. Preclinical proof of concept has so far been achieved for influenza, respiratory syncytial virus, rabies, Ebola, cytomegalovirus, human immunodeficiency virus and malaria. This editorial highlights the key milestones in the discovery and development of self-amplifying mRNA vaccines, and reviews how they might be used as a rapid response platform. The paper points out how future improvements in RNA vector design and non-viral delivery may lead to decreases in effective dose and increases in production capacity. The prospects for non-viral delivery of self-amplifying mRNA vaccines are very promising. Like other types of nucleic acid vaccines, these vaccines have the potential to draw on the positive attributes of live-attenuated vaccines while obviating many potential safety limitations. Hence, this approach could enable the concept of vaccines on demand as a rapid response to a real threat rather than the deployment of strategic stockpiles based on epidemiological predictions for possible threats.

  5. 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.

  6. Drug design: structure- and ligand-based approaches

    National Research Council Canada - National Science Library

    Merz, Kenneth M; Ringe, Dagmar; Reynolds, Charles H

    2010-01-01

    ..., computational ADME-Tox, and drug discovery case studies. A variety of authors from academic and commercial institutions all over the world have contributed to this book, which is illustrated with more than 200 images...

  7. Membrane Transporters: Structure, Function and Targets for Drug Design

    Science.gov (United States)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  8. Design of Novel Ophthalmic Formulation Containing Drug Nanoparticles and Its Usefulness as Anti-glaucoma Drugs.

    Science.gov (United States)

    Nagai, Noriaki

    2016-01-01

    The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the administered drug penetrate the cornea to reach the desired intraocular tissue due to corneal barriers. Recently, nanoparticulate drug delivery is expected as a technology to overcome the difficulties in delivering drugs across biological barriers (improvement of bioavailability). In this study, we attempted to establish a new method for preparing solid drug nanoparticles by using a bead mill and various additives, and succeeded in preparing a high quality dispersion containing drug nanoparticles. For a more concrete example, a mean particle size of disulfiram (DSF) treated with bead mill is 183 nm. The corneal penetration and corneal residence time of DSF from the ophthalmic dispersion containing DSF nanoparticles were significantly higher than those from a 2-hydroxypropyl-β-cyclodextrin solution containing DSF (DSF solution). It is known that the administration of DSF has intraocular pressure (IOP)-reducing effects. The IOP-reducing effects of the ophthalmic dispersion containing DSF nanoparticles were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, the ophthalmic dispersion containing DSF nanoparticles is better tolerated by corneal epithelial cells than DSF solution. It is possible that dispersions containing DSF nanoparticles provide new possibilities for effectively treating glaucoma, and that ocular drug delivery systems using drug nanoparticles may expand their usage for therapy in the ophthalmologic field.

  9. Nucleic acid therapeutic carriers with on-demand triggered release.

    Science.gov (United States)

    Venkatesh, Siddarth; Wower, Jacek; Byrne, Mark E

    2009-09-01

    optimization of a rich toolbox of novel drug and gene delivery platforms. We anticipate further inquiry into nucleic acid based programmable on-demand switches and modulatory devices of exquisite sensitivity and control.

  10. 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

  11. 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…

  12. Risk-taking related to drug use: an application of the shift-to-risk design.

    Science.gov (United States)

    Deren, S; Des Jarlais, D C

    1977-01-01

    The utility of the shift-to-risk design for studying the influence of peer groups on drug taking was investigated. Two studies using this design with drug content were conducted, varying the level of information provided about a drug. Subjects were from two college classes consisting of 26 and 28 students. Results indicated that the specification of possible harmful drug effects which are somewhat minimal lead to a significantly greater willingness to recommend trying the drug. In addition, a tendency for a shift-to-caution was found. It was concluded that the shift-to-risk designwas useful for studying decision-making regarding drug use, and that both users and nonusers of drugs should be included in future research.

  13. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  14. 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.

  15. 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.

  16. Versatile and on-demand biologics co-production in yeast.

    Science.gov (United States)

    Cao, Jicong; Perez-Pinera, Pablo; Lowenhaupt, Ky; Wu, Ming-Ru; Purcell, Oliver; de la Fuente-Nunez, Cesar; Lu, Timothy K

    2018-01-08

    Current limitations to on-demand drug manufacturing can be addressed by technologies that streamline manufacturing processes. Combining the production of two or more drugs into a single batch could not only be useful for research, clinical studies, and urgent therapies but also effective when combination therapies are needed or where resources are scarce. Here we propose strategies to concurrently produce multiple biologics from yeast in single batches by multiplexing strain development, cell culture, separation, and purification. We demonstrate proof-of-concept for three biologics co-production strategies: (i) inducible expression of multiple biologics and control over the ratio between biologic drugs produced together; (ii) consolidated bioprocessing; and (iii) co-expression and co-purification of a mixture of two monoclonal antibodies. We then use these basic strategies to produce drug mixtures as well as to separate drugs. These strategies offer a diverse array of options for on-demand, flexible, low-cost, and decentralized biomanufacturing applications without the need for specialized equipment.

  17. Computational drug designing of fungal pigments as potential aromatase inhibitors

    Directory of Open Access Journals (Sweden)

    Nighat Fatima

    2014-12-01

    Full Text Available The existing aromatase inhibitors produced unwelcome effects impose the discovery of novel drugs with privileged selectivity, a reduced amount of toxicity and humanizing potency. In this study, we illuminate the binding mode of polyketide azaphilanoid pigments monascin, ankaflavin, monascorubrin and monascorubramine isolated from Monascus fungus to the aromatase by molecular docking. The 3-dimensional structure of aromatase enzyme (PDB: 4KQ8 was obtained from the Protein Data Bank. PatchDock docking software was used to analyze structural complexes of the aromatase with monascus pigments. Comparatively, the AutoGrid model presented the most briskly constructive binding mode of monascin to aromatase. Docked energies in kcal/mol are: monascin;-13.2; monascorubramine:-12.8, monascorubrin:-12.3; ankaflavin: -10.5. These outcomes exposed these ligands could be potential drugs to treat hormone dependent breast cancer.

  18. Design of Drug Delivery Systems Containing Artemisinin and Its Derivatives

    Directory of Open Access Journals (Sweden)

    Blessing Atim Aderibigbe

    2017-02-01

    Full Text Available Artemisinin and its derivatives have been reported to be experimentally effective for the treatment of highly aggressive cancers without developing drug resistance, they are useful for the treatment of malaria, other protozoal infections and they exhibit antiviral activity. However, they are limited pharmacologically by their poor bioavailability, short half-life in vivo, poor water solubility and long term usage results in toxicity. They are also expensive for the treatment of malaria when compared to other antimalarials. In order to enhance their therapeutic efficacy, they are incorporated onto different drug delivery systems, thus yielding improved biological outcomes. This review article is focused on the currently synthesized derivatives of artemisinin and different delivery systems used for the incorporation of artemisinin and its derivatives.

  19. Fragment-based drug discovery using rational design.

    Science.gov (United States)

    Jhoti, H

    2007-01-01

    Fragment-based drug discovery (FBDD) is established as an alternative approach to high-throughput screening for generating novel small molecule drug candidates. In FBDD, relatively small libraries of low molecular weight compounds (or fragments) are screened using sensitive biophysical techniques to detect their binding to the target protein. A lower absolute affinity of binding is expected from fragments, compared to much higher molecular weight hits detected by high-throughput screening, due to their reduced size and complexity. Through the use of iterative cycles of medicinal chemistry, ideally guided by three-dimensional structural data, it is often then relatively straightforward to optimize these weak binding fragment hits into potent and selective lead compounds. As with most other lead discovery methods there are two key components of FBDD; the detection technology and the compound library. In this review I outline the two main approaches used for detecting the binding of low affinity fragments and also some of the key principles that are used to generate a fragment library. In addition, I describe an example of how FBDD has led to the generation of a drug candidate that is now being tested in clinical trials for the treatment of cancer.

  20. [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.

  1. Scalable video on demand adaptive Internet-based distribution

    CERN Document Server

    Zink, Michael

    2013-01-01

    In recent years, the proliferation of available video content and the popularity of the Internet have encouraged service providers to develop new ways of distributing content to clients. Increasing video scaling ratios and advanced digital signal processing techniques have led to Internet Video-on-Demand applications, but these currently lack efficiency and quality. Scalable Video on Demand: Adaptive Internet-based Distribution examines how current video compression and streaming can be used to deliver high-quality applications over the Internet. In addition to analysing the problems

  2. VuFind: eBooks on Demand Suchmaschine

    OpenAIRE

    Gstrein, Silvia

    2011-01-01

    The eBooks-on-Demand (EOD) network provides a trans-European digital document delivery service for end-users from all over the world offering digitization on demand of the public domain holdings of participating libraries. Currently the EOD network comprises over 30 libraries from 12 European countries. The service is offered through „EOD buttons“ placed at each record in the different library catalogues. Already in the first years of the service a common interface to search for all books off...

  3. 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.

  4. 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.

  5. 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.

  6. TRPV1: A Target for Rational Drug Design

    Directory of Open Access Journals (Sweden)

    Vincenzo Carnevale

    2016-08-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX. Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.

  7. 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...

  8. Scaling architecture-on-demand based optical networks

    NARCIS (Netherlands)

    Meyer, Hugo; Sancho, Jose Carlos; Mrdakovic, Milica; Peng, Shuping; Simeonidou, Dimitra; Miao, Wang; Calabretta, Nicola

    2016-01-01

    This paper analyzes methodologies that allow scaling properly Architecture-On-Demand (AoD) based optical networks. As Data Centers and HPC systems are growing in size and complexity, optical networks seem to be the way to scale the bandwidth of current network infrastructures. To scale the number of

  9. Security framework for virtualised infrastructure services provisioned on-demand

    NARCIS (Netherlands)

    Ngo, C.; Membrey, P.; Demchenko, Y.; de Laat, C.

    2011-01-01

    Cloud computing is developing as a new wave of ICT technologies, offering a common approach to on-demand provisioning computation, storage and network resources which are generally referred to as infrastructure services. Most of currently available commercial Cloud services are built and organized

  10. Security Services Lifecycle Management in on-demand infrastructure services

    NARCIS (Netherlands)

    Demchenko, Y.; de Laat, C.; Lopez, D.R.; García-Espín, J.A.; Qiu, J.; Zhao, G.; Rong, C.

    2010-01-01

    Modern e-Science and high technology industry require high-performance and complicated network and computer infrastructure to support distributed collaborating groups of researchers and applications that should be provisioned on-demand. The effective use and management of the dynamically provisioned

  11. A digital laser for on-demand laser modes

    CSIR Research Space (South Africa)

    Ngcobo, S

    2013-08-01

    Full Text Available -cavity digitally addressed holographic mirror. The phase and amplitude of the holographic mirror may be controlled simply by writing a computer- generated hologram in the form of a grey-scale image to the device, for on-demand laser modes. We show that we can...

  12. Security infrastructure for on-demand provisioned Cloud infrastructure services

    NARCIS (Netherlands)

    Demchenko, Y.; Ngo, C.; de Laat, C.; Wlodarczyk, T.W.; Rong, C.; Ziegler, W.

    2011-01-01

    Providing consistent security services in on-demand provisioned Cloud infrastructure services is of primary importance due to multi-tenant and potentially multi-provider nature of Clouds Infrastructure as a Service (IaaS) environment. Cloud security infrastructure should address two aspects of the

  13. Trusted Virtual Infrastructure Bootstrapping for On Demand Services

    NARCIS (Netherlands)

    Membrey, P.; Chan, K.C.C.; Ngo, C.; Demchenko, Y.; de Laat, C.

    2012-01-01

    As cloud computing continues to gain traction, a great deal of effort is being expended in researching the most effective ways to build and manage secure and trustworthy clouds. Providing consistent security services in on-demand provisioned Cloud infrastructure services is of primary importance due

  14. A primer on on-demand polymerase chain reaction technology.

    Science.gov (United States)

    Spencer, Maureen; Barnes, Sue; Parada, Jorge; Brown, Scott; Perri, Luci; Uettwiller-Geiger, Denise; Johnson, Helen Boehm; Graham, Denise

    2015-10-01

    Efforts to reduce health care-associated infections (HAIs) have grown in both scale and sophistication over the past few decades; however, the increasing threat of antimicrobial resistance and the impact of new legislation regarding HAIs on health care economics make the fight against them all the more urgent. On-demand polymerase chain reaction (PCR) technology has proven to be a highly effective weapon in this fight, offering the ability to accurately and efficiently identify disease-causing pathogens such that targeted and directed therapy can be initiated at the point of care. As a result, on-demand PCR technology has far-reaching influences on HAI rates, health care outcomes, hospital length of stay, isolation days, patient satisfaction, antibiotic stewardship, and health care economics. The basics of on-demand PCR technology and its potential to impact health care have not been widely incorporated into health care education and enrichment programs for many of those involved in infection control and prevention, however. This article serves as a primer on on-demand PCR technology and its ramifications. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  15. In silico ADME in drug design – enhancing the impact

    Directory of Open Access Journals (Sweden)

    Susanne Winiwarter

    2018-03-01

    Full Text Available Each year the pharmaceutical industry makes thousands of compounds, many of which do not meet the desired efficacy or pharmacokinetic properties, describing the absorption, distribution, metabolism and excretion (ADME behavior. Parameters such as lipophilicity, solubility and metabolic stability can be measured in high throughput in vitro assays. However, a compound needs to be synthesized in order to be tested. In silico models for these endpoints exist, although with varying quality. Such models can be used before synthesis and, together with a potency estimation, influence the decision to make a compound. In practice, it appears that often only one or two predicted properties are considered prior to synthesis, usually including a prediction of lipophilicity. While it is important to use all information when deciding which compound to make, it is somewhat challenging to combine multiple predictions unambiguously. This work investigates the possibility of combining in silico ADME predictions to define the minimum required potency for a specified human dose with sufficient confidence. Using a set of drug discovery compounds,in silico predictions were utilized to compare the relative ranking based on minimum potency calculation with the outcomes from the selection of lead compounds. The approach was also tested on a set of marketed drugs and the influence of the input parameters investigated.

  16. Computational Fragment-Based Drug Design: Current Trends, Strategies, and Applications.

    Science.gov (United States)

    Bian, Yuemin; Xie, Xiang-Qun Sean

    2018-04-09

    Fragment-based drug design (FBDD) has become an effective methodology for drug development for decades. Successful applications of this strategy brought both opportunities and challenges to the field of Pharmaceutical Science. Recent progress in the computational fragment-based drug design provide an additional approach for future research in a time- and labor-efficient manner. Combining multiple in silico methodologies, computational FBDD possesses flexibilities on fragment library selection, protein model generation, and fragments/compounds docking mode prediction. These characteristics provide computational FBDD superiority in designing novel and potential compounds for a certain target. The purpose of this review is to discuss the latest advances, ranging from commonly used strategies to novel concepts and technologies in computational fragment-based drug design. Particularly, in this review, specifications and advantages are compared between experimental and computational FBDD, and additionally, limitations and future prospective are discussed and emphasized.

  17. Marijuana-based Drugs: Innovative Therapeutics or Designer Drugs of Abuse?

    OpenAIRE

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

    2011-01-01

    Marijuana has been used recreationally and medicinally for centuries. The principle psychoactive component, Δ9-tetrahydrocannabinol (Δ9-THC), activates CB1 cannabinoid receptors (CB1Rs). CB1R agonists and antagonists could potentially treat a wide variety of diseases; unfortunately, therapeutic doses produce unacceptable psychiatric effects. “K2” or “Spice” (K2/Spice), an emerging drug of abuse, exhibits psychotropic actions via CB1R activation. Because of structural dissimilarity to Δ9-THC, ...

  18. Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.

    Science.gov (United States)

    Arafat, Basel; Wojsz, Magdalena; Isreb, Abdullah; Forbes, Robert T; Isreb, Mohammad; Ahmed, Waqar; Arafat, Tawfiq; Alhnan, Mohamed A

    2018-06-15

    Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks was investigated. Increasing the inter-block space reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for friability. Upon introduction into gastric medium, the 1 mm spaces gaplet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix expanded due to swelling of hydroxypropyl cellulose (HPC) upon introduction to the dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 μm/min. The design approach was more efficient than a comparison conventional formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a novel example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as the foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that is usually achieved by a sophisticated formulation approach. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Ball Bearings Equipped for In Situ Lubrication on Demand

    Science.gov (United States)

    Marchetti, Mario; Jones, William R., Jr.; Pepper, Stephen V.; Jansen, Mark; Predmore, Roamer

    2005-01-01

    In situ systems that provide fresh lubricants to ball/race contacts on demand have been developed to prolong the operational lives of ball bearings. These systems were originally intended to be incorporated into ball bearings in mechanisms that are required to operate in outer space for years, in conditions in which lubricants tend to deteriorate and/or evaporate. These systems may also be useful for similarly prolonging bearing lifetimes on Earth. Reservoirs have been among the means used previously to resupply lubricants. Lubricant- resupply reservoirs are bulky and add complexity to bearing assemblies. In addition, such a reservoir cannot be turned on or off as needed: it supplies lubricant continuously, often leading to an excess of lubricant in the bearing. A lubricator of the present type includes a porous ring cartridge attached to the inner or the outer ring of a ball bearing (see Figure 1). Oil is stored in the porous cartridge and is released by heating the cartridge: Because the thermal expansion of the oil exceeds that of the cartridge, heating causes the ejection of some oil. A metal film can be deposited on a face of the cartridge to serve as an electrical-resistance heater. The heater can be activated in response to a measured increase in torque that signals depletion of oil from the bearing/race contacts. Because the oil has low surface tension and readily wets the bearing-ring material, it spreads over the bearing ring and eventually reaches the ball/race contacts. The Marangoni effect (a surface-tension gradient associated with a temperature gradient) is utilized to enhance the desired transfer of lubricant to the ball/race contacts during heating. For a test, a ball bearing designed for use at low speed was assembled without lubricant and equipped with a porous-ring lubricator, the resistance heater of which consumed a power of less than 1 W when triggered on by a torque-measuring device. In the test, a load of 20 lb (.89 N) was applied and the

  4. 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...

  5. 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.

  6. On-demand Overlay Networks for Large Scientific Data Transfers

    Energy Technology Data Exchange (ETDEWEB)

    Ramakrishnan, Lavanya [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Guok, Chin [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Jackson, Keith [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Kissel, Ezra [Univ. of Delaware, Newark, DE (United States); Swany, D. Martin [Univ. of Delaware, Newark, DE (United States); Agarwal, Deborah [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2009-10-12

    Large scale scientific data transfers are central to scientific processes. Data from large experimental facilities have to be moved to local institutions for analysis or often data needs to be moved between local clusters and large supercomputing centers. In this paper, we propose and evaluate a network overlay architecture to enable highthroughput, on-demand, coordinated data transfers over wide-area networks. Our work leverages Phoebus and On-demand Secure Circuits and AdvanceReservation System (OSCARS) to provide high performance wide-area network connections. OSCARS enables dynamic provisioning of network paths with guaranteed bandwidth and Phoebus enables the coordination and effective utilization of the OSCARS network paths. Our evaluation shows that this approach leads to improved end-to-end data transfer throughput with minimal overheads. The achievedthroughput using our overlay was limited only by the ability of the end hosts to sink the data.

  7. On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions.

    Science.gov (United States)

    Waldinger, Marcel D; Schweitzer, Dave H; Olivier, Berend

    2005-01-01

    Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation. To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration. We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation. Intravaginal ejaculation latency time (IELT). Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration. On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.

  8. Health care on demand: four telehealth priorities for 2016.

    Science.gov (United States)

    Grube, Mark E; Kaufman, Kenneth; Clarin, Dan; O'Riordan, Jason

    2016-01-01

    Consumers who are accustomed to on-demand, virtual services are looking for more convenient ways to access health care. Giving patients the opportunity to connect with physicians remotely can promote higher patient satisfaction and engagement. Telehealth options may have a high start-up cost, but that cost is likely well-justified by the potential to enhance quality, outcomes, and customer attraction and satisfaction/retention over the long-term.

  9. Towards Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis.

    Science.gov (United States)

    Francipane, Maria Giovanna; Lagasse, Eric

    2016-09-01

    In recent years, functional three-dimensional (3D) tissue generation in vitro has been significantly advanced by tissue-engineering methods, achieving better reproduction of complex native organs compared to conventional culture systems. This review will discuss traditional 3D cell culture techniques as well as newly developed technology platforms. These recent techniques provide new possibilities in the creation of human body parts and provide more accurate predictions of tissue response to drug and chemical challenges. Given the rapid advancement in the human induced pluripotent stem cell (iPSC) field, these platforms also hold great promise in the development of patient-specific, transplantable tissues and organs on demand.

  10. Molecular dynamics in drug design: new generations of compstatin analogs.

    Science.gov (United States)

    Tamamis, Phanourios; López de Victoria, Aliana; Gorham, Ronald D; Bellows-Peterson, Meghan L; Pierou, Panayiota; Floudas, Christodoulos A; Morikis, Dimitrios; Archontis, Georgios

    2012-05-01

    We report the computational and rational design of new generations of potential peptide-based inhibitors of the complement protein C3 from the compstatin family. The binding efficacy of the peptides is tested by extensive molecular dynamics-based structural and physicochemical analysis, using 32 atomic detail trajectories in explicit water for 22 peptides bound to human, rat or mouse target protein C3, with a total of 257 ns. The criteria for the new design are: (i) optimization for C3 affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity, human-rat/mouse C3 inhibitors, which could be used in animal disease models. Three of the new analogs are analyzed in more detail as they possess strong and novel binding characteristics and are promising candidates for further optimization. This work paves the way for the development of an improved therapeutic for age-related macular degeneration, and other complement system-mediated diseases, compared to known compstatin variants. © 2012 John Wiley & Sons A/S.

  11. 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.

  12. On-Demand Treatment of Premature Ejaculation with Citalopram: A Randomized Double-Blind Study

    Directory of Open Access Journals (Sweden)

    Ghafuri Zahra

    2009-10-01

    Full Text Available "nAs the most common male sexual disorder premature ejaculation (PE, also referred to as early ejaculation (EE or rapid ejaculation (RE, affects 30%-40% of sexually active men. Despite the limited number of available studies comparing the efficacy of selective serotonin re-uptake inhibitors (SSRI they have been thought to have beneficial effects for the treatment of patients with PE. In the present study, we assessed the efficacy of on-demand use of citalopram, in the treatment of premature ejaculation. A randomized double blind study of fixed dose on-demand use of citalopram was performed in Roozbeh Psychiatry Hospital, Tehran University of Medical Sciences. The sample was consisted of 80 married patients diagnosed with PE according to Diagnostic and Statistical Manual of Mental Disorders. The patients were randomly assigned to two groups: group 1 consisting of 42 patients received 20mg citalopram, and group 2 consisting of 38 patients received placebo four hours before intercourse for a 4-week treatment course. The effects of drug on the ejaculatory function in each group were assessed by the intravaginal ejaculation latency time (IELT, and the Chinese Index of Premature Ejaculation (CIPE before and at the end of treatment course. The mean IELT increased from 66.78±36.94 to 80.85±43.05 seconds in group 1 and from 63.44±33.16 to 65.71±34.26 seconds in group 2 (P = 0.000. Mean CIPE score increased 1.14±1.04 and 0.52±0.50 in group 1 and 2 respectively (P = 0.002. The patients treated with on demand citalopram showed significantly greater improvement in IELT and CIPE score compared to the patients receiving placebo. It seems that citalopram may be an effective treatment of premature ejaculation with on-demand usage. However further studies are warranted.

  13. 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.

  14. Protein-Protein Docking in Drug Design and Discovery.

    Science.gov (United States)

    Kaczor, Agnieszka A; Bartuzi, Damian; Stępniewski, Tomasz Maciej; Matosiuk, Dariusz; Selent, Jana

    2018-01-01

    Protein-protein interactions (PPIs) are responsible for a number of key physiological processes in the living cells and underlie the pathomechanism of many diseases. Nowadays, along with the concept of so-called "hot spots" in protein-protein interactions, which are well-defined interface regions responsible for most of the binding energy, these interfaces can be targeted with modulators. In order to apply structure-based design techniques to design PPIs modulators, a three-dimensional structure of protein complex has to be available. In this context in silico approaches, in particular protein-protein docking, are a valuable complement to experimental methods for elucidating 3D structure of protein complexes. Protein-protein docking is easy to use and does not require significant computer resources and time (in contrast to molecular dynamics) and it results in 3D structure of a protein complex (in contrast to sequence-based methods of predicting binding interfaces). However, protein-protein docking cannot address all the aspects of protein dynamics, in particular the global conformational changes during protein complex formation. In spite of this fact, protein-protein docking is widely used to model complexes of water-soluble proteins and less commonly to predict structures of transmembrane protein assemblies, including dimers and oligomers of G protein-coupled receptors (GPCRs). In this chapter we review the principles of protein-protein docking, available algorithms and software and discuss the recent examples, benefits, and drawbacks of protein-protein docking application to water-soluble proteins, membrane anchoring and transmembrane proteins, including GPCRs.

  15. 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

  16. 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 ...

  17. Minecraft® on Demand - A new IGN service which combines game and 3D cartography

    Science.gov (United States)

    Lecordix, François; Fremont, David; Jilani, Moez; Séguin, Emmanuel; Kriat, Sofiane

    2018-05-01

    The French national mapping agency, Institut national de l'information géographique et forestière (IGN), decided to develop a new web service, called Minecraft on Demand (www.ign.fr/Minecraft), designed to provide Minecraft maps from the geographic data that IGN produces. This free web service enables the user to select the center of the map and to get a Minecraft world of 5 km long and 5 km wide, at the scale 1 : 1. The player can easily input this map into Minecraft, the world's most popular video game with 121 million copies sold. Launched in June 2016 in France, the service Minecraft® on Demand obtained a fair success (10,000 maps downloaded), more specifically among young people, since it may enable them to discover IGN data and geography.

  18. 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.

  19. 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?

  20. 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.

  1. Simulation Framework for Rebalancing of Autonomous Mobility on Demand Systems

    Directory of Open Access Journals (Sweden)

    Marczuk Katarzyna A.

    2016-01-01

    This study is built upon our previous work on Autonomous Mobility on Demand (AMOD systems. Our methodology is simulation-based and we make use of SimMobility, an agent-based microscopic simulation platform. In the current work we focus on the framework for testing different rebalancing policies for the AMOD systems. We compare three different rebalancing methods: (i no rebalancing, (ii offline rebalancing, and (iii online rebalancing. Simulation results indicate that rebalancing reduces the required fleet size and shortens the customers’ wait time.

  2. 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.

  3. Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and On-Demand Release.

    Science.gov (United States)

    Guldris, Noelia; Gallo, Juan; García-Hevia, Lorena; Rivas, José; Bañobre-López, Manuel; Salonen, Laura M

    2018-04-12

    A versatile iron oxide nanoparticle platform is reported that can be orthogonally functionalized to obtain highly derivatized nanomaterials required for a wide variety of applications, such as drug delivery, targeted therapy, or imaging. Facile functionalization of the nanoparticles with two ligands containing isocyanate moieties allows for high coverage of the surface with maleimide and alkyne groups. As a proof-of-principle, the nanoparticles were subsequently functionalized with a fluorophore as a drug model and with biotin as a targeting ligand towards tumor cells through Diels-Alder and azide-alkyne cycloaddition reactions, respectively. The thermoreversibility of the Diels-Alder product was exploited to induce the on-demand release of the loaded molecules by magnetic hyperthermia. Additionally, the nanoparticles were shown to target cancer cells through in vitro experiments, as analyzed by magnetic resonance imaging. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. 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.

  5. A high turndown, ultra low emission low swirl burner for natural gas, on-demand water heaters

    Energy Technology Data Exchange (ETDEWEB)

    Rapp, Vi H. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cheng, Robert K. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Therkelsen, Peter L. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2017-06-13

    Previous research has shown that on-demand water heaters are, on average, approximately 37% more efficient than storage water heaters. However, approximately 98% of water heaters in the U.S. use storage water heaters while the remaining 2% are on-demand. A major market barrier to deployment of on-demand water heaters is their high retail cost, which is due in part to their reliance on multi-stage burner banks that require complex electronic controls. This project aims to research and develop a cost-effective, efficient, ultra-low emission burner for next generation natural gas on-demand water heaters in residential and commercial buildings. To meet these requirements, researchers at the Lawrence Berkeley National Laboratory (LBNL) are adapting and testing the low-swirl burner (LSB) technology for commercially available on-demand water heaters. In this report, a low-swirl burner is researched, developed, and evaluated to meet targeted on-demand water heater performance metrics. Performance metrics for a new LSB design are identified by characterizing performance of current on-demand water heaters using published literature and technical specifications, and through experimental evaluations that measure fuel consumption and emissions output over a range of operating conditions. Next, target metrics and design criteria for the LSB are used to create six 3D printed prototypes for preliminary investigations. Prototype designs that proved the most promising were fabricated out of metal and tested further to evaluate the LSB’s full performance potential. After conducting a full performance evaluation on two designs, we found that one LSB design is capable of meeting or exceeding almost all the target performance metrics for on-demand water heaters. Specifically, this LSB demonstrated flame stability when operating from 4.07 kBTU/hr up to 204 kBTU/hr (50:1 turndown), compliance with SCAQMD Rule 1146.2 (14 ng/J or 20 ppm NOX @ 3% O2), and lower CO emissions than state

  6. 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.

  7. 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

  8. 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.

  9. 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...

  10. 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

  11. 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

  12. 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.

  13. Comparing image quality of print-on-demand books and photobooks from web-based vendors

    Science.gov (United States)

    Phillips, Jonathan; Bajorski, Peter; Burns, Peter; Fredericks, Erin; Rosen, Mitchell

    2010-01-01

    Because of the emergence of e-commerce and developments in print engines designed for economical output of very short runs, there are increased business opportunities and consumer options for print-on-demand books and photobooks. The current state of these printing modes allows for direct uploading of book files via the web, printing on nonoffset printers, and distributing by standard parcel or mail delivery services. The goal of this research is to assess the image quality of print-on-demand books and photobooks produced by various Web-based vendors and to identify correlations between psychophysical results and objective metrics. Six vendors were identified for one-off (single-copy) print-on-demand books, and seven vendors were identified for photobooks. Participants rank ordered overall quality of a subset of individual pages from each book, where the pages included text, photographs, or a combination of the two. Observers also reported overall quality ratings and price estimates for the bound books. Objective metrics of color gamut, color accuracy, accuracy of International Color Consortium profile usage, eye-weighted root mean square L*, and cascaded modulation transfer acutance were obtained and compared to the observer responses. We introduce some new methods for normalizing data as well as for strengthening the statistical significance of the results. Our approach includes the use of latent mixed-effect models. We found statistically significant correlation with overall image quality and some of the spatial metrics, but correlations between psychophysical results and other objective metrics were weak or nonexistent. Strong correlation was found between psychophysical results of overall quality assessment and estimated price associated with quality. The photobook set of vendors reached higher image-quality ratings than the set of print-on-demand vendors. However, the photobook set had higher image-quality variability.

  14. 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...

  15. 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.

  16. 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....

  17. 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.

  18. 10 CFR 707.7 - Random drug testing requirements and identification of testing designated positions.

    Science.gov (United States)

    2010-01-01

    ... contractor, to have the potential to significantly affect the environment, public health and safety, or... evidence of the use of illegal drugs of employees in testing designated positions identified in this... section shall provide for random tests at a rate equal to 30 percent of the total number of employees in...

  19. 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…

  20. 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...

  1. 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

  2. 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

  3. A Smart Audio on Demand Application on Android Systems

    Directory of Open Access Journals (Sweden)

    Ing-Jr Ding

    2015-05-01

    Full Text Available This paper describes a study of the realization of intelligent Audio on Demand (AOD processing in the embedded system environment. This study describes the development of innovative Android software that will enhance user experience of the increasingly popular number of smart mobile devices now available on the market. The application we developed can accumulate records of the songs that are played and automatically analyze the favorite song types of a user. The application can also select sound control playback functions to make operation more convenient. A large number of different types of music genre were collected to create a sound database and build an intelligent AOD processing mechanism. Formant analysis was used to extract voice features and the K-means clustering method and acoustic modeling technology of the Gaussian mixture model (GMM were used to study and develop the application mechanism. The processes we developed run smoothly in the embedded Android platform.

  4. On-Demand Microwave Generator of Shaped Single Photons

    Science.gov (United States)

    Forn-Díaz, P.; Warren, C. W.; Chang, C. W. S.; Vadiraj, A. M.; Wilson, C. M.

    2017-11-01

    We demonstrate the full functionality of a circuit that generates single microwave photons on demand, with a wave packet that can be modulated with a near-arbitrary shape. We achieve such a high tunability by coupling a superconducting qubit near the end of a semi-infinite transmission line. A dc superconducting quantum interference device shunts the line to ground and is employed to modify the spatial dependence of the electromagnetic mode structure in the transmission line. This control allows us to couple and decouple the qubit from the line, shaping its emission rate on fast time scales. Our decoupling scheme is applicable to all types of superconducting qubits and other solid-state systems and can be generalized to multiple qubits as well as to resonators.

  5. Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing.

    Science.gov (United States)

    Zhang, Ping; Weeranoppanant, Nopphon; Thomas, Dale A; Tahara, Kohei; Stelzer, Torsten; Russell, Mary Grace; O'Mahony, Marcus; Myerson, Allan S; Lin, Hongkun; Kelly, Liam P; Jensen, Klavs F; Jamison, Timothy F; Dai, Chunhui; Cui, Yuqing; Briggs, Naomi; Beingessner, Rachel L; Adamo, Andrea

    2018-02-21

    As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. 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

  7. 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...

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Energy efficient ventilation based on demand humidity control. Demonstration project with 49 apartments in Soenderborg

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-09-01

    The aim of the project is to demonstrate how the overall energy consumption in apartment buildings can be reduced through a combination of: 1) Energy efficient ventilation based on demand humidity control; 2) Energy efficient design of the building shell including passive solar and seasonally flexible sunspaces; 3) Use of low temperature heating system. The 3 blocks in the project, each with 16 apartments, are furnished with 3 different ventilation systems: 1) Standard exhaust system according to building codes; 2) Ventilation system with humidity control. Each room is furnished with an air inlet valve controlled by a processor, which monitors the humidity; 3) Standard ventilation system with heat recovery. (au)

  13. 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.

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

    Science.gov (United States)

    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.

  15. 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.

  16. 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

  17. Drug delivery across length scales.

    Science.gov (United States)

    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.

  18. 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

  19. 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

  20. On demand processing of climate station sensor data

    Science.gov (United States)

    Wöllauer, Stephan; Forteva, Spaska; Nauss, Thomas

    2015-04-01

    Large sets of climate stations with several sensors produce big amounts of finegrained time series data. To gain value of this data, further processing and aggregation is needed. We present a flexible system to process the raw data on demand. Several aspects need to be considered to process the raw data in a way that scientists can use the processed data conveniently for their specific research interests. First of all, it is not feasible to pre-process the data in advance because of the great variety of ways it can be processed. Therefore, in this approach only the raw measurement data is archived in a database. When a scientist requires some time series, the system processes the required raw data according to the user-defined request. Based on the type of measurement sensor, some data validation is needed, because the climate station sensors may produce erroneous data. Currently, three validation methods are integrated in the on demand processing system and are optionally selectable. The most basic validation method checks if measurement values are within a predefined range of possible values. For example, it may be assumed that an air temperature sensor measures values within a range of -40 °C to +60 °C. Values outside of this range are considered as a measurement error by this validation method and consequently rejected. An other validation method checks for outliers in the stream of measurement values by defining a maximum change rate between subsequent measurement values. The third validation method compares measurement data to the average values of neighboring stations and rejects measurement values with a high variance. These quality checks are optional, because especially extreme climatic values may be valid but rejected by some quality check method. An other important task is the preparation of measurement data in terms of time. The observed stations measure values in intervals of minutes to hours. Often scientists need a coarser temporal resolution

  1. 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.

  2. Design of shared unit-dose drug distribution network using multi-level particle swarm optimization.

    Science.gov (United States)

    Chen, Linjie; Monteiro, Thibaud; Wang, Tao; Marcon, Eric

    2018-03-01

    Unit-dose drug distribution systems provide optimal choices in terms of medication security and efficiency for organizing the drug-use process in large hospitals. As small hospitals have to share such automatic systems for economic reasons, the structure of their logistic organization becomes a very sensitive issue. In the research reported here, we develop a generalized multi-level optimization method - multi-level particle swarm optimization (MLPSO) - to design a shared unit-dose drug distribution network. Structurally, the problem studied can be considered as a type of capacitated location-routing problem (CLRP) with new constraints related to specific production planning. This kind of problem implies that a multi-level optimization should be performed in order to minimize logistic operating costs. Our results show that with the proposed algorithm, a more suitable modeling framework, as well as computational time savings and better optimization performance are obtained than that reported in the literature on this subject.

  3. 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.

  4. 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

  5. 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.

  6. Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

    Science.gov (United States)

    Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

    2010-09-01

    We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

  7. 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.

  8. Reversible, on-demand generation of aqueous two-phase microdroplets

    Science.gov (United States)

    Collier, Charles Patrick; Retterer, Scott Thomas; Boreyko, Jonathan Barton; Mruetusatorn, Prachya

    2017-08-15

    The present invention provides methods of on-demand, reversible generation of aqueous two-phase microdroplets core-shell microbeads, microparticle preparations comprising the core-shell microbeads, and drug delivery formulation comprising the microparticle preparations. Because these aqueous microdroplets have volumes comparable to those of cells, they provide an approach to mimicking the dynamic microcompartmentation of biomaterial that naturally occurs within the cytoplasm of cells. Hence, the present methods generate femtoliter aqueous two-phase droplets within a microfluidic oil channel using gated pressure pulses to generate individual, stationary two-phase microdroplets with a well-defined time zero for carrying out controlled and sequential phase transformations over time. Reversible phase transitions between single-phase, two-phase, and core-shell microbead states are obtained via evaporation-induced dehydration and water rehydration.

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

    Science.gov (United States)

    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.

  10. 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.

  11. 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...

  12. 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...

  13. Product diffusion through on-demand information-seeking behaviour.

    Science.gov (United States)

    Riedl, Christoph; Bjelland, Johannes; Canright, Geoffrey; Iqbal, Asif; Engø-Monsen, Kenth; Qureshi, Taimur; Sundsøy, Pål Roe; Lazer, David

    2018-02-01

    Most models of product adoption predict S-shaped adoption curves. Here we report results from two country-scale experiments in which we find linear adoption curves. We show evidence that the observed linear pattern is the result of active information-seeking behaviour: individuals actively pulling information from several central sources facilitated by modern Internet searches. Thus, a constant baseline rate of interest sustains product diffusion, resulting in a linear diffusion process instead of the S-shaped curve of adoption predicted by many diffusion models. The main experiment seeded 70 000 (48 000 in Experiment 2) unique voucher codes for the same product with randomly sampled nodes in a social network of approximately 43 million individuals with about 567 million ties. We find that the experiment reached over 800 000 individuals with 80% of adopters adopting the same product-a winner-take-all dynamic consistent with search engine driven rankings that would not have emerged had the products spread only through a network of social contacts. We provide evidence for (and characterization of) this diffusion process driven by active information-seeking behaviour through analyses investigating (a) patterns of geographical spreading; (b) the branching process; and (c) diffusion heterogeneity. Using data on adopters' geolocation we show that social spreading is highly localized, while on-demand diffusion is geographically independent. We also show that cascades started by individuals who actively pull information from central sources are more effective at spreading the product among their peers. © 2018 The Authors.

  14. Ventilation on demand (VOD) projects : Vale Inco Ltd.

    Energy Technology Data Exchange (ETDEWEB)

    Allen, C.L. [Vale Inco Ltd., Sudbury, ON (Canada)

    2008-07-01

    This paper presented a dynamic ventilation on Demand (VOD) system that is in the developmental stages at Vale Inco. The VOD addresses the need to minimize ventilation costs associated with mining at depth. The physical components of the system are in the process of being tested at Vale Inco's mine sites in Sudbury, Ontario, where the company operates 6 base metal mines that vary in depth from 1200 metres to 2400 metres. Two pilot projects are simultaneously testing the physical components of the VOD system at Coleman and Creighton mines. A Scope of Work is also being finalized in which the architecture of the system is being optimized for testing a prototype dynamic VOD installation. The primary ventilation systems at the mines were described along with future ventilation requirements and air flow regulations with reference to both conventional and automated regulators. The development of the VOD system involved software development, computer networking, electrical planning, PLC programming and accurate ventilation modeling. The common objective was to reduce ventilation cost and increase production in the mine by maximizing the efficiency of the ventilation system. This will be accomplished through communication training and following safety standards and protocols. 7 refs., 2 tabs., 6 figs.

  15. Reciprocity on Demand : Sharing and Exchanging Food in Northwestern Namibia.

    Science.gov (United States)

    Schnegg, Michael

    2015-09-01

    Two competing models concerning food transfers prominent in the anthropological literature conceptualize such transfers either as sharing or as exchange. Sharing is understood as situational transactions formed through demands and unconditional giving, whereas reciprocal exchange is understood in terms of networking and keeping score. I propose that the picture is more complicated than these classifications suggests. Drawing on data collected in Northwestern Namibia, I show that sharing and reciprocal exchange are dynamically interrelated in actual food transfers. As a local norm, people can demand food from anyone, and they are typically given food in response to a demand. However, in practice, food transfer networks emerge (N = 62) that are highly reciprocal and fit the exchange model much better. Although the sharing norm makes no restrictions on whom to ask, in practice people often turn to their neighbors. Interpersonal dynamics account for why some of those ties become strongly reciprocal and others do not. Under these circumstances, unconditional sharing, a norm that has been viewed as an alternative to exchange, can lead to reciprocity via reciprocity on demand.

  16. 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.

  17. Self nano-emulsifying drug delivery system for Embelin: Design, characterization and in-vitro studies

    Directory of Open Access Journals (Sweden)

    Komal Parmar

    2015-10-01

    Full Text Available CThe objective of the present study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS containing Capryol-90 as oil phase for the delivery of Embelin, a poorly water soluble herbal active ingredient. Box-Behnken experimental design was employed to optimise the formulation variables, X1 (amount of oil; Capryol 90, X2 (amount of surfactant; Acrysol EL 135 and X3 (amount of co-surfactant; PEG 400. Systems were appraised for visual characteristics for self emulsifying time, globule size and drug release. Optimised liquid formulations were formulated into free flowing granules (S-SNEDDS by adsorption on the porous materials like Aerosil 200 and Neusilin and thereby compressed into tablet. In vitro dissolution studies of SNEDDS revealed increased in the dissolution rate of the drug. FT-IR data revealed no physicochemical interaction between drug and excipients. Solid state characterization of S-SNEDDS by DSC and Powder XRD confirmed reduction in drug crystallinity which further supports the results of dissolution studies. TEM analysis exhibited spherical globules. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS of Embelin are found to be stable without any significant change in physicochemical properties. Thus, the present studies demonstrated dissolution enhancement potential of porous carrier based S-SNEDDS for poorly water soluble herbal active ingredient, Embelin.

  18. The solubility-permeability interplay and oral drug formulation design: Two heads are better than one.

    Science.gov (United States)

    Dahan, Arik; Beig, Avital; Lindley, David; Miller, Jonathan M

    2016-06-01

    Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility-permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure. Overall, depending on the type of solubility-permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. [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.

  20. Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.

    Science.gov (United States)

    Guimarães, Ana P; de Souza, Felipe R; Oliveira, Aline A; Gonçalves, Arlan S; de Alencastro, Ricardo B; Ramalho, Teodorico C; França, Tanos C C

    2015-02-16

    Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. 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.

  2. Performance Analysis of On-Demand Routing Protocols in Wireless Mesh Networks

    Directory of Open Access Journals (Sweden)

    Arafatur RAHMAN

    2009-01-01

    Full Text Available Wireless Mesh Networks (WMNs have recently gained a lot of popularity due to their rapid deployment and instant communication capabilities. WMNs are dynamically self-organizing, self-configuring and self-healing with the nodes in the network automatically establishing an adiej hoc network and preserving the mesh connectivity. Designing a routing protocol for WMNs requires several aspects to consider, such as wireless networks, fixed applications, mobile applications, scalability, better performance metrics, efficient routing within infrastructure, load balancing, throughput enhancement, interference, robustness etc. To support communication, various routing protocols are designed for various networks (e.g. ad hoc, sensor, wired etc.. However, all these protocols are not suitable for WMNs, because of the architectural differences among the networks. In this paper, a detailed simulation based performance study and analysis is performed on the reactive routing protocols to verify the suitability of these protocols over such kind of networks. Ad Hoc On-Demand Distance Vector (AODV, Dynamic Source Routing (DSR and Dynamic MANET On-demand (DYMO routing protocol are considered as the representative of reactive routing protocols. The performance differentials are investigated using varying traffic load and number of source. Based on the simulation results, how the performance of each protocol can be improved is also recommended.

  3. 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

  4. 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.

  5. 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

  6. [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.

  7. Protein folding and non-conventional drug design: a primer for nuclear structure physicists

    International Nuclear Information System (INIS)

    Broglia, R.A.; Tiana, G.; Provasi, D.

    2004-01-01

    Some of the paradigms emerging from the study of the phenomena of phase transitions in finite many-body systems, like e.g. the atomic nucleus can be used at profit to solve the protein folding problem within the framework of simple (although not oversimplified) models. From this solution a paradigm emerges for the design of non-conventional drugs, which inhibit enzymatic action without inducing resistance (mutations). The application of these concepts to the design of an inhibitor to the HIV-protease central in the life cycle of the HIV virus is discussed

  8. 76 FR 20892 - Prohibition Against Payment of Interest on Demand Deposits

    Science.gov (United States)

    2011-04-14

    ... Interest on Demand Deposits AGENCY: Board of Governors of the Federal Reserve System. ACTION: Notice of... proposed amendments that would repeal Regulation Q, Prohibition Against Payment of Interest on Demand... interest on demand deposits by institutions that are member banks of the Federal Reserve System set forth...

  9. Performansi Video on Demand (VOD) Pada Virtual Private Network (VPN) Menggunakan OpenVPN

    OpenAIRE

    Priyambudi, Henry Okta

    2013-01-01

    Multimedia streaming menggunakanmedia video, sebagai cara penyampaian informasi yanglebih baik dibandingkan dengan teks atau suara. Salahsatu jenis multimedia streaming adalah Video OnDemand (VOD). Pada sistem video on demand, file videotelah disimpan terlebih dahulu di dalam server. Clientmerequest file video yang diinginkan dan prosesstreaming dapat dilakukan.. Salah satu kelemahan darivideo on demand adalah tidak ada sistem authentifikasipada client. Setiap client dapat melakukan streaming...

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. Auction-Based Cloud Service Pricing and Penalty with Availability on Demand

    Directory of Open Access Journals (Sweden)

    Xiaohong Wu

    2018-04-01

    Full Text Available Availability is one of the main concerns of cloud users, and cloud providers always try to provide higher availability to improve user satisfaction. However, higher availability results in higher provider costs and lower social welfare. In this paper, taking into account both the users’ valuation and desired availability, we design resource allocation, pricing and penalty mechanisms with availability on demand. Considering two scenarios: public availability in which the desired availabilities of all users are public information, and private availability in which the desired availabilities are private information of users, and, analyzing the possible behaviours of users, we design a truthful deterministic mechanism with 2-approximation in public availability scenario and a universal truthful mechanism with 1 1 + γ approximation in private availability scenario, where γ is the backup ratio of resources with the highest availability. The experiment results show that our mechanisms significantly improve the social welfare compared to the mechanism without considering availability demand of users.

  17. 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

  18. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D.

    Science.gov (United States)

    Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-Bin

    2016-01-01

    The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability.

  19. [Benzimidazole and its derivatives--from fungicides to designer drugs. A new occupational and environmental hazards].

    Science.gov (United States)

    Lutz, Piotr

    2012-01-01

    Benzimidazole and benzimidazole derivatives play an important role in controlling various fungal pathogens. The benzimidazoles are also used to treat nematode and trematode infections in humans and animals. It acts by binding to the microtubules and stopping hyphal growth. It also binds to the spindle microtubules and blocks nuclear division. The most popular fungicide is carbendazim. The fungicide is used to control plant diseases in cereals and fruits. Laboratory studies have shown that carbendazim cause infertility and destroy the testicles of laboratory animals. Other benzimidazole derivatives are used as a preservative in paint, textile, papermaking, leather industry, and warehousing practices, as well as a preservative of fruits. Occupational exposure to benzimidazole may occur through inhalation and dermal contact with those compounds at workplaces where benzimidazole is used or produced. Some of the benzimidazoles are common environmental pollutants. They are often found in food and fruit products. Some of the benzimidazoles, like a astemizole or esomeprazole have found applications in diverse therapeutical areas. Despite of the clear advantages afforded by the use of benzimidazole derivatives, they share a danger potential. The most hazardous, however, are new illegally synthesed psychoactive drugs known as designer drugs. Some of them, like nitazene, etonitazene or clonitazene belong to benzimidazole derivatives. Laboratory animal studies revealed that etonitazene produced very similar effects in central nervous system as those observed after morphine administration. Considering etonitazene's properties, it seems reasonable to expected that long-term exposure to other benzimidazole derivatives may result in drug abuse and development of drug dependence.

  20. Optimization of primaquine diphosphate tablet formulation for controlled drug release using the mixture experimental design.

    Science.gov (United States)

    Duque, Marcelo Dutra; Kreidel, Rogério Nepomuceno; Taqueda, Maria Elena Santos; Baby, André Rolim; Kaneko, Telma Mary; Velasco, Maria Valéria Robles; Consiglieri, Vladi Olga

    2013-01-01

    A tablet formulation based on hydrophilic matrix with a controlled drug release was developed, and the effect of polymer concentrations on the release of primaquine diphosphate was evaluated. To achieve this purpose, a 20-run, four-factor with multiple constraints on the proportions of the components was employed to obtain tablet compositions. Drug release was determined by an in vitro dissolution study in phosphate buffer solution at pH 6.8. The polynomial fitted functions described the behavior of the mixture on simplex coordinate systems to study the effects of each factor (polymer) on tablet characteristics. Based on the response surface methodology, a tablet composition was optimized with the purpose of obtaining a primaquine diphosphate release closer to a zero order kinetic. This formulation released 85.22% of the drug for 8 h and its kinetic was studied regarding to Korsmeyer-Peppas model, (Adj-R(2) = 0.99295) which has confirmed that both diffusion and erosion were related to the mechanism of the drug release. The data from the optimized formulation were very close to the predictions from statistical analysis, demonstrating that mixture experimental design could be used to optimize primaquine diphosphate dissolution from hidroxypropylmethyl cellulose and polyethylene glycol matrix tablets.

  1. Does the Drug Facts Label for nonprescription drugs meet its design objectives? A new procedure for assessing label effectiveness

    Directory of Open Access Journals (Sweden)

    Michael P Ryan

    2017-07-01

    Full Text Available We demonstrate an expanded procedure for assessing drug-label comprehension. Innovations include a pretest of drug preconceptions, verbal ability and label attentiveness measures, a label-scanning task, a free-recall test, category-clustering measures, and preconception-change scores. In total, 55 female and 39 male undergraduates read a facsimile Drug Facts Label for aspirin, a Cohesive-Prose Label, or a Scrambled-Prose Label. The Drug Facts Label outperformed the Scrambled-Prose Label, but not the Cohesive-Prose Label, in scanning effectiveness. The Drug Facts Label was no better than the Cohesive-Prose Label or the Scrambled-Prose Label in promoting attentiveness, recall and organization of drug facts, or misconception refutation. Discussion focuses on the need for refutational labels based on a sequence-of-events text schema.

  2. A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

    Science.gov (United States)

    Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

    2016-02-01

    Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. High Speed Mobility Through On-Demand Aviation

    Science.gov (United States)

    Moore, Mark D.; Goodrich, Ken; Viken, Jeff; Smith, Jeremy; Fredericks, Bill; Trani, Toni; Barraclough, Jonathan; German, Brian; Patterson, Michael

    2013-01-01

    automobiles. ?? Community Noise: Hub and smaller GA airports are facing increasing noise restrictions, and while commercial airliners have dramatically decreased their community noise footprint over the past 30 years, GA aircraft noise has essentially remained same, and moreover, is located in closer proximity to neighborhoods and businesses. ?? Operating Costs: GA operating costs have risen dramatically due to average fuel costs of over $6 per gallon, which has constrained the market over the past decade and resulted in more than 50% lower sales and 35% less yearly operations. Infusion of autonomy and electric propulsion technologies can accomplish not only a transformation of the GA market, but also provide a technology enablement bridge for both larger aircraft and the emerging civil Unmanned Aerial Systems (UAS) markets. The NASA Advanced General Aviation Transport Experiments (AGATE) project successfully used a similar approach to enable the introduction of primary composite structures and flat panel displays in the 1990s, establishing both the technology and certification standardization to permit quick adoption through partnerships with industry, academia, and the Federal Aviation Administration (FAA). Regional and airliner markets are experiencing constant pressure to achieve decreasing levels of community emissions and noise, while lowering operating costs and improving safety. But to what degree can these new technology frontiers impact aircraft safety, the environment, operations, cost, and performance? Are the benefits transformational enough to fundamentally alter aircraft competiveness and productivity to permit much greater aviation use for high speed and On-Demand Mobility (ODM)? These questions were asked in a Zip aviation system study named after the Zip Car, an emerging car-sharing business model. Zip Aviation investigates the potential to enable new emergent markets for aviation that offer "more flexibility than the existing transportation solutions

  8. History and evolution of the pharmacophore concept in computer-aided drug design.

    Science.gov (United States)

    Güner, Osman F

    2002-12-01

    With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the three-dimensional arrangement of chemical features or to develop predictive models (e.g., 3D-QSAR) that correlate with the experimental activities of a given training set. Pharmacophores can be also used as search queries for retrieving potential leads from structural databases, for designing molecules with specific desired attributes, or as fingerprints for assessing similarity and diversity of molecules. This review article presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical, biotechnology, and fragrances industry with published examples of how the technology has contributed and advanced the field.

  9. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

    Directory of Open Access Journals (Sweden)

    Ke ZC

    2016-06-01

    Full Text Available Zhongcheng Ke,1–3 Xuefeng Hou,4 Xiao-bin Jia31Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 2Huangshan University, Huangshan, Anhui, 3Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 4Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of ChinaBackground: The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug.Materials and methods: Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets.Results: The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits.Conclusion: SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability.Keywords: self-nanoemulsifying drug delivery, bioavailability, cyclovirobuxine D

  10. Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings.

    Science.gov (United States)

    Mehta, Prina; Al-Kinani, Ali A; Haj-Ahmad, Rita; Arshad, Muhammad Sohail; Chang, Ming-Wei; Alany, Raid G; Ahmad, Zeeshan

    2017-10-01

    Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were drainage. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Tatyana Dyakonov

    2012-01-01

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

  12. Computational Biology Tools for Identifying Specific Ligand Binding Residues for Novel Agrochemical and Drug Design.

    Science.gov (United States)

    Neshich, Izabella Agostinho Pena; Nishimura, Leticia; de Moraes, Fabio Rogerio; Salim, Jose Augusto; Villalta-Romero, Fabian; Borro, Luiz; Yano, Inacio Henrique; Mazoni, Ivan; Tasic, Ljubica; Jardine, Jose Gilberto; Neshich, Goran

    2015-01-01

    The term "agrochemicals" is used in its generic form to represent a spectrum of pesticides, such as insecticides, fungicides or bactericides. They contain active components designed for optimized pest management and control, therefore allowing for economically sound and labor efficient agricultural production. A "drug" on the other side is a term that is used for compounds designed for controlling human diseases. Although drugs are subjected to much more severe testing and regulation procedures before reaching the market, they might contain exactly the same active ingredient as certain agrochemicals, what is the case described in present work, showing how a small chemical compound might be used to control pathogenicity of Gram negative bacteria Xylella fastidiosa which devastates citrus plantations, as well as for control of, for example, meningitis in humans. It is also clear that so far the production of new agrochemicals is not benefiting as much from the in silico new chemical compound identification/discovery as pharmaceutical production. Rational drug design crucially depends on detailed knowledge of structural information about the receptor (target protein) and the ligand (drug/agrochemical). The interaction between the two molecules is the subject of analysis that aims to understand relationship between structure and function, mainly deciphering some fundamental elements of the nanoenvironment where the interaction occurs. In this work we will emphasize the role of understanding nanoenvironmental factors that guide recognition and interaction of target protein and its function modifier, an agrochemical or a drug. The repertoire of nanoenvironment descriptors is used for two selected and specific cases we have approached in order to offer a technological solution for some very important problems that needs special attention in agriculture: elimination of pathogenicity of a bacterium which is attacking citrus plants and formulation of a new fungicide. Finally

  13. 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:...

  14. An Experimental Comparison of a Co-Design Visualizing Personal Drug Information and Patient Information Leaflets: Usability Aspects.

    Science.gov (United States)

    Khodambashi, Soudabeh; Haugland, Dagrun; Ellingsberg, Anette; Kottum, Hanne; Sund, Janne Kutschera; Nytrø, Øystein

    2017-01-01

    Providing patients with specific information about their own drugs can reduce unintentional misuse and improve compliance. Searching for information is time-consuming when information is not personalized and is written using medical vocabulary that is difficult for patients to understand. In this study we explored patient information needs regarding visualizing of drug information and interrelationships by conducting a total of four co-design workshops with patients, other users and pharmacists. We developed a prototype and drug ontology to support reasoning about drug interactions. We evaluated individual performance in finding information, understanding the drug interactions, and learning from the provided information in the prototype compared to using patient information leaflets (PILs). We concluded that interactive visualization of drug information helps individuals find information about drugs, their side effects and interactions more quickly and correctly compared to using PILs. Our study is limited to co-morbid patients with transient ischaemic attack with several chronic diseases.

  15. 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.

  16. Concept of combinatorial de novo design of drug-like molecules by particle swarm optimization.

    Science.gov (United States)

    Hartenfeller, Markus; Proschak, Ewgenij; Schüller, Andreas; Schneider, Gisbert

    2008-07-01

    We present a fast stochastic optimization algorithm for fragment-based molecular de novo design (COLIBREE, Combinatorial Library Breeding). The search strategy is based on a discrete version of particle swarm optimization. Molecules are represented by a scaffold, which remains constant during optimization, and variable linkers and side chains. Different linkers represent virtual chemical reactions. Side-chain building blocks were obtained from pseudo-retrosynthetic dissection of large compound databases. Here, ligand-based design was performed using chemically advanced template search (CATS) topological pharmacophore similarity to reference ligands as fitness function. A weighting scheme was included for particle swarm optimization-based molecular design, which permits the use of many reference ligands and allows for positive and negative design to be performed simultaneously. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor subtype-selective agonists. The results demonstrate the ability of the technique to cope with large combinatorial chemistry spaces and its applicability to focused library design. The technique was able to perform exploitation of a known scheme and at the same time explorative search for novel ligands within the framework of a given molecular core structure. It thereby represents a practical solution for compound screening in the early hit and lead finding phase of a drug discovery project.

  17. On-demand treatment of premature ejaculation with clomipramine and paroxetine: A randomized, double-blind fixed-dose study with stopwatch assessment

    NARCIS (Netherlands)

    Waldinger, Marcel D.; Zwinderman, Aeilko H.; Olivier, Berend

    2004-01-01

    Objective: To investigate the degree of ejaculation delay induced by on-demand treatment with 20 mg paroxetine and 25 mg clomipramine and to assess the type and severity of non-sexual side-effects of treatment at the day of and the day after treatment with these drugs. Method: A randomized,

  18. 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.

  19. 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...

  20. Design of interior-functionalized fully acetylated dendrimers for anticancer drug delivery.

    Science.gov (United States)

    Hu, Jingjing; Su, Yunzhang; Zhang, Hongfeng; Xu, Tongwen; Cheng, Yiyun

    2011-12-01

    In this study, dendrimers was synthesized by introducing functional groups into the interior pockets of fully acetylated dendrimers. NMR techniques including COSY and 2D-NOESY revealed the molecular structures of the synthesized dendrimers and the encapsulation of guest molecule such as methotrexate within their interior pockets. The synthesized polymeric nanocarriers showed much lower cytotoxicity on two cell lines than cationic dendrimers, and exhibited better performance than fully acetylated dendrimers in the sustained release of methotrexate. The results provided a new strategy in the design of non-toxic dendrimers with high performance in the delivery of anti-cancer drugs for clinical applications. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. 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

  2. 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…

  3. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Guarino, Vincenzo, E-mail: vguarino@unina.it; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi [Institute for Polymers, Composites and Biomaterials, Department of Chemical Sciences & Materials Technology, National Research Council of Italy, V.le Kennedy 54, Naples (Italy)

    2015-12-17

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial’s manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell–biomaterial and cell– cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues.

  4. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    International Nuclear Information System (INIS)

    Guarino, Vincenzo; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi

    2015-01-01

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial’s manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell–biomaterial and cell– cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues

  5. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    Science.gov (United States)

    Guarino, Vincenzo; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi

    2015-12-01

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial's manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell-biomaterial and cell- cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues.

  6. 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.

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

    Science.gov (United States)

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

    2018-03-01

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

  8. Origami-inspired, on-demand deployable and collapsible mechanical metamaterials with tunable stiffness

    Science.gov (United States)

    Zhai, Zirui; Wang, Yong; Jiang, Hanqing

    2018-03-01

    Origami has been employed to build deployable mechanical metamaterials through folding and unfolding along the crease lines. Deployable metamaterials are usually flexible, particularly along their deploying and collapsing directions, which unfortunately in many cases leads to an unstable deployed state, i.e., small perturbations may collapse the structure along the same deployment path. Here we create an origami-inspired mechanical metamaterial with on-demand deployability and selective collapsibility through energy analysis. This metamaterial has autonomous deployability from the collapsed state and can be selectively collapsed along two different paths, embodying low stiffness for one path and substantially high stiffness for another path. The created mechanical metamaterial yields load-bearing capability in the deployed direction while possessing great deployability and collapsibility. The principle in this work can be utilized to design and create versatile origami-inspired mechanical metamaterials that can find many applications.

  9. Stimuli-Responsive NO Release for On-Demand Gas-Sensitized Synergistic Cancer Therapy.

    Science.gov (United States)

    Fan, Wenpei; Yung, Bryant C; Chen, Xiaoyuan

    2018-03-08

    Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state-of-the-art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli-responsive NO-releasing nanomedicines and their biomedical applications for on-demand NO-sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. 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

  11. Design of dual action antibiotics as an approach to search for new promising drugs

    International Nuclear Information System (INIS)

    Tevyashova, A N; Olsufyeva, E N; Preobrazhenskaya, M N

    2015-01-01

    The review is devoted to the latest achievements in the design of dual action antibiotics — heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure–activity relationships are analyzed. The bibliography includes 225 references

  12. Projected Demand and Potential Impacts to the National Airspace System of Autonomous, Electric, On-Demand Small Aircraft

    Science.gov (United States)

    Smith, Jeremy C.; Viken, Jeffrey K.; Guerreiro, Nelson M.; Dollyhigh, Samuel M.; Fenbert, James W.; Hartman, Christopher L.; Kwa, Teck-Seng; Moore, Mark D.

    2012-01-01

    Electric propulsion and autonomy are technology frontiers that offer tremendous potential to achieve low operating costs for small-aircraft. Such technologies enable simple and safe to operate vehicles that could dramatically improve regional transportation accessibility and speed through point-to-point operations. This analysis develops an understanding of the potential traffic volume and National Airspace System (NAS) capacity for small on-demand aircraft operations. Future demand projections use the Transportation Systems Analysis Model (TSAM), a tool suite developed by NASA and the Transportation Laboratory of Virginia Polytechnic Institute. Demand projections from TSAM contain the mode of travel, number of trips and geographic distribution of trips. For this study, the mode of travel can be commercial aircraft, automobile and on-demand aircraft. NASA's Airspace Concept Evaluation System (ACES) is used to assess NAS impact. This simulation takes a schedule that includes all flights: commercial passenger and cargo; conventional General Aviation and on-demand small aircraft, and operates them in the simulated NAS. The results of this analysis projects very large trip numbers for an on-demand air transportation system competitive with automobiles in cost per passenger mile. The significance is this type of air transportation can enhance mobility for communities that currently lack access to commercial air transportation. Another significant finding is that the large numbers of operations can have an impact on the current NAS infrastructure used by commercial airlines and cargo operators, even if on-demand traffic does not use the 28 airports in the Continental U.S. designated as large hubs by the FAA. Some smaller airports will experience greater demand than their current capacity allows and will require upgrading. In addition, in future years as demand grows and vehicle performance improves other non-conventional facilities such as short runways incorporated into

  13. Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health

    Directory of Open Access Journals (Sweden)

    Aviv M. Weinstein

    2017-08-01

    Full Text Available As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment.

  14. Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil.

    Science.gov (United States)

    Villar, Ana Maria Sierra; Naveros, Beatriz Clares; Campmany, Ana Cristina Calpena; Trenchs, Monserrat Aróztegui; Rocabert, Coloma Barbé; Bellowa, Lyda Halbaut

    2012-07-15

    Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor(®) EL), X(2) (Capmul(®) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. 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.

  16. 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.

  17. 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.

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

    Science.gov (United States)

    Poulin, Patrick

    2015-07-01

    fraction in plasma derived from a static in vitro environment might be biased to guide drug design (the old paradigm), and, hence, it is recommended to use a PBPK model to reproduce more accurately the in vivo condition in tissue (the new paradigm). This newly developed approach can be used to predict free drug concentration in diverse tissue compartments for small molecules in toxicology and pharmacology studies, which can be leveraged to optimize the pharmacokinetics drivers of tissue distribution based upon physicochemical and physiological input parameters in an attempt to optimize free drug level in tissue. Overall, this present study provides guidance on the application of plasma and tissue concentration information in PBPK/PD research in preclinical and clinical studies, which is in accordance with the recent literature. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  19. Spatial filters on demand based on aperiodic Photonic Crystals

    Energy Technology Data Exchange (ETDEWEB)

    Gailevicius, Darius; Purlys, Vytautas; Peckus, Martynas; Gadonas, Roaldas [Laser Research Center, Department of Quantum Electronics, Vilnius University (Lithuania); Staliunas, Kestutis [DONLL, Departament de Fisica, Universitat Politecnica de Catalunya (UPC), Terrassa (Spain); Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona (Spain)

    2017-08-15

    Photonic Crystal spatial filters, apart from stand-alone spatial filtering function, can also suppress multi-transverse-mode operation in laser resonators. Here it is shown that such photonic crystals can be designed by solving the inverse problem: for a given spatial filtering profile. Optimized Photonic Crystal filters were fabricated in photosensitive glass. Experiments have shown that such filters provide a more pronounced filtering effect for total and partial transmissivity conditions. (copyright 2017 by WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  20. 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.

  1. A Novel Software Platform Extending Advances in Monitoring Technologies to On-demand Decision Support

    Science.gov (United States)

    Ormerod, R.; Scholl, M.

    2017-12-01

    Rapid evolution is occurring in the monitoring and assessment of air emissions and their impacts. The development of next generation lower cost sensor technologies creates the potential for much more intensive and far-reaching monitoring networks that provide spatially rich data. While much attention at present is being directed at the types and performance characteristics of sensor technologies, it is important also that the full potential of rich data sources be realized. Parallel to sensor developments, software platforms to display and manage data in real time are increasingly common adjuncts to sensor networks. However, the full value of data can be realized by extending platform capabilities to include complex scientific functions that are integrated into an action-oriented management framework. Depending on the purpose and nature of a monitoring network, there will be a variety of potential uses of the data or its derivatives, for example: statistical analysis for policy development, event analysis, real-time issue management including emergency response and complaints, and predictive management. Moving these functions into an on-demand, optionally mobile, environment greatly increases the value and accessibility of the data. Increased interplay between monitoring data and decision-making in an operational environment is optimised by a system that is designed with equal weight on technical robustness and user experience. A system now being used by several regulatory agencies and a larger number of industries in the US, Latin America, Europe, Australia and Asia has been developed to provide a wide range of on-demand decision-support in addition to the basic data collection, display and management that most platforms offer. With stable multi-year operation, the platform, known as Envirosuite, is assisting organisations to both reduce operating costs and improve environmental performance. Some current examples of its application across a range of applications

  2. On-demand calibration and evaluation for electromagnetically tracked laparoscope in augmented reality visualization.

    Science.gov (United States)

    Liu, Xinyang; Plishker, William; Zaki, George; Kang, Sukryool; Kane, Timothy D; Shekhar, Raj

    2016-06-01

    Common camera calibration methods employed in current laparoscopic augmented reality systems require the acquisition of multiple images of an entire checkerboard pattern from various poses. This lengthy procedure prevents performing laparoscope calibration in the operating room (OR). The purpose of this work was to develop a fast calibration method for electromagnetically (EM) tracked laparoscopes, such that the calibration can be performed in the OR on demand. We designed a mechanical tracking mount to uniquely and snugly position an EM sensor to an appropriate location on a conventional laparoscope. A tool named fCalib was developed to calibrate intrinsic camera parameters, distortion coefficients, and extrinsic parameters (transformation between the scope lens coordinate system and the EM sensor coordinate system) using a single image that shows an arbitrary portion of a special target pattern. For quick evaluation of calibration results in the OR, we integrated a tube phantom with fCalib prototype and overlaid a virtual representation of the tube on the live video scene. We compared spatial target registration error between the common OpenCV method and the fCalib method in a laboratory setting. In addition, we compared the calibration re-projection error between the EM tracking-based fCalib and the optical tracking-based fCalib in a clinical setting. Our results suggest that the proposed method is comparable to the OpenCV method. However, changing the environment, e.g., inserting or removing surgical tools, might affect re-projection accuracy for the EM tracking-based approach. Computational time of the fCalib method averaged 14.0 s (range 3.5 s-22.7 s). We developed and validated a prototype for fast calibration and evaluation of EM tracked conventional (forward viewing) laparoscopes. The calibration method achieved acceptable accuracy and was relatively fast and easy to be performed in the OR on demand.

  3. 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

  4. Challenges in small screening laboratories: implementing an on-demand laboratory information management system.

    Science.gov (United States)

    Lemmon, Vance P; Jia, Yuanyuan; Shi, Yan; Holbrook, S Douglas; Bixby, John L; Buchser, William

    2011-11-01

    The Miami Project to Cure Paralysis, part of the University of Miami Miller School of Medicine, includes a laboratory devoted to High Content Analysis (HCA) of neurons. The goal of the laboratory is to uncover signaling pathways, genes, compounds, or drugs that can be used to promote nerve growth. HCA permits the quantification of neuronal morphology, including the lengths and numbers of axons. HCA of various libraries on primary neurons requires a team-based approach, a variety of process steps and complex manipulations of cells and libraries to obtain meaningful results. HCA itself produces vast amounts of information including images, well-based data and cell-based phenotypic measures. Documenting and integrating the experimental workflows, library data and extensive experimental results is challenging. For academic laboratories generating large data sets from experiments involving thousands of perturbagens, a Laboratory Information Management System (LIMS) is the data tracking solution of choice. With both productivity and efficiency as driving rationales, the Miami Project has equipped its HCA laboratory with an On Demand or Software As A Service (SaaS) LIMS to ensure the quality of its experiments and workflows. The article discusses how the system was selected and integrated into the laboratory. The advantages of a SaaS based LIMS over a client-server based system are described. © 2011 Bentham Science Publishers

  5. 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.

  6. Drugs against avian influenza a virus: design of novel sulfonate inhibitors of neuraminidase N1.

    Science.gov (United States)

    Udommaneethanakit, Thanyarat; Rungrotmongkol, Thanyada; Frecer, Vladimir; Seneci, Pierfausto; Miertus, Stanislav; Bren, Urban

    2014-01-01

    The outbreak of avian influenza A (H5N1) virus has raised a global concern for both the animal as well as human health. Besides vaccination, that may not achieve full protection in certain groups of patients, inhibiting neuraminidase or the transmembrane protein M2 represents the main measure of controlling the disease. Due to alarming emergence of influenza virus strains resistant to the currently available drugs, development of new neuraminidase N1 inhibitors is of utmost importance. The present paper provides an overview of the recent advances in the design of new antiviral drugs against avian influenza. It also reports findings in binding free energy calculations for nine neuraminidase N1 inhibitors (oseltamivir, zanamivir, and peramivir -carboxylate, -phosphonate, and -sulfonate) using the Linear Interaction Energy method. Molecular dynamics simulations of these inhibitors were performed in a free and two bound states - the so called open and closed conformations of neuraminidase N1. Obtained results successfully reproduce the experimental binding affinities of the already known neuraminidase N1 inhibitors, i.e. peramivir being a stronger binder than zanamivir that is in turn stronger binder than oseltamivir, or phosphonate inhibitors being stronger binders than their carboxylate analogues. In addition, the newly proposed sulfonate inhibitors are predicted to be the strongest binders - a fact to be confirmed by their chemical synthesis and a subsequent test of their biological activity. Finally, contributions of individual inhibitor moieties to the overall binding affinity are explicitly evaluated to assist further drug development towards inhibition of the H5N1 avian influenza A virus.

  7. 21 CFR 316.29 - Revocation of orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... sponsor's exclusive marketing rights for the drug but not the approval of the drug's marketing application... condition (or, in the case of vaccines, diagnostic drugs, or preventive drugs, the target population) is... the ground that the prevalence of the disease or condition (or the target population) becomes more...

  8. Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer

    Directory of Open Access Journals (Sweden)

    Jian Gao

    2016-03-01

    Full Text Available Human peptide deformylase (HsPDF is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticancer activities against HeLa, A549 and MCF-7 cell lines with IC50s of 35.26, 29.63 and 24.63 μM, respectively. Molecular docking studies suggested that M7594_0037 and its three derivatives could interact with HsPDF by several conserved hydrogen bonds. Moreover, the pharmacokinetic and toxicity properties of M7594_0037 and its derivatives were predicted using the OSIRIS property explorer. Thus, M7594_0037 and its derivatives might represent a promising scaffold for the further development of novel anticancer drugs.

  9. Design of a microemulsion-based drug delivery system for diclofenac sodium

    International Nuclear Information System (INIS)

    Kkizibash, N.A.; Asif, S.; Nazar, M.F.; Alenizi, D.; Shah, S.S.

    2011-01-01

    A microemulsion-based drug delivery system has been designed for Diclofenac Sodium(DS) comprising Span 60, 1-Propanol, Water, and Lemon Oil. The microemulsion system has been characterized by a pseudo-ternary phase diagram using the water titration method. The properties and structure of this system have been studied by the use of refractive index, electrical conductivity, viscosity and UV-Visible spectroscopy. The conductivity (s) and viscosity (k nu) measurements have provided evidence for percolation behavior with variation in F (weight fraction of aqueous phase). This phase transition corresponds to the structural change from water-in-oil to a bicontinuous microemulsion system. The percolation threshold (FC) obtained from conductivity measurements was in accordance with that obtained by viscosity measurements. Five microemulsion samples were selected and the changes in microstructure after incorporation of the drug, Diclofenac Sodium (DS) were examined by centrifugation, conductivity measurements, viscosity measurements and spectroscopic studies. The conductivity measurements showed that DS-loaded samples have higher conductivity values when compared to non-loaded samples. It was also found that DS is inter facially active. In addition, loading of DS had no negative effect on the stability of the system. (author)

  10. 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.

  11. Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options.

    Science.gov (United States)

    Aungst, Bruce J

    2017-04-01

    For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability. An initial assessment of absorption potential may be made computationally, and high throughput in vitro assays are typically performed to prioritize compounds for in vivo studies. The initial pharmacokinetic study is a critical decision point in compound evaluation, and the importance of the effect the dosing vehicle or formulation can have on oral bioavailability, especially for poorly water soluble compounds, is emphasized. Dosing vehicles and bioavailability-enabling formulations that can be used for discovery and preclinical studies are described. Optimizing oral bioavailability within a chemical series or for a lead compound requires identification of the barrier limiting bioavailability, and methods used for this purpose are outlined. Finally, a few key guidelines are offered for consideration when facing the challenges of optimizing oral bioavailability in drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Designing a Poly (N-isopropylacrylamide) Nanocapsule for Magnetic Field-assisted Drug Delivery

    Science.gov (United States)

    Denmark, Daniel; Mukherjee, Pritish; Witanachchi, Sarath

    2014-03-01

    The method of synthesis and the characteristics of polymer based nanocapsules as biomedical drug delivery systems are presented. Magnetic iron oxide nanoparticles have been incorporated into these capsules for effective guidance with external magnetic fields to transport therapeutic compounds to various parts of the human body. Once they have reached their destination they can be stimulated to release the drug to the target tissue through externally applied fields. The polymeric material that constitutes the capsules is specifically designed to melt away with the external stimuli to deliver the therapeutic bio agents near the target tissue. In this work we use nebulization to create aqueous poly (N-isopropylacrylamide) nanoparticles that decompose after being heated beyond their transition temperature. Transmission Electron Microscopic imaging (TEM) and dynamic light scattering (DLS) experiments have been conducted to study the decomposition of the capsules under external stimuli. Distribution of the magnetic nanoparticles within the capsules and their role in delivering the bio agents have been investigated by the Magnetic Force Microscopy (MFM).

  13. Designing cyclopentapeptide inhibitor as potential antiviral drug for dengue virus ns5 methyltransferase.

    Science.gov (United States)

    Idrus, Syarifuddin; Tambunan, Usman Sumo Friend; Zubaidi, Ahmad Ardilla

    2012-01-01

    NS5 methyltransferase (Mtase) has a crucial role in the replication of dengue virus. There are two active sites on NS5 Mtase i.e., SAM and RNA-cap binding sites. Inhibition of the NS5 Mtase activity is expected to prevent the propagation of dengue virus. This study was conducted to design cyclic peptide ligands as enzyme inhibitors of dengue virus NS5 Mtase through computational approach. Cyclopentapeptides were designed as ligand of SAM binding site as much as 1635 and 736 cyclopentpeptides were designed as ligand of RNA-cap binding site. Interaction between ligand and NS5 Mtase has been conducted on the Docking simulation. The result shows that cyclopentapeptide CTWYC was the best peptide candidate on SAM binding site, with estimated free binding energy -30.72 kca/mol. Cyclopentapeptide CYEFC was the best peptide on RNA-cap binding site with estimated free binding energy -22.89 kcal/mol. Both peptides did not have tendency toward toxicity properties. So it is expected that both CTWYC and CYEFC ligands could be used as a potential antiviral drug candidates, which can inhibit the SAM and RNA-cap binding sites of dengue virus NS5 Mtase.

  14. 31 CFR 501.602 - Reports to be furnished on demand.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Reports to be furnished on demand. 501.602 Section 501.602 Money and Finance: Treasury Regulations Relating to Money and Finance... REGULATIONS Reports § 501.602 Reports to be furnished on demand. Every person is required to furnish under...

  15. Design of Probabilistic Random Forests with Applications to Anticancer Drug Sensitivity Prediction.

    Science.gov (United States)

    Rahman, Raziur; Haider, Saad; Ghosh, Souparno; Pal, Ranadip

    2015-01-01

    Random forests consisting of an ensemble of regression trees with equal weights are frequently used for design of predictive models. In this article, we consider an extension of the methodology by representing the regression trees in the form of probabilistic trees and analyzing the nature of heteroscedasticity. The probabilistic tree representation allows for analytical computation of confidence intervals (CIs), and the tree weight optimization is expected to provide stricter CIs with comparable performance in mean error. We approached the ensemble of probabilistic trees' prediction from the perspectives of a mixture distribution and as a weighted sum of correlated random variables. We applied our methodology to the drug sensitivity prediction problem on synthetic and cancer cell line encyclopedia dataset and illustrated that tree weights can be selected to reduce the average length of the CI without increase in mean error.

  16. A Bayesian approach for incorporating economic factors in sample size design for clinical trials of individual drugs and portfolios of drugs.

    Science.gov (United States)

    Patel, Nitin R; Ankolekar, Suresh

    2007-11-30

    Classical approaches to clinical trial design ignore economic factors that determine economic viability of a new drug. We address the choice of sample size in Phase III trials as a decision theory problem using a hybrid approach that takes a Bayesian view from the perspective of a drug company and a classical Neyman-Pearson view from the perspective of regulatory authorities. We incorporate relevant economic factors in the analysis to determine the optimal sample size to maximize the expected profit for the company. We extend the analysis to account for risk by using a 'satisficing' objective function that maximizes the chance of meeting a management-specified target level of profit. We extend the models for single drugs to a portfolio of clinical trials and optimize the sample sizes to maximize the expected profit subject to budget constraints. Further, we address the portfolio risk and optimize the sample sizes to maximize the probability of achieving a given target of expected profit.

  17. Thermo-responsive mesoporous silica/lipid bilayer hybrid nanoparticles for doxorubicin on-demand delivery and reduced premature release.

    Science.gov (United States)

    Zhang, Qing; Chen, Xuanxuan; Shi, Huihui; Dong, Gaoqiu; Zhou, Meiling; Wang, Tianji; Xin, Hongliang

    2017-12-01

    Hybrid nanocarriers based on mesoporous silica nanoparticles (MSNs) and supported lipid bilayer (SLB) have been studied as drug delivery system. It still remains challenges to develop these nanocarriers (SLB-MSNs) with on-demand drug release profile for chemotherapy. Here, we reported the biocompatible SLB-MSNs with high drug loading, which could release doxorubicin (DOX) in response to hyperthermia and reduce premature release. After synthesis of MSNs via a sol-gel procedure, the thermo-responsive SLB was deposited on the MSNs by sonication to completely seal the mesopores. The obtained SLB-MSNs consisted of 50 nm-sized MSN cores and 6.3 nm-thick SLB shells. Due to the big surface and pore volume of MSNs, the high drug loading content (7.30±0.02%) and encapsulation efficiency (91.16±0.28%) were achieved. The SLB blocking the mesopores reduced 50% of premature release and achieved on-demand release in a thermo-responsive manner. Moreover, SLB-MSNs showed good hemocompatibility at any tested concentration (25-700μg/mL), while bare MSNs caused 100% of hemolysis at concentration larger than 325μg/mL. In addition, in vitro U251 cell uptake experiment demonstrated that compared with uncapped MSNs, SLB-MSNs could prevent untargeted cellular uptake of DOX owing to reduced premature release and steric hindrance of PEG, which would be beneficial to minimize toxicity for healthy tissues. These results indicated that SLB-MSNs with thermo-responsive release capacity possessed great potential in future synergistic thermo-chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery

    Czech Academy of Sciences Publication Activity Database

    Tykvart, Jan; Schimer, Jiří; Bařinková, Jitka; Pachl, Petr; Poštová Slavětínská, Lenka; Majer, Pavel; Konvalinka, Jan; Šácha, Pavel

    2014-01-01

    Roč. 22, č. 15 (2014), s. 4099-4108 ISSN 0968-0896 R&D Projects: GA ČR GBP208/12/G016 Grant - others:OPPK(CZ) CZ.2.16/3.1.00/24016 Institutional support: RVO:61388963 Keywords : GCPII * PSMA * structure-aided drug design * specific drug targeting Subject RIV: CE - Biochemistry Impact factor: 2.793, year: 2014

  19. Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E (“Europa”)

    OpenAIRE

    Sacks, Justin; Ray, M. Jordan; Williams, Sue; Opatowsky, Michael J.

    2012-01-01

    We present a case of a fatal toxic leukoencephalopathy following ingestion of a new psychoactive designer drug known as 2C-E or “Europa.” Recreational drugs, particularly hallucinogenic substances, appear to be growing in popularity, with increasing amounts of information available via the Internet to entice potential users. In addition, some newer “designer” psychoactive substances are available for purchase online without adverse legal consequences, therefore adding to their popularity. We ...

  20. Investigation of Effective Parameters of Drop-on-Demand Droplet Generator

    Directory of Open Access Journals (Sweden)

    Mojtaba Ghodsi

    2017-06-01

    Full Text Available This article presents a design and development of a drop-on-demand (DOD droplets generator. This generator uses molten metal as a liquid and can be used in fabrication, prototyping and any kind of printing with solder droplets. This setup consists of a vibrator solenoid with tunable frequency to produce a semi-spherical shape of molten metal, close to the surface of fabrication. This design also has a nozzle with micro-size orifice, a rod for transmitting force and a heater to melt the metal and keep it in superheat temperature. This DOD can produce droplets in different sizes (less than 550 µm by controlling the vibration frequency of solenoid. This ability together with the accuracy of the droplets in positioning (the error is less than ±20 µm for 1.5 mm amplitude can be used in different applications.  Moreover, in this paper, the impact of initial position of the head and temperature on the average diameter of droplets and the impact of the frequency on the shape of the droplets have been tested and discussed

  1. GREEN: A program package for docking studies in rational drug design

    Science.gov (United States)

    Tomioka, Nobuo; Itai, Akiko

    1994-08-01

    A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

  2. The Use of Stilbene Scaffold in Medicinal Chemistry and Multi- Target Drug Design.

    Science.gov (United States)

    Giacomini, Elisa; Rupiani, Sebastiano; Guidotti, Laura; Recanatini, Maurizio; Roberti, Marinella

    2016-01-01

    The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

  3. Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation.

    Science.gov (United States)

    Xing, Junhao; Yang, Lingyun; Li, Hui; Li, Qing; Zhao, Leilei; Wang, Xinning; Zhang, Yuan; Zhou, Muxing; Zhou, Jinpei; Zhang, Huibin

    2015-05-05

    The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 = 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  5. 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.

  6. Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.

    Science.gov (United States)

    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 nonoverlapping 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 and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities.

  7. Designing Predictive Models for Beta-Lactam Allergy Using the Drug Allergy and Hypersensitivity Database.

    Science.gov (United States)

    Chiriac, Anca Mirela; Wang, Youna; Schrijvers, Rik; Bousquet, Philippe Jean; Mura, Thibault; Molinari, Nicolas; Demoly, Pascal

    Beta-lactam antibiotics represent the main cause of allergic reactions to drugs, inducing both immediate and nonimmediate allergies. The diagnosis is well established, usually based on skin tests and drug provocation tests, but cumbersome. To design predictive models for the diagnosis of beta-lactam allergy, based on the clinical history of patients with suspicions of allergic reactions to beta-lactams. The study included a retrospective phase, in which records of patients explored for a suspicion of beta-lactam allergy (in the Allergy Unit of the University Hospital of Montpellier between September 1996 and September 2012) were used to construct predictive models based on a logistic regression and decision tree method; a prospective phase, in which we performed an external validation of the chosen models in patients with suspicion of beta-lactam allergy recruited from 3 allergy centers (Montpellier, Nîmes, Narbonne) between March and November 2013. Data related to clinical history and allergy evaluation results were retrieved and analyzed. The retrospective and prospective phases included 1991 and 200 patients, respectively, with a different prevalence of confirmed beta-lactam allergy (23.6% vs 31%, P = .02). For the logistic regression method, performances of the models were similar in both samples: sensitivity was 51% (vs 60%), specificity 75% (vs 80%), positive predictive value 40% (vs 57%), and negative predictive value 83% (vs 82%). The decision tree method reached a sensitivity of 29.5% (vs 43.5%), specificity of 96.4% (vs 94.9%), positive predictive value of 71.6% (vs 79.4%), and negative predictive value of 81.6% (vs 81.3%). Two different independent methods using clinical history predictors were unable to accurately predict beta-lactam allergy and replace a conventional allergy evaluation for suspected beta-lactam allergy. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  8. Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Xiaoyu; Yu, Hongwei; Yang, Haitao; Xue, Fei; Wu, Zhixin; Shen, Wei; Li, Jun; Zhou, Zhe; Ding, Yi; Zhao, Qi; Zhang, Xuejun C.; Liao, Ming; Bartlam, Mark; Rao, Zihe (SCAU); (Tsinghua); (Chinese Aca. Sci.)

    2008-07-21

    Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M{sup pro}), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) MP{sup pro} and a severe acute respiratory syndrome CoV (SARS-CoV) M{sup pro} mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M{sup pro}. A monomeric form of IBV M{sup pro} was identified for the first time in CoV M{sup pro} structures. A comparison of these two structures to other available M{sup pro} structures provides new insights for the design of substrate-based inhibitors targeting CoV M{sup pro}s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M{sup pro} and was found to demonstrate in vitro inactivation of IBV M{sup pro} and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M{sup pro}.

  9. 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.

  10. Direct and Indirect Drug Design Approaches for the Development of Novel Tricyclic Antipsychotics: Potential 5-HT2A Antagonist

    Directory of Open Access Journals (Sweden)

    Mahantesh Namdev Jadhav

    2013-01-01

    Full Text Available Schizophrenia is a mental disorder manifested largely by disintegration of thought processes and emotional responsiveness. Given the therapeutic and toxic limitations of clinically available drugs, it is clear that there is still a need for the development of new generation antipsychotic agents with an improved clinical profile. Development of novel hybrid atypical tricyclic antipsychotic pharmacophore was achieved using direct (by measuring docking score of designed molecules on modelled 5- receptor and indirect (current, clinically available therapeutic agents’ data drug design approaches.

  11. 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...

  12. Adjusting inkjet printhead parameters to deposit drugs into micro-sized reservoirs

    Directory of Open Access Journals (Sweden)

    Mau Robert

    2016-09-01

    Full Text Available Drug delivery systems (DDS ensure that therapeutically effective drug concentrations are delivered locally to the target site. For that reason, it is common to coat implants with a degradable polymer which contains drugs. However, the use of polymers as a drug carrier has been associated with adverse side effects. For that reason, several technologies have been developed to design polymer-free DDS. In literature it has been shown that micro-sized reservoirs can be applied as drug reservoirs. Inkjet techniques are capable of depositing drugs into these reservoirs. In this study, two different geometries of micro-sized reservoirs have been laden with a drug (ASA using a drop-on-demand inkjet printhead. Correlations between the characteristics of the drug solution, the operating parameters of the printhead and the geometric parameters of the reservoir are shown. It is indicated that wettability of the surface play a key role for drug deposition into micro-sized reservoirs.

  13. An informatics approach to assess pediatric pharmacotherapy: design and implementation of a hospital drug utilization system.

    Science.gov (United States)

    Zuppa, Athena; Vijayakumar, Sundararajan; Jayaraman, Bhuvana; Patel, Dimple; Narayan, Mahesh; Vijayakumar, Kalpana; Mondick, John T; Barrett, Jeffrey S

    2007-09-01

    Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost-effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time-dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web-based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi-institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general.

  14. Design of dendrimer-based drug delivery nanodevices with enhanced therapeutic efficacies

    Science.gov (United States)

    Kannan, Rangaramanujam

    2007-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, `peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. They have significant potential compared to liposomes and nanoparticles, because of the reduced macrophage update, increased cellular transport, and the ability to modulate the local environment through functional groups. We are developing nanodevices based on dendritic systems for drug delivery, that contain a high drug payload, ligands, and imaging agents, resulting in `smart' drug delivery devices that can target, deliver, and signal. In collaboration with the Children's Hospital of Michigan, Karmanos Cancer Institute, and College of Pharmacy, we are testing the in vitro and in vivo response of these nanodevices, by adapting the chemistry for specific clinical applications such as asthma and cancer. These materials are characterized by UV/Vis spectroscopy, flow cytometry, fluorescence/confocal microscopy, and appropriate animal models. Our results suggest that: (1) We can prepare drug-dendrimer conjugates with drug payloads of greater than 50%, for a variety of drugs; (2) The dendritic polymers are capable of transporting and delivering drugs into cells faster than free drugs, with superior therapeutic efficiency. This can be modulated by the surface functionality of the dendrimer; (3) For chemotherapy drugs, the conjugates are a factor of 6-20 times more effective even in drug-resistant cell lines; (4) For corticosteroidal drugs, the dendritic polymers provide higher drug residence times in the lung, allowing for passive targeting. The ability of the drug-dendrimer-ligand conjugates to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  15. Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization.

    Science.gov (United States)

    Sokar, M; Hanafy, A; Elkamel, A; El-Gamal, S

    2015-01-01

    The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time

  16. Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation.

    Science.gov (United States)

    Verma, Sanjay; Rudraraju, Varma S

    2015-02-01

    The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months.

  17. 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...

  18. Design and Development of Mixed Film of Pectin: Ethyl Cellulose for Colon Specific Drug Delivery of Sennosides and Triphala

    Science.gov (United States)

    Momin, Munira; Pundarikakshudu, K.; Nagori, S. A.

    2008-01-01

    The present study was aimed at developing colon specific drug delivery system for sennosides and Triphala. These drugs are reputed Ayurvedic medicines for constipation in India. The proposed device explored the application of pectin and ethyl cellulose as a mixed film for colon specific delivery. This mixed film was prepared using non-aqueous solvents like acetone and isopropyl alcohol. A 32 factorial design was adopted to optimize the formulation variables like, ratio of ethyl cellulose to pectin (X1) and coat weight (X2). The rate and extent of drug release were found to be related to the thickness and the ratio of pectin to ethyl cellulose within the film. Statistical treatments to the drug release data revealed that the X1 variable was more important than X2. Under simulated colonic conditions, drug release was more pronounced from coating formulations containing higher proportions of pectin. The surface of the device was coated with Eudragit S100 to ensure that the device was more pH dependent and trigger the drug release only at higher pH. The final product is expected to have the advantage of being biodegradable and pH dependant. This type of a film effectively releases the drug while maintaining its integrity. PMID:20046742

  19. 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.

  20. Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design

    Science.gov (United States)

    Basith, Shaherin; Cui, Minghua; Macalino, Stephani J. Y.; Park, Jongmi; Clavio, Nina A. B.; Kang, Soosung; Choi, Sun

    2018-01-01

    The primary goal of rational drug discovery is the identification of selective ligands which act on single or multiple drug targets to achieve the desired clinical outcome through the exploration of total chemical space. To identify such desired compounds, computational approaches are necessary in predicting their drug-like properties. G Protein-Coupled Receptors (GPCRs) represent one of the largest and most important integral membrane protein families. These receptors serve as increasingly attractive drug targets due to their relevance in the treatment of various diseases, such as inflammatory disorders, metabolic imbalances, cardiac disorders, cancer, monogenic disorders, etc. In the last decade, multitudes of three-dimensional (3D) structures were solved for diverse GPCRs, thus referring to this period as the “golden age for GPCR structural biology.” Moreover, accumulation of data about the chemical properties of GPCR ligands has garnered much interest toward the exploration of GPCR chemical space. Due to the steady increase in the structural, ligand, and functional data of GPCRs, several cheminformatics approaches have been implemented in its drug discovery pipeline. In this review, we mainly focus on the cheminformatics-based paradigms in GPCR drug discovery. We provide a comprehensive view on the ligand– and structure-based cheminformatics approaches which are best illustrated via GPCR case studies. Furthermore, an appropriate combination of ligand-based knowledge with structure-based ones, i.e., integrated approach, which is emerging as a promising strategy for cheminformatics-based GPCR drug design is also discussed. PMID:29593527

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

    Directory of Open Access Journals (Sweden)

    Hui Huang

    2015-07-01

    Full Text Available 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 disposal. This paper establishes a tri-level programming model to study how the government can optimize an expired drug recycling logistics network and the appropriate subsidy policies. Furthermore, a Hybrid Genetic Simulated Annealing Algorithm (HGSAA is proposed to search for the optimal solution of the model. An experiment is discussed to illustrate the good quality of the recycling logistics network and government subsides obtained by the HGSAA. The HGSAA is proven to have the ability to converge on the global optimal solution, and to act as an effective algorithm for solving the optimization problem of expired drug recycling logistics network and government subsidies.

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

    Science.gov (United States)

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

    2015-07-09

    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 disposal. This paper establishes a tri-level programming model to study how the government can optimize an expired drug recycling logistics network and the appropriate subsidy policies. Furthermore, a Hybrid Genetic Simulated Annealing Algorithm (HGSAA) is proposed to search for the optimal solution of the model. An experiment is discussed to illustrate the good quality of the recycling logistics network and government subsides obtained by the HGSAA. The HGSAA is proven to have the ability to converge on the global optimal solution, and to act as an effective algorithm for solving the optimization problem of expired drug recycling logistics network and government subsidies.

  3. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety.

    Science.gov (United States)

    Meanwell, Nicholas A

    2011-09-19

    The development of small molecule drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclinical profiling that have improved compound triaging and altered the underlying reasons for compound attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochemical properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by molecules with increased molecular weight and higher overall lipophilicity. The preponderance of molecules expressing these properties is frequently a function of increased aromatic ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochemical properties associated with marketed drugs, guidelines for drug design have been developed that are based largely on calculated parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochemical properties of a molecule that are consistent with the potential for good oral absorption were initially defined by Lipinski, with additional insights allowing further

  4. Access control infrastructure for on-demand provisioned virtualised infrastructure services

    NARCIS (Netherlands)

    Demchenko, Y.; Ngo, C.; de Laat, C.; Smari, W.W.; Fox, G.C.

    2011-01-01

    Cloud technologies are emerging as a new way of provisioning virtualised computing and infrastructure services on-demand for collaborative projects and groups. Security in provisioning virtual infrastructure services should address two general aspects: supporting secure operation of the provisioning

  5. On-Demand Dark Soliton Train Manipulation in a Spinor Polariton Condensate

    KAUST Repository

    Pinsker, F.; Flayac, H.

    2014-01-01

    or electrically to provide a stable and efficient output signal modulation. Taking the polarization of the condensate into account, we elucidate the possibility of forming on-demand half-soliton trains. © 2014 American Physical Society.

  6. An Efficient Interactive Model for On-Demand Sensing-As-A-Servicesof Sensor-Cloud

    Directory of Open Access Journals (Sweden)

    Thanh Dinh

    2016-06-01

    Full Text Available This paper proposes an efficient interactive model for the sensor-cloud to enable the sensor-cloud to efficiently provide on-demand sensing services for multiple applications with different requirements at the same time. The interactive model is designed for both the cloud and sensor nodes to optimize the resource consumption of physical sensors, as well as the bandwidth consumption of sensing traffic. In the model, the sensor-cloud plays a key role in aggregating application requests to minimize the workloads required for constrained physical nodes while guaranteeing that the requirements of all applications are satisfied. Physical sensor nodes perform their sensing under the guidance of the sensor-cloud. Based on the interactions with the sensor-cloud, physical sensor nodes adapt their scheduling accordingly to minimize their energy consumption. Comprehensive experimental results show that our proposed system achieves a significant improvement in terms of the energy consumption of physical sensors, the bandwidth consumption from the sink node to the sensor-cloud, the packet delivery latency, reliability and scalability, compared to current approaches. Based on the obtained results, we discuss the economical benefits and how the proposed system enables a win-win model in the sensor-cloud.

  7. A Rule-Based Data Transfer Protocol for On-Demand Data Exchange in Vehicular Environment

    Directory of Open Access Journals (Sweden)

    Liao Hsien-Chou

    2009-01-01

    Full Text Available The purpose of Intelligent Transport System (ITS is mainly to increase the driving safety and efficiency. Data exchange is an important way to achieve the purpose. An on-demand data exchange is especially useful to assist a driver avoiding some emergent events. In order to handle the data exchange under dynamic situations, a rule-based data transfer protocol is proposed in this paper. A set of rules is designed according to the principle of request-forward-reply (RFR. That is, they are used to determine the timing of data broadcasting, forwarding, and replying automatically. Two typical situations are used to demonstrate the operation of rules. One is the front view of a driver occluded by other vehicles. The other is the traffic jam. The proposed protocol is flexible and extensible for unforeseen situations. Three simulation tools were also implemented to demonstrate the feasibility of the protocol and measure the network transmission under high density of vehicles. The simulation results show that the rule-based protocol is efficient on data exchange to increase the driving safety.

  8. On-demand liquid-in-liquid droplet metering and fusion utilizing pneumatically actuated membrane valves

    International Nuclear Information System (INIS)

    Lin, Bo-Chih; Su, Yu-Chuan

    2008-01-01

    This paper presents an active emulsification scheme that is capable of producing micro-droplets with desired volumes and compositions on demand. Devices with pneumatically actuated membranes constructed on top of specially designed microfluidic channels are utilized to meter and fuse liquid-in-liquid droplets. By steadily pressurizing a fluid and intermittently blocking its flow, droplets with desired volumes are dispersed into another fluid. Furthermore, droplets from multiple sources are fused together to produce combined droplets with desired compositions. In the prototype demonstration, a three-layer PDMS molding and irreversible bonding process was employed to fabricate the proposed microfluidic devices. For a dispersed-phase flow that is normally blocked by a membrane valve, the relationship between the volume (V) of a metered droplet and the corresponding valve open time (T) is found to be approximately V = kT a , in which k and a are constants determined mainly by the fluid-driving pressures. In addition to the metering device, functional droplet entrapment, fusion and flow-switching devices were also integrated in the system to produce desired combined droplets and deliver them to intended destinations upon request. As such, the demonstrated microfluidic system could potentially realize the controllability on droplet volume, composition and motion, which is desired for a variety of chemical and biological applications

  9. On-Demand Sensor Node Wake-Up Using Solar Panels and Visible Light Communication

    Directory of Open Access Journals (Sweden)

    Carolina Carrascal

    2016-03-01

    Full Text Available To significantly reduce, or eliminate completely, the energy waste caused by the standby (idle mode of wireless sensor nodes, we propose a novel on-demand wake-up system, which allows the nodes to be put into sleep mode unless their activation is truly necessary. Although there have been many studies proposing RF-based wake-up radio systems, in this work, we develop the first visible light communication (VLC-based wake-up system. The developed system can extend the existing VLC systems and can be exploited to derive new application areas such as VLC tags. The system uses an off-the-shell indoor solar panel as receptor device of the wake-up signal as well as for energy harvesting purposes, through which it is able to harvest enough energy for its autonomous work. The design, implementation details and the experimental evaluation results are presented, which include flickering characterization and wake-up range evaluations. The results show that the developed system achieve reasonable wake-up distances for indoor environments, mainly where the use of VLC systems are considered.

  10. On-Demand Sensor Node Wake-Up Using Solar Panels and Visible Light Communication.

    Science.gov (United States)

    Carrascal, Carolina; Demirkol, Ilker; Paradells, Josep

    2016-03-22

    To significantly reduce, or eliminate completely, the energy waste caused by the standby (idle) mode of wireless sensor nodes, we propose a novel on-demand wake-up system, which allows the nodes to be put into sleep mode unless their activation is truly necessary. Although there have been many studies proposing RF-based wake-up radio systems, in this work, we develop the first visible light communication (VLC)-based wake-up system. The developed system can extend the existing VLC systems and can be exploited to derive new application areas such as VLC tags. The system uses an off-the-shell indoor solar panel as receptor device of the wake-up signal as well as for energy harvesting purposes, through which it is able to harvest enough energy for its autonomous work. The design, implementation details and the experimental evaluation results are presented, which include flickering characterization and wake-up range evaluations. The results show that the developed system achieve reasonable wake-up distances for indoor environments, mainly where the use of VLC systems are considered.

  11. Design and evaluation of novel interferon lambda analogs with enhanced antiviral activity and improved drug attributes

    Directory of Open Access Journals (Sweden)

    Yu D

    2016-01-01

    Full Text Available Debin Yu,1 Mingzhi Zhao,2 Liwei Dong,1 Lu Zhao,1 Mingwei Zou,3 Hetong Sun,4 Mengying Zhang,4 Hongyu Liu,4 Zhihua Zou1 1National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, 2State Key Laboratory of Proteomics, National Engineering Research Center for Protein Drugs, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3Department of Psychology, College of Liberal Arts and Social Sciences, University of Houston, Houston, TX, USA; 4Prosit Sole Biotechnology, Co., Ltd., Beijing, People’s Republic of China Abstract: Type III interferons (IFNs (also called IFN-λ: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4 are critical players in the defense against viral infection of mucosal epithelial cells, where the activity of type I IFNs is weak, and unlike type I IFNs that are associated with severe and diverse side effects, type III IFNs cause minimal side effects due to the highly restricted expression of their receptors, and thus appear to be promising agents for the treatment and prevention of respiratory and gastrointestinal viral infection. However, the antiviral potency of natural type III IFNs is weak compared to type I and, although IFN-λ3 possesses the highest bioactivity among the type III IFNs, IFN-λ1, instead of IFN-λ3, is being developed as a therapeutic drug due to the difficulty to express IFN-λ3 in the prokaryotic expression system. Here, to develop optimal IFN-λ molecules with improved drug attributes, we designed a series of IFN-λ analogs by replacing critical amino acids of IFN-λ1 with the IFN-λ3 counterparts, and vice versa. Four of the designed analogs were successfully expressed in Escherichia coli with high yield and were easily purified from inclusion bodies. Interestingly, all four analogs showed potent activity in inducing the

  12. The Surveillance and On-demand Sentinel-1 SBAS Services on the Geohazards Exploitation Platforms

    Science.gov (United States)

    Casu, F.; de Luca, C.; Zinno, I.; Manunta, M.; Lanari, R.

    2017-12-01

    The Geohazards Exploitation Platform (GEP) is an ESA R&D activity of the EO ground segment to demonstrate the benefit of new technologies for large scale processing of EO data. GEP aims at providing on-demand processing services for specific user needs, as well as systematic processing services to address the need of the geohazards community for common information layers and, finally, to integrate newly developed processors for scientists and other expert users. In this context, a crucial role is played by the recently launched Sentinel-1 (S1) constellation that, with its global acquisition policy, has flooded the scientific community with a huge amount of data acquired over large part of the Earth on a regular basis (down to 6-days with both Sentinel-1A and 1B passes). The Sentinel-1 data, as part of the European Copernicus program, are openly and freely accessible, thus fostering their use for the development of automated and systematic tools for Earth surface monitoring. In particular, due to their specific SAR Interferometry (InSAR) design, Sentinel-1 satellites can be exploited to build up operational services for the easy and rapid generation of advanced InSAR products useful for risk management and natural hazard monitoring. In this work we present the activities carried out for the development, integration, and deployment of two SBAS Sentinel-1 services of CNR-IREA within the GEP framework, namely the Surveillance and On-demand services. The Surveillance service consists on the systematic and automatic processing of Sentinel-1 data over selected Areas of Interest (AoI) to generate updated surface displacement time series via the SBAS-InSAR algorithm. We built up a system that is automatically triggered by every new Sentinel-1 acquisition over the AoI, once it is available on the S1 catalogue. Then, the system processes the new acquisitions only, thus saving storage space and computing time. The processing, which relies on the Parallel version of the SBAS (P

  13. Mission Planning and Decision Support for Underwater Glider Networks: A Sampling on-Demand Approach

    Science.gov (United States)

    Ferri, Gabriele; Cococcioni, Marco; Alvarez, Alberto

    2015-01-01

    This paper describes an optimal sampling approach to support glider fleet operators and marine scientists during the complex task of planning the missions of fleets of underwater gliders. Optimal sampling, which has gained considerable attention in the last decade, consists in planning the paths of gliders to minimize a specific criterion pertinent to the phenomenon under investigation. Different criteria (e.g., A, G, or E optimality), used in geosciences to obtain an optimum design, lead to different sampling strategies. In particular, the A criterion produces paths for the gliders that minimize the overall level of uncertainty over the area of interest. However, there are commonly operative situations in which the marine scientists may prefer not to minimize the overall uncertainty of a certain area, but instead they may be interested in achieving an acceptable uncertainty sufficient for the scientific or operational needs of the mission. We propose and discuss here an approach named sampling on-demand that explicitly addresses this need. In our approach the user provides an objective map, setting both the amount and the geographic distribution of the uncertainty to be achieved after assimilating the information gathered by the fleet. A novel optimality criterion, called Aη, is proposed and the resulting minimization problem is solved by using a Simulated Annealing based optimizer that takes into account the constraints imposed by the glider navigation features, the desired geometry of the paths and the problems of reachability caused by ocean currents. This planning strategy has been implemented in a Matlab toolbox called SoDDS (Sampling on-Demand and Decision Support). The tool is able to automatically download the ocean fields data from MyOcean repository and also provides graphical user interfaces to ease the input process of mission parameters and targets. The results obtained by running SoDDS on three different scenarios are provided and show that So

  14. Mission Planning and Decision Support for Underwater Glider Networks: A Sampling on-Demand Approach.

    Science.gov (United States)

    Ferri, Gabriele; Cococcioni, Marco; Alvarez, Alberto

    2015-12-26

    This paper describes an optimal sampling approach to support glider fleet operators and marine scientists during the complex task of planning the missions of fleets of underwater gliders. Optimal sampling, which has gained considerable attention in the last decade, consists in planning the paths of gliders to minimize a specific criterion pertinent to the phenomenon under investigation. Different criteria (e.g., A, G, or E optimality), used in geosciences to obtain an optimum design, lead to different sampling strategies. In particular, the A criterion produces paths for the gliders that minimize the overall level of uncertainty over the area of interest. However, there are commonly operative situations in which the marine scientists may prefer not to minimize the overall uncertainty of a certain area, but instead they may be interested in achieving an acceptable uncertainty sufficient for the scientific or operational needs of the mission. We propose and discuss here an approach named sampling on-demand that explicitly addresses this need. In our approach the user provides an objective map, setting both the amount and the geographic distribution of the uncertainty to be achieved after assimilating the information gathered by the fleet. A novel optimality criterion, called A η , is proposed and the resulting minimization problem is solved by using a Simulated Annealing based optimizer that takes into account the constraints imposed by the glider navigation features, the desired geometry of the paths and the problems of reachability caused by ocean currents. This planning strategy has been implemented in a Matlab toolbox called SoDDS (Sampling on-Demand and Decision Support). The tool is able to automatically download the ocean fields data from MyOcean repository and also provides graphical user interfaces to ease the input process of mission parameters and targets. The results obtained by running SoDDS on three different scenarios are provided and show that So

  15. Mission Planning and Decision Support for Underwater Glider Networks: A Sampling on-Demand Approach

    Directory of Open Access Journals (Sweden)

    Gabriele Ferri

    2015-12-01

    Full Text Available This paper describes an optimal sampling approach to support glider fleet operators and marine scientists during the complex task of planning the missions of fleets of underwater gliders. Optimal sampling, which has gained considerable attention in the last decade, consists in planning the paths of gliders to minimize a specific criterion pertinent to the phenomenon under investigation. Different criteria (e.g., A, G, or E optimality, used in geosciences to obtain an optimum design, lead to different sampling strategies. In particular, the A criterion produces paths for the gliders that minimize the overall level of uncertainty over the area of interest. However, there are commonly operative situations in which the marine scientists may prefer not to minimize the overall uncertainty of a certain area, but instead they may be interested in achieving an acceptable uncertainty sufficient for the scientific or operational needs of the mission. We propose and discuss here an approach named sampling on-demand that explicitly addresses this need. In our approach the user provides an objective map, setting both the amount and the geographic distribution of the uncertainty to be achieved after assimilating the information gathered by the fleet. A novel optimality criterion, called A η , is proposed and the resulting minimization problem is solved by using a Simulated Annealing based optimizer that takes into account the constraints imposed by the glider navigation features, the desired geometry of the paths and the problems of reachability caused by ocean currents. This planning strategy has been implemented in a Matlab toolbox called SoDDS (Sampling on-Demand and Decision Support. The tool is able to automatically download the ocean fields data from MyOcean repository and also provides graphical user interfaces to ease the input process of mission parameters and targets. The results obtained by running SoDDS on three different scenarios are provided

  16. Multimodal system designed to reduce errors in recording and administration of drugs in anaesthesia: prospective randomised clinical evaluation.

    Science.gov (United States)

    Merry, Alan F; Webster, Craig S; Hannam, Jacqueline; Mitchell, Simon J; Henderson, Robert; Reid, Papaarangi; Edwards, Kylie-Ellen; Jardim, Anisoara; Pak, Nick; Cooper, Jeremy; Hopley, Lara; Frampton, Chris; Short, Timothy G

    2011-09-22

    To clinically evaluate a new patented multimodal system (SAFERSleep) designed to reduce errors in the recording and administration of drugs in anaesthesia. Prospective randomised open label clinical trial. Five designated operating theatres in a major tertiary referral hospital. Eighty nine consenting anaesthetists managing 1075 cases in which there were 10,764 drug administrations. Use of the new system (which includes customised drug trays and purpose designed drug trolley drawers to promote a well organised anaesthetic workspace and aseptic technique; pre-filled syringes for commonly used anaesthetic drugs; large legible colour coded drug labels; a barcode reader linked to a computer, speakers, and touch screen to provide automatic auditory and visual verification of selected drugs immediately before each administration; automatic compilation of an anaesthetic record; an on-screen and audible warning if an antibiotic has not been administered within 15 minutes of the start of anaesthesia; and certain procedural rules-notably, scanning the label before each drug administration) versus conventional practice in drug administration with a manually compiled anaesthetic record. Primary: composite of errors in the recording and administration of intravenous drugs detected by direct observation and by detailed reconciliation of the contents of used drug vials against recorded administrations; and lapses in responding to an intermittent visual stimulus (vigilance latency task). Secondary: outcomes in patients; analyses of anaesthetists' tasks and assessments of workload; evaluation of the legibility of anaesthetic records; evaluation of compliance with the procedural rules of the new system; and questionnaire based ratings of the respective systems by participants. The overall mean rate of drug errors per 100 administrations was 9.1 (95% confidence interval 6.9 to 11.4) with the new system (one in 11 administrations) and 11.6 (9.3 to 13.9) with conventional methods (one

  17. Full factorial design optimization of anti-inflammatory drug release by PCL–PEG–PCL microspheres

    Energy Technology Data Exchange (ETDEWEB)

    Azouz, L' Hachemi, E-mail: azouz.chimie@gmail.com [Laboratoire des Matériaux Organiques (LMO), Faculté des Sciences Exactes, Département de Chimie, Université de Bejaia, 06000 Bejaia Algérie (Algeria); Dahmoune, Farid, E-mail: farid.dahmoune@yahoo.fr [Laboratoire de Biomathématiques, Biophysique, Biochimie et Scientométrie (L3BS-Bejaia), Faculté des Sciences de la Nature et de la Vie et des Sciences de la Terre, Université de Bouira 10000 Bouira (Algeria); Rezgui, Farouk, E-mail: rezgui-farouk@netcourrier.com [Laboratoire des Matériaux Organiques (LMO), Faculté de Technologie, Département de Génie des Procédés, Université de Bejaia, 06000 Bejaia (Algeria); G' Sell, Christian, E-mail: gsell.christian@univ-lorraine.fr [Université de Lorraine, Pôle scientifique M4, Institut Jean Lamour - UMR CNRS-UL 7198, Département SI2M, 54000 Nancy (France)

    2016-01-01

    A biodegradable triblock poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) copolymer was successfully synthesized by ring-opening polymerization of ε-caprolactone, and was characterized by intrinsic viscosimetry, {sup 1}H nuclear magnetic resonance, infrared spectroscopy and X-ray diffraction. Copolymer microparticles loaded with ibuprofen were prepared by an oil-in-water (o/w) emulsion solvent evaporation process. They were carefully weighted and characterized through their zeta potential. In this work, 4 selected process parameters (shaking speed X{sub 1}, time of contact X{sub 2}, poly(vinyl alcohol) concentration X{sub 3}, and ibuprofen concentration X{sub 4}) were adjusted at 2 different values. For each of the 16 experimental conditions, repeated twice, the drug encapsulation efficiency of the microspheres was determined, according to the following definition: EE (X{sub 1}, X{sub 2}, X{sub 3}, X{sub 4}) = mass of encapsulated ibuprofen / total weight of ibuprofen. A “full factorial design method” was applied to analyze the results statistically according to a polynomial fit and to determine the optimal conditions for the microencapsulation of the ibuprofen through an accurate statistical protocol. The microparticles obtained exhibit a spherical shape as shown by electron microscopy. - Highlights: • PCEC copolymer was synthesized by ring-opening polymerization of ε-caprolactone. • 2{sup 4} experimental design was used to optimize the IBF encapsulation efficiency (EE). • 88.86% of ibuprofen (IBF) was encapsulated in PCEC microspheres. • EE significantly decreases with increasing shaking speed (antagonist effect). • EE significantly increases with increasing IBF concentration (synergetic effect).

  18. Characterization of a human peptide deformylase: implications for antibacterial drug design.

    Science.gov (United States)

    Nguyen, Kiet T; Hu, Xubo; Colton, Craig; Chakrabarti, Ratna; Zhu, Michael X; Pei, Dehua

    2003-08-26

    Ribosomal protein synthesis in eubacteria and eukaryotic organelles initiates with an N-formylmethionyl-tRNA(i), resulting in N-terminal formylation of all nascent polypeptides. Peptide deformylase (PDF) catalyzes the subsequent removal of the N-terminal formyl group from the majority of bacterial proteins. Deformylation was for a long time thought to be a feature unique to the prokaryotes, making PDF an attractive target for designing novel antibiotics. However, recent genomic sequencing has revealed PDF-like sequences in many eukaryotes, including man. In this work, the cDNA encoding Homo sapiens PDF (HsPDF) has been cloned and a truncated form that lacks the N-terminal 58-amino-acid targeting sequence was overexpressed in Escherichia coli. The recombinant, Co(2+)-substituted protein is catalytically active in deformylating N-formylated peptides, shares many of the properties of bacterial PDF, and is strongly inhibited by specific PDF inhibitors. Expression of HsPDF fused to the enhanced green fluorescence protein in human embryonic kidney cells revealed its location in the mitochondrion. However, HsPDF is much less active than its bacterial counterpart, providing a possible explanation for the apparent lack of deformylation in the mammalian mitochondria. The lower catalytic activity is at least partially due to mutation of a highly conserved residue (Leu-91 in E. coli PDF) in mammalian PDF. PDF inhibitors had no detectable effect on two different human cell lines. These results suggest that HsPDF is likely an evolutional remnant without any functional role in protein formylation/deformylation and validates PDF as an excellent target for antibacterial drug design.

  19. Design of multifunctional nanoparticles for combined in-vivo imaging and advanced drug delivery

    Science.gov (United States)

    Leary, James F.

    2018-02-01

    Design of multifunctional nanoparticles for multimodal in-vivo imaging and advanced targeting to diseased single cells for massive parallel processing nanomedicine approaches requires careful overall design and a multilayered approach. Initial core materials can include non-toxic metals which not only serve as an x-ray contrast agent for CAT scan imaging, but can contain T1 or T2 contrast agents for MRI imaging. One choice is superparamagnetic iron oxide NPs which also allow for convenient magnetic manipulation during manufacturing but also for re-positioning inside the body and for single cell hyperthermia therapies. To permit real-time fluorescence-guided surgery, fluorescence molecules can be included. Advanced targeting can be achieved by attaching antibodies, peptides, aptamers, or other targeting molecules to the nanoparticle in a multilayered approach producing "programmable nanoparticles" whereby the "programming" means controlling a sequence of multi-step targeting methods. Addition of membrane permeating peptides can facilitate uptake by the cell. Addition of "stealth" molecules (e.g. PEG or chitosan) to the outer surfaces of the nanoparticles can permit greatly enhanced circulation times in-vivo which in turn lead to lower amounts of drug exposure to the patient which can reduce undesirable side effects. Nanoparticles with incomplete layers can be removed by affinity purification methods to minimize mistargeting events in-vivo. Nanoscale imaging of these manufactured, multifunctional nanoparticles can be achieved either directly through superresolution microscopy or indirectly through single nanoparticle zeta-sizing or x-ray correlation microscopy. Since these multifunctional nanoparticles are best analyzed by technologies permitting analysis in aqueous environments, superresolution microscopy is, in most cases, the preferred method.

  20. Full factorial design optimization of anti-inflammatory drug release by PCL–PEG–PCL microspheres

    International Nuclear Information System (INIS)

    Azouz, L'Hachemi; Dahmoune, Farid; Rezgui, Farouk; G'Sell, Christian

    2016-01-01

    A biodegradable triblock poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) copolymer was successfully synthesized by ring-opening polymerization of ε-caprolactone, and was characterized by intrinsic viscosimetry, 1 H nuclear magnetic resonance, infrared spectroscopy and X-ray diffraction. Copolymer microparticles loaded with ibuprofen were prepared by an oil-in-water (o/w) emulsion solvent evaporation process. They were carefully weighted and characterized through their zeta potential. In this work, 4 selected process parameters (shaking speed X 1 , time of contact X 2 , poly(vinyl alcohol) concentration X 3 , and ibuprofen concentration X 4 ) were adjusted at 2 different values. For each of the 16 experimental conditions, repeated twice, the drug encapsulation efficiency of the microspheres was determined, according to the following definition: EE (X 1 , X 2 , X 3 , X 4 ) = mass of encapsulated ibuprofen / total weight of ibuprofen. A “full factorial design method” was applied to analyze the results statistically according to a polynomial fit and to determine the optimal conditions for the microencapsulation of the ibuprofen through an accurate statistical protocol. The microparticles obtained exhibit a spherical shape as shown by electron microscopy. - Highlights: • PCEC copolymer was synthesized by ring-opening polymerization of ε-caprolactone. • 2 4 experimental design was used to optimize the IBF encapsulation efficiency (EE). • 88.86% of ibuprofen (IBF) was encapsulated in PCEC microspheres. • EE significantly decreases with increasing shaking speed (antagonist effect). • EE significantly increases with increasing IBF concentration (synergetic effect).

  1. Receptor-based 3D-QSAR in Drug Design: Methods and Applications in Kinase Studies.

    Science.gov (United States)

    Fang, Cheng; Xiao, Zhiyan

    2016-01-01

    Receptor-based 3D-QSAR strategy represents a superior integration of structure-based drug design (SBDD) and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. It combines the accurate prediction of ligand poses by the SBDD approach with the good predictability and interpretability of statistical models derived from the 3D-QSAR approach. Extensive efforts have been devoted to the development of receptor-based 3D-QSAR methods and two alternative approaches have been exploited. One associates with computing the binding interactions between a receptor and a ligand to generate structure-based descriptors for QSAR analyses. The other concerns the application of various docking protocols to generate optimal ligand poses so as to provide reliable molecular alignments for the conventional 3D-QSAR operations. This review highlights new concepts and methodologies recently developed in the field of receptorbased 3D-QSAR, and in particular, covers its application in kinase studies.

  2. Magnetic field pattern synthesis and its application in targeted drug delivery: Design and implementation.

    Science.gov (United States)

    Hajiaghajani, Amirhossein; Abdolali, Ali

    2018-05-01

    In cancer therapy, magnetic drug targeting is considered as an effective treatment to reduce chemotherapy's side effects. The accurate design and shaping of magnetic fields are crucial for healthy cells to be immune from chemotherapeutics. In this paper, arbitrary 2-dimensional spatial patterns of magnetic fields from DC to megahertz are represented in terms of spatial Fourier spectra with sinusoidal eigenfunctions. Realization of each spatial frequency was investigated by a set of elliptical coils. Therefore, it is shown that the desired pattern was synthesized by simultaneous use of coil sets. Currents running on each set were obtained via fast and straightforward analytical Fourier series calculation. Experimentally scanned sample patterns were in close agreement with full wave analysis. Discussions include the evaluation of the Fourier series approximation error and cross-polarization of produced magnetic fields. It was observed that by employing the controlled magnetic field produced by the proposed setup, we were able to steer therapeutic particles toward the right or left half-spheres of the breast, with an efficiency of 90%. Such a pattern synthesizer may be employed in numerous human arteries as well as other bioelectromagnetic patterning applications, e.g., wireless power transfer, magnetic innervation, and tomography. Bioelectromagnetics. 39:325-338, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

  3. Counterpublic health and the design of drug services for methamphetamine consumers in Melbourne.

    Science.gov (United States)

    Duff, Cameron; Moore, David

    2015-01-01

    This article is interested in how notions of the 'public' are conceived, marshalled and enacted in drug-treatment responses to methamphetamine use in Melbourne, Australia. After reviewing qualitative data collected among health-care providers and methamphetamine consumers, we draw on the work of Michael Warner to argue that services for methamphetamine consumers in Melbourne betray ongoing tensions between 'public' and 'counterpublic' constituencies. Our analysis indicates that these tensions manifest in two ways: in the management of 'street business' in the delivery of services and in negotiating the meaning of health and the terms of its restoration or promotion. Reflecting these tensions, while the design of services for methamphetamine consumers is largely modelled on public health principles, the everyday experience of these services may be more accurately characterised in terms of what Kane Race has called 'counterpublic health'. Extending Race's analysis, we conclude that more explicit focus on the idea of counterpublic health may help local services engage with methamphetamine consumers in new ways, providing grounds for novel outreach, harm-reduction and treatment strategies. © The Author(s) 2014.

  4. Kite-powered design-to-robotic-production for affordable building on demand

    NARCIS (Netherlands)

    Bier, H.H.; Schmehl, R.; Mostafavi, S.S.; Anton, A.M.; Bodea, I.S.B.

    2017-01-01

    Building technologies employed today in 2nd and 3rd world countries are imported, expensive, outdated and unsustainable. Highly developed countries, on the other hand, rapidly advance in developing affordable, numerically controlled and robotically supported material- and energy-efficient methods

  5. Technology Transfer Opportunities: On-Demand Printing in Support of National Geospatial Data

    Science.gov (United States)

    ,

    1997-01-01

    The U.S. Geological Survey (USGS) and the 3M Company of St. Paul, Minnesota, have entered into a cooperative research and development agreement (CRADA) to investigate maps-on-demand technology to support the production of USGS mapping products. The CRADA will potentially help the USGS to develop on-demand alternatives to lithographic maps and help 3M to develop a series of commercial instant map-printing systems.

  6. Development of a New Web Portal for the Database on Demand Service

    CERN Document Server

    Altinigne, Can Yilmaz

    2017-01-01

    The Database on Demand service allows members of CERN communities to provision and manage database instances of different flavours (MySQL, Oracle, PostgreSQL and InfluxDB). Users can create and edit these instances using the web interface of DB On Demand. This web front end is currently on Java technologies and the ZK web framework, for which is generally difficult to find experienced developers and which has gotten to lack behind more modern web stacks in capabilities and usability.

  7. Window-Based Popularity Caching for IPTV On-Demand Services

    OpenAIRE

    Hsuan Chiu; Chi-He Chang; Chao-Wei Tseng; Chi-Shi Liu

    2011-01-01

    In recent years, many telecommunication companies have regarded IP network as a new delivery platform for providing TV services because IP network is equipped with two-way and high-speed communication abilities which are appropriate to provide on-demand services and linear TV programs. However, in this IPTV system, the requests of VOD (video on demand) are usually aggregated in a short period intensively and user preferences are fluctuated dynamically. Moreover, the VOD content is updated fre...

  8. Tailoring single-photon and multiphoton probabilities of a single-photon on-demand source

    International Nuclear Information System (INIS)

    Migdall, A.L.; Branning, D.; Castelletto, S.

    2002-01-01

    As typically implemented, single-photon sources cannot be made to produce single photons with high probability, while simultaneously suppressing the probability of yielding two or more photons. Because of this, single-photon sources cannot really produce single photons on demand. We describe a multiplexed system that allows the probabilities of producing one and more photons to be adjusted independently, enabling a much better approximation of a source of single photons on demand

  9. Efficacy of On-Demand Therapy Using 20-mg Vonoprazan for Mild Reflux Esophagitis.

    Science.gov (United States)

    Umezawa, Mariko; Kawami, Noriyuki; Hoshino, Shintaro; Hoshikawa, Yoshimasa; Koizumi, Eriko; Takenouchi, Nana; Hanada, Yuriko; Kaise, Mitsuru; Iwakiri, Katsuhiko

    2018-01-01

    The study aimed to evaluate the efficacy of on-demand therapy using 20-mg vonoprazan for mild reflux esophagitis (RE). On-demand therapy by taking one 20-mg tablet of vonoprazan only when reflux symptoms occurred was performed for 24 weeks using 30 patients with mild RE who were receiving maintenance therapy with proton pomp inhibitors (PPIs). The presence or absence of RE, degree of overall satisfaction with the treatment, score of symptoms, and fasting gastrin level before breakfast were examined before and after on-demand therapy. The number of tablets taken during the 24-week period was also noted. One of the 30 patients dropped out of on-demand therapy 1 week after its initiation. Remission was maintained in 25 (86.2%) of the 29 patients (all 10 [100%] Los Angeles classification grade A patients and 15 (78.9%) of the 19 grade B patients). However, 4 grade B patients exhibited grade B relapse. There were no differences in the degree of overall satisfaction, score of symptoms or the gastrin level between PPI and on-demand therapies. The number of vonoprazan tablets taken during the observation period was 33 tablets (median)/24 weeks. On-demand therapy using 20-mg vonoprazan tablets is an effective alternative maintenance therapy for mild RE. © 2018 S. Karger AG, Basel.

  10. 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.

  11. 76 FR 39883 - Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis...

    Science.gov (United States)

    2011-07-07

    ...] Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis Media... Clinical Trials for Systemic Antibacterial Agents for the Treatment of Acute Otitis Media. This public... the treatment of acute otitis media (middle ear infection). Discussions will focus on [[Page 39884...

  12. Characteristic Trends in Prevalence and Use of New Synthetic "Designer" Drugs over the Territory of the Republic of Bashkortostan

    Science.gov (United States)

    Asadullin, Azat R.; Yuldashev, Vladimir L.; Galeeva, Elena Kh.; Achmetova, Elvina A.; Nikolaev, Ivan V.

    2016-01-01

    The urgency of this study has become vivid in the light of the growing problem of prevalence and use of new synthetic drug types, incidence rate of comorbid states, and pathomorphism of psychoactive substances consumption. The aim of this paper consists in analysis and disclosure of the research data obtained on consumption of such designer drugs…

  13. 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.

  14. A new drug design targeting the adenosinergic system for Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Nai-Kuei Huang

    Full Text Available BACKGROUND: Huntington's disease (HD is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt gene. The expanded CAG repeats are translated into polyglutamine (polyQ, causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6-(4-hydroxybenzyladenine riboside (designated T1-11 which activates the A(2AR and a major adenosine transporter (ENT1. T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml to the drinking water of a transgenic mouse model of HD (R6/2 ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor

  15. Designing an Effective Prevention Program: Principles Underlying the Rand Smoking and Drug Prevention Experiment.

    Science.gov (United States)

    Ellickson, Phyllis L.

    This paper describes the Project ALERT program (Adolescent Learning Experiences in Resistance Training) which was established by the Rand Corporation to prevent smoking and drug use among seventh graders. The program is based on the social influence model of drug use initiation. Curriculum features are described including motivation to resist and…

  16. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  17. Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design.

    Science.gov (United States)

    Dabhi, Mahesh R; Nagori, Stavan A; Gohel, Mukesh C; Parikh, Rajesh K; Sheth, Navin R

    2010-01-01

    Smart gel periodontal drug delivery systems (SGPDDS) containing gellan gum (0.1-0.8% w/v), lutrol F127 (14, 16, and 18% w/v), and ornidazole (1% w/v) were designed for the treatment of periodontal diseases. Each formulation was characterized in terms of in vitro gelling capacity, viscosity, rheology, content uniformity, in vitro drug release, and syringeability. In vitro gelation time and the nature of the gel formed in simulated saliva for prepared formulations showed polymeric concentration dependency. Drug release data from all formulations was fitted to different kinetic models and the Korsemeyer-Peppas model was the best fit model. Drug release was significantly decreased as the concentration of each polymer component was increased. Increasing the concentration of each polymeric component significantly increased viscosity, syringeability, and time for 50%, 70%, and 90% drug release. In conclusion, the formulations described offer a wide range of physical and drug release characteristics. The formulation containing 0.8% w/v of gellan gum and 16% w/v of lutrol F127 exhibited superior physical characteristics.

  18. Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

    Science.gov (United States)

    Salunkhe, Sachin S; Bhatia, Neela M; Bhatia, Manish S

    2016-05-01

    The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

  19. Preliminary biocompatibility investigation of magnetic albumin nanosphere designed as a potential versatile drug delivery system

    Directory of Open Access Journals (Sweden)

    Estevanato L

    2011-08-01

    Full Text Available Luciana Estevanato1, Débora Cintra1, Nayara Baldini1, Flávia Portilho1, Luzirlane Barbosa1, Olímpia Martins2, Bruno Lacava3, Ana Luisa Miranda-Vilela1, Antônio Cláudio Tedesco2, Sônia Báo1, Paulo C Morais4, Zulmira GM Lacava11Instituto de Ciências Biológicas, Universidade de Brasília, 2Departamento de Química, Laboratório de Fotobiologia e Fotomedicina, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 3Instituto de Química, Universidade de Brasília, Brasília, 4Instituto de Física, Universidade de Brasília, Brasília, BrazilBackground: The magnetic albumin nanosphere (MAN, encapsulating maghemite nanoparticles, was designed as a magnetic drug delivery system (MDDS able to perform a variety of biomedical applications. It is noteworthy that MAN was efficient in treating Ehrlich's tumors by the magnetohyperthermia procedure.Methods and materials: In this study, several nanotoxicity tests were systematically carried out in mice from 30 minutes until 30 days after MAN injection to investigate their biocompatibility status. Cytometry analysis, viability tests, micronucleus assay, and histological analysis were performed.Results: Cytometry analysis and viability tests revealed MAN promotes only slight and temporary alterations in the frequency of both leukocyte populations and viable peritoneal cells, respectively. Micronucleus assay showed absolutely no genotoxicity or cytotoxicity effects and histological analysis showed no alterations or even nanoparticle clusters in several investigated organs but, interestingly, revealed the presence of MAN clusters in the central nervous system (CNS.Conclusion: The results showed that MAN has desirable in vivo biocompatibility, presenting potential for use as a MDDS, especially in CNS disease therapy.Keywords: nanotoxicity, nanoparticle, genotoxicity, cytotoxicity, brain

  20. Caffeic Acid-PLGA Conjugate to Design Protein Drug Delivery Systems Stable to Irradiation

    Directory of Open Access Journals (Sweden)

    Francesca Selmin

    2015-01-01

    Full Text Available This work reports the feasibility of caffeic acid grafted PLGA (g-CA-PLGA to design biodegradable sterile microspheres for the delivery of proteins. Ovalbumin (OVA was selected as model compound because of its sensitiveness of γ-radiation. The adopted grafting procedure allowed us to obtain a material with good free radical scavenging properties, without a significant modification of Mw and Tg of the starting PLGA (Mw PLGA = 26.3 ± 1.3 kDa vs. Mw g-CA-PLGA = 22.8 ± 0.7 kDa; Tg PLGA = 47.7 ± 0.8 °C vs. Tg g-CA-PLGA = 47.4 ± 0.2 °C. By using a W1/O/W2 technique, g-CA-PLGA improved the encapsulation efficiency (EE, suggesting that the presence of caffeic residues improved the compatibility between components (EEPLGA = 35.0% ± 0.7% vs. EEg-CA-PLGA = 95.6% ± 2.7%. Microspheres particle size distribution ranged from 15 to 50 µm. The zeta-potential values of placebo and loaded microspheres were −25 mV and −15 mV, respectively. The irradiation of g-CA-PLGA at the dose of 25 kGy caused a less than 1% variation of Mw and the degradation patterns of the non-irradiated and irradiated microspheres were superimposable. The OVA content in g-CA-PLGA microspheres decreased to a lower extent with respect to PLGA microspheres. These results suggest that g-CA-PLGA is a promising biodegradable material to microencapsulate biological drugs.

  1. 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.

  2. 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

  3. ATR-FTIR Based Pre and Post Formulation Compatibility Studies for the Design of Niosomal Drug Delivery System Containing Nonionic Amphiphiles and Chondroprotective Drug

    International Nuclear Information System (INIS)

    Khan, M.I.; Madni, A.; Ahmad, S.; Rehmanand, M.; Mahmood, M.A.; Khan, A.

    2015-01-01

    Pharmaceutical compatibility studies are considered as the most important and first screening stage during development of pharmaceutical drug product. Attenuated total reflectance/fourier transform infrared (ATR-FTIR) is one of the techniques currently available to pharmaceutical scientists for investigating the compatibilities between active drug and inactive pharmaceutical ingredients. The present study was designed to assess the interaction among different niosomes forming components i.e nonionic amphiphiles and chondroprotective/antiinflamatory drug Diacerein by ATR-FTIR method. Physical mixtures and niosomes were prepared by physical mixing and thin film hydration method, respectively. The individual niosomal components, physical mixtures as well as niosomal formulations were analyzed. The spectra of Diacerein showed characteristic peaks at 3300 cm/sup -1/(-COOH) and 760 cm/sup -1/(msubstituted benzene), Span 60 at 2916 cm/sup -1/(-OH), Span 80 at 1740 cm/sup -1/(5- membered ring), Span 85 at 1643 cm/sup -1/(ketone with 5-membered ring), Tween 20 at 1734 cm/sup 1/ (5-membered ring) and Tween 80 at 3488 cm/sup -1/(-OH). The characteristic peaks of Diacerein were present in niosomal formulations with slight shift at 3355-3379 cm/sup -1/(-COOH) and 760-770 cm/sup -1/(m-substituted benzene). This work suggested no significant interaction in characteristic peaks of Diacerein after combining with nonionic surfactants as physical mixtures and niosomal formulations which proposed potential for niosomes to encapsulate diacerein in their micro vicinity. (author)

  4. A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine

    Directory of Open Access Journals (Sweden)

    S.Mojtaba Taghizadeh

    2015-03-01

    Full Text Available A series of drug-in-adhesive transdermal drug delivery systems (patch with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application. The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box–Behnken experimental design. The response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value. Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0–8% of each chemical penetration enhancer. Buprenorphine was used as a model penetrant drug. The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased. Also that skin flux in presence of levulinic acid (1.594 μg/cm2 h was higher than Tween 80 (1.473 μg/cm2 h and lauryl alcohol (0.843 μg/cm2 h, and in mixing these enhancers together, an additional effect was observed. Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it. These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid. Among the designed formulations, the one which contained 12% (wt/wt enhancers exhibited the highest efficiency.

  5. A statistical experimental design approach to evaluate the influence of various penetration enhancers on transdermal drug delivery of buprenorphine.

    Science.gov (United States)

    Taghizadeh, S Mojtaba; Moghimi-Ardakani, Ali; Mohamadnia, Fatemeh

    2015-03-01

    A series of drug-in-adhesive transdermal drug delivery systems (patch) with different chemical penetration enhancers were designed to deliver drug through the skin as a site of application. The objective of our effort was to study the influence of various chemical penetration enhancers on skin permeation rate and adhesion properties of a transdermal drug delivery system using Box-Behnken experimental design. The response surface methodology based on a three-level, three-variable Box-Behnken design was used to evaluate the interactive effects on dependent variables including, the rate of skin permeation and adhesion properties, namely peel strength and tack value. Levulinic acid, lauryl alcohol, and Tween 80 were used as penetration enhancers (patch formulations, containing 0-8% of each chemical penetration enhancer). Buprenorphine was used as a model penetrant drug. The results showed that incorporation of 20% chemical penetration enhancer into the mixture led to maximum skin permeation flux of buprenorphine from abdominal rat skin while the adhesion properties decreased. Also that skin flux in presence of levulinic acid (1.594 μg/cm(2) h) was higher than Tween 80 (1.473 μg/cm(2) h) and lauryl alcohol (0.843 μg/cm(2) h), and in mixing these enhancers together, an additional effect was observed. Moreover, it was found that each enhancer increased the tack value, while levulinic acid and lauryl alcohol improved the peel strength but Tween 80 reduced it. These findings indicated that the best chemical skin penetration enhancer for buprenorphine patch was levulinic acid. Among the designed formulations, the one which contained 12% (wt/wt) enhancers exhibited the highest efficiency.

  6. DESIGN AND CHARACTERIZATION OF A BIOCOMPATIBLE PHYSICAL HYDROGEL BASED ON SCLEROGLUCAN FOR TOPICAL DRUG DELIVERY.

    Science.gov (United States)

    Paolicelli, Patrizia; Varani, Gabriele; Pacelli, Settimio; Ogliani, Elisa; Nardoni, Martina; Petralito, Stefania; Adrover, Alessandra; Casadei, Maria Antonietta

    2017-10-15

    Physical hydrogels of a high-carboxymethylated derivative of scleroglucan (Scl-CM 300 ) were investigated as potential systems for topical drug delivery using three different therapeutic molecules (fluconazole, diclofenac and betamethasone). Rheological tests were carried out on drug-loaded hydrogels along with in-vitro release studies in a vertical Franz cell, in order to investigate if and how different drugs may influence the rheological and release properties of Scl-CM 300 hydrogels. Experimental results and theoretical modeling highlighted that, in the absence of drug/polymer interactions (as for fluconazole and betamethasone) Scl-CM 300 matrices offer negligible resistance to drug diffusion and a Fickian transport model can be adopted to estimate the effective diffusion coefficient in the swollen hydrogel. The presence of weak drug/hydrogel chemical bonds (as for diclofenac), confirmed by frequency sweep tests, slow down the drug release kinetics and a non-Fickian two-phase transport model has to be adopted. In-vivo experiments on rabbits evidenced optimal skin tolerability of Scl-CM 300 hydrogels after topical application. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Design and optimization of self-nanoemulsifying formulations for lipophilic drugs

    International Nuclear Information System (INIS)

    Zhao, Tianjing; Maniglio, Devid; Motta, Antonella; Migliaresi, Claudio; Chen, Jie; Chen, Bin

    2015-01-01

    The purpose of the current study was to develop and optimize novel self-nanoemulsifying drug delivery systems (SNEDDS) with a high proportion of essential oil as carriers for lipophilic drugs. Solubility and droplet size as a function of the composition were investigated, and a ternary phase diagram was constructed in order to identify the self-emulsification regions. The optimized SNEDDS formulation consisted of lemon essential oil (oil), Cremophor RH40 (surfactant) and Transcutol HP (co-surfactant) in the ratio 50:30:20 (v/v). Ibuprofen was chosen as the model drug. The droplet size, ζ-potential and stability of the drug-loaded optimized formulations were determined. The stability of SNEDDS was proved after triple freezing/thawing cycles and storage at 4 °C and 25 °C for 3 months. In vitro drug release studies of optimized SNEDDS revealed a significant increase of the drug release and release rate in comparison to the Ibuprofen suspension (80% versus approximately 40% in 2 h). The results indicated that these SNEDDS formulations could be used to improve the bioavailability of lipophilic drugs. (paper)

  8. Solid cellulose nanofiber based foams - Towards facile design of sustained drug delivery systems

    DEFF Research Database (Denmark)

    Svagan, Anna J; Benjamins, Jan-Willem; Al-Ansari, Zeinab

    2016-01-01

    acceptable surfactant (lauric acid sodium salt). The drug was suspended in the wet-stable foams followed by a drying step to obtain dry foams. Flexible cellular solid materials of different thicknesses, shapes and drug loadings (up to 50wt%) could successfully be prepared. The drug was released from...... the solid foams in a diffusion-controlled, sustained manner due to the presence of intact air bubbles which imparted a tortuous diffusion path. The diffusion coefficient was assessed using Franz cells and shown to be more than one order of magnitude lower for the cellular solids compared to the bubble...

  9. Design and statistical optimization of an effervescent floating drug delivery system of theophylline using response surface methodology

    Directory of Open Access Journals (Sweden)

    Srikanth Meka Venkata

    2016-03-01

    Full Text Available The aim of this research was to formulate effervescent floating drug delivery systems of theophylline using different release retarding polymers such as ethyl cellulose, Eudragit® L100, xanthan gum and polyethylene oxide (PEO N12K. Sodium bicarbonate was used as a gas generating agent. Direct compression was used to formulate floating tablets and the tablets were evaluated for their physicochemical and dissolution characteristics. PEO based formulations produced better drug release properties than other formulations. Hence, it was further optimized by central composite design. Further subjects of research were the effect of formulation variables on floating lag time and the percentage of drug released at the seventh hour (D7h. The optimum quantities of PEO and sodium bicarbonate, which had the highest desirability close to 1.0, were chosen as the statistically optimized formulation. No interaction was found between theophylline and PEO by Fourier Transformation Infrared spectroscopy (FTIR and Differential Scanning Calorimetry (DSC studies.

  10. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... subset is medically plausible. (7) A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries, e.g., IND and marketing application status and...

  11. Structure-based drug design approach to target toll-like receptor ...

    African Journals Online (AJOL)

    TLRs are now viewed as potential therapeutic targets in the treatment of autoimmune diseases. This ... Vascular endothelial growth factor. NMR .... induces the release of tumor necrosis factor ... Alternative anticancer drugs called CpG-based.

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  13. 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.

  14. DDDAS Design of Drug Interventions for the Treatment of Dyslipidemia in ApoE−/− Mice

    Science.gov (United States)

    Metts, Brittney; Thatcher, Sean; Lewis, Eboni; Karounos, Mike; Cassis, Lisa; Smith, Rebecca; Lodder, Robert A

    2014-01-01

    Computational models of complex systems, such as signaling networks and biological systems, can be used to explain the behavior of such systems under various conditions. The large number of integrated processes and variables, and the nonlinearities inherent in the fundamental processes, make it difficult for scientists unassisted by computer simulations to effectively predict the consequences of a particular intervention. For this reason, computer simulation has become an important tool for generating hypotheses about the behavior of these systems that can then be tested in the laboratory and clinic. A dynamic data-driven application simulation (DDDAS) was designed by Biospherics to model complex metabolic disease pathways by testing potential binary therapies in simulations at various combinations of two points in the pathways. Since DDDAS chooses the most effective pair-wise combinations, this data-driven system allows for the implementation of real-time data to model or predict a measurement or event. By incorporating data dynamically rather than statically, the predictions and measurements become more reliable. Dyslipidemia, a common precursor to atherosclerosis, can be manifested by high triglycerides, increased apolipoprotein (Apo) B, high levels of LDL, and low levels of HDL. SPX106 and D-tagatose is a combination drug therapy composed of a carbohydrate (D-tagatose) and SPX106. D-tagatose has been studied for the treatment of diabetes for several years, and has the ability to lower blood insulin levels and to decrease glycogen formation. SPX106 is a natural substance that accelerates lipid catabolism and inhibits dyslipidemia. In apolipoprotein E knockout mice (ApoE−/−), this drug combination has been shown to significantly lower both the amount of atherosclerosis and blood cholesterol levels. This study used 26 male ApoE−/− mice (n=13 in each group, control and treated). The control group received the normal “Western” diet (Harlan TD88137) and

  15. Quantum mechanical approaches to in silico enzyme characterization and drug design

    Energy Technology Data Exchange (ETDEWEB)

    Nilmeier, J P; Fattebert, J L; Jacobson, M P; Kalyanaraman, C

    2012-01-17

    The astonishing, exponentially increasing rates of genome sequencing has led to one of the most significant challenges for the biological and computational sciences in the 21st century: assigning the likely functions of the encoded proteins. Enzymes represent a particular challenge, and a critical one, because the universe of enzymes is likely to contain many novel functions that may be useful for synthetic biology, or as drug targets. Current approaches to protein annotation are largely based on bioinformatics. At the simplest level, this annotation involves transferring the annotations of characterized enzymes to related sequences. In practice, however, there is no simple, sequence based criterion for transferring annotations, and bioinformatics alone cannot propose new enzymatic functions. Structure-based computational methods have the potential to address these limitations, by identifying potential substrates of enzymes, as we and others have shown. One successful approach has used in silico 'docking' methods, more commonly applied in structure-based drug design, to identify possible metabolite substrates. A major limitation of this approach is that it only considers substrate binding, and does not directly assess the potential of the enzyme to catalyze a particular reaction using a particular substrate. That is, substrate binding affinity is necessary but not sufficient to assign function. A reaction profile is ultimately what is needed for a more complete quantitative description of function. To address this rather fundamental limitation, they propose to use quantum mechanical methods to explicitly compute transition state barriers that govern the rates of catalysis. Although quantum mechanical, and mixed quantum/classical (QM/MM), methods have been used extensively to investigate enzymatic reactions, the focus has been primarily on elucidating complex reaction mechanisms. Here, the key catalytic steps are known, and they use these methods quantify

  16. Why Research Design and Methods Is So Crucial to Understanding Drug Use/Abuse: Introduction to the Special Issue.

    Science.gov (United States)

    Scheier, Lawrence M

    2018-06-01

    The collection of articles in this special issue both raise the bar and inspire new thinking with regard to both design and methodology concerns that influence drug use/abuse research. Thematically speaking, the articles focus on issues related to missing data, response formats, strategies for data harmonization, propensity scoring methods as an alternative to randomized control trials, integrative data analysis, statistical corrections to reduce bias from attrition, challenges faced from conducting large-scale evaluations, and employing abductive theory of method as an alternative to the more traditional hypothetico-deductive reasoning. Collectively, these issues are of paramount importance as they provide specific means to improve our investigative tools and refine the logical framework we employ to examine the problem of drug use/abuse. Each of the authors addresses a specific challenge outlining how it affects our current research efforts and then outlines remedies that can advance the field. To their credit, they have included issues that affect both etiology and prevention, thus broadening our horizons as we learn more about developmental processes causally related to drug use/abuse and intervention strategies that can mitigate developmental vulnerability. This is the essential dialogue required to advance our intellectual tool kit and improve the research skills we bring to bear on the important questions facing the field of drug use/abuse. Ultimately, the goal is to increase our ability to identify the causes and consequences of drug use/abuse and find ways to ameliorate these problems as we engage the public health agenda.

  17. Differences in physicochemical properties to consider in the design, evaluation and choice between microparticles and nanoparticles for drug delivery.

    Science.gov (United States)

    Otto, Daniel P; Otto, Anja; de Villiers, Melgardt M

    2015-05-01

    The increase in the development of novel nanoparticle drug delivery systems makes the choice between micro- and nanoscale drug delivery systems ubiquitous. Changes in physical and chemical properties between micro- to nanosized particles give them different properties that influence their physiological, anatomical and clinical behavior and therefore potential application. This review focuses on the effect changes in the surface-to-volume ratio have on the thermal properties, solubility, dissolution and crystallization of micro- versus nanosized drug delivery systems. With these changes in the physicochemical properties in mind, the review covers computational and biophysical approaches to the design and evaluation of micro- and nanodelivery systems. The emphasis of the review is on the effect these properties have on clinical performance in terms of drug release, tissue retention, biodistribution, efficacy, toxicity and therefore choice of delivery system. Ultimately, the choice between micro- and nanometer-sized delivery systems is not straightforward. However, if the fundamental differences in physical and chemical properties are considered, it can be much easier to make a rational choice of the appropriate drug delivery system size.

  18. Design of Protein-Coated Carbon Nanotubes Loaded with Hydrophobic Drugs through Sacrificial Templating of Mesoporous Silica Shells.

    Science.gov (United States)

    Fiegel, Vincent; Harlepp, Sebastien; Begin-Colin, Sylvie; Begin, Dominique; Mertz, Damien

    2018-03-26

    One key challenge in the fields of nanomedicine and tissue engineering is the design of theranostic nanoplatforms able to monitor their therapeutic effect by imaging. Among current developed nano-objects, carbon nanotubes (CNTs) were found suitable to combine imaging, photothermal therapy, and to be loaded with hydrophobic drugs. However, a main problem is their resulting low hydrophilicity. To face this problem, an innovative method is developed here, which consists in loading the surface of carbon nanotubes (CNTs) with drugs followed by a protein coating around them. The originality of this method relies on first covering CNTs with a sacrificial template mesoporous silica (MS) shell grafted with isobutyramide (IBAM) binders on which a protein nanofilm is strongly adhered through IBAM-mediated physical cross-linking. This concept is first demonstrated without drugs, and is further improved with the suitable loading of hydrophobic drugs, curcumin (CUR) and camptothecin (CPT), which are retained between the CNTs and human serum albumin (HSA) layer. Such novel nanocomposites with favorable photothermal properties are very promising for theranostic systems, drug delivery, and phototherapy applications. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Synergistic Interplay of Medicinal Chemistry and Formulation Strategies in Nanotechnology - From Drug Discovery to Nanocarrier Design and Development.

    Science.gov (United States)

    Sunoqrot, Suhair; Hamed, Rania; Abdel-Halim, Heba; Tarawneh, Ola

    2017-01-01

    Over the last few decades, nanotechnology has given rise to promising new therapies and diagnostic tools for a wide range of diseases, especially cancer. The unique properties of nanocarriers such as liposomes, polymeric nanoparticles, micelles, and bioconjugates have mainly been exploited to enhance drug solubility, dissolution, and bioavailability. The most important advantage offered by nanotechnology is the ability to specifically target organs, tissues, and individual cells, which ultimately reduces the systemic side effects and improves the therapeutic index of drug molecules. The contribution of medicinal chemistry to nanotechnology is evident in the abundance of new active molecules that are being discovered but are faced with tremendous delivery challenges by conventional formulation strategies. Additionally, medicinal chemistry plays a crucial role in all the steps involved in the preparation of nanocarriers, where structure-activity relationships of the drug molecule as well as the nanocarrier are harnessed to enhance the design, efficacy, and safety of nanoformulations. The aim of this review is to provide an overview of the contributions of medicinal chemistry to nanotechnology, from supplying drug candidates and inspiring high-throughput nanocarrier design strategies, to structure-activity relationship elucidation and construction of computational models for better understanding of nanocarrier physicochemical properties and biological behavior. These two fields are undoubtedly interconnected and we will continue to see the fruits of that communion for years to come. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy

    Science.gov (United States)

    Chen, Haijun; Yang, Zhengduo; Ding, Chunyong; Chu, Lili; Zhang, Yusong; Terry, Kristin; Liu, Huiling; Shen, Qiang; Zhou, Jia

    2013-01-01

    Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. PMID:23416191

  1. Prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII) in adults with severe haemophilia A.

    Science.gov (United States)

    Tiede, A; Oldenburg, J; Lissitchkov, T; Knaub, S; Bichler, J; Manco-Johnson, M J

    2016-05-01

    Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults. The aim of this analysis was to compare prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII), a new-generation rFVIII expressed in a human cell line, in previously treated patients (PTPs) with severe haemophilia A. Data were analysed from two similarly designed, multinational, prospective, open-label studies with similar inclusion and exclusion criteria and comparable patient demographics. Human-cl rhFVIII was administered either prophylactically in a study of 32 adults or on-demand in a study of 22 patients (20 adults and two adolescents). Patients treated prophylactically experienced 36 bleeds compared with 997 bleeds in patients treated on-demand (mean observation periods: 180 and 335 days respectively). Based on a negative binomial regression model, annualized bleeding rate (ABR) during prophylaxis was 2.30 (95% CI: 1.54, 3.44) compared with 57.74 (95% CI: 43.36, 76.91) during on-demand treatment, which equates to a 96% lower ABR during prophylaxis. 'Excellent' or 'good' efficacy in the treatment of bleeds was achieved with Human-cl rhFVIII in 100% of 28 evaluated bleeds during the prophylaxis study and 94.5% of 985 evaluated bleeds during the on-demand study. No inhibitors, treatment-related serious adverse events or severe adverse events were recorded during prophylaxis or or-demand treatment. Prophylaxis with Human-cl rhFVIII reduces recurrent bleeding in adult PTPs with severe haemophilia A and adds further supportive evidence for the benefits of prophylaxis in adults. © 2015 John Wiley & Sons Ltd.

  2. Evaluation of 8-Hydroxyquinoline Derivatives as Hits for Antifungal Drug Design.

    Science.gov (United States)

    Pippi, Bruna; Reginatto, Paula; Machado, Gabriella da Rosa Monte; Bergamo, Vanessa Zafaneli; Lana, Daiane Flores Dalla; Teixeira, Mario Lettieri; Franco, Lucas Lopardi; Alves, Ricardo José; Andrade, Saulo Fernandes; Fuentefria, Alexandre Meneghello

    2017-10-01

    Clioquinol is an 8-hydroxyquinoline derivative that was widely used from the 1950s to 1970s as an oral antiparasitic agent. In 1970, the oral forms were withdrawn from the market due to reports of toxicity, but topical formulations for antifungal treatment remained available. Thus, the purpose of this study was to evaluate the toxicity, anti-Candida and antidermatophyte activity and to determine pharmacodynamic characteristics of clioquinol and other 8-hydroxyquinoline derivatives (8-hydroxy-5-quinolinesulfonic acid and 8-hydroxy-7-iodo-5-quinolinesulfonic acid). Antifungal activity was tested by broth microdilution and the fungicidal or fungistatic effect was checked by a time-kill assay. Permeation and histopathological evaluation were performed in Franz diffusion cells with ear skin of pigs and examined under light microscopy. An HET-CAM test was used to determine the potential irritancy. The three compounds were active against all isolates showing anti-Candida and antidermatophyte activity, with MIC ranges of 0.031-2 μg/ml, 1-512 μg/ml, and 2-1024 μg/ml for clioquinol, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid, respectively. All compounds showed fungistatic effect for Candida, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid showed a fungicidal effect for M. canis and T. mentagrophytes, and clioquinol showed a fungicidal effect only for T. mentagrophytes. Furthermore, they presented a fungicidal effect depending on the time and concentration. The absence of lesions was observed in histopathological evaluation and no compound was irritating. Moreover, clioquinol and 8-hydroxy-5-quinolinesulfonic acid accumulated in the epithelial tissue, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid had a high degree of permeation. In conclusion, 8-hydroxyquinoline derivatives showed antifungal activity and 8-hydroxy-5-quinolinesulfonic acid demonstrated the potential for antifungal drug design.

  3. P-glycoprotein recognition of substrates and circumvention through rational drug design.

    Science.gov (United States)

    Raub, Thomas J

    2006-01-01

    It is now well recognized that membrane efflux transporters, especially P-glycoprotein (P-gp; ABCB1), play a role in determining the absorption, distribution, metabolism, excretion, and toxicology behaviors of some drugs and molecules in development. An investment in screening structure-activity relationship (SAR) is warranted in early discovery when exposure and/or target activity in an in vivo efficacy model is not achieved and P-gp efflux is identified as a rate-limiting factor. However, the amount of investment in SAR must be placed into perspective by assessing the risks associated with the intended therapeutic target, the potency and margin of safety of the compound, the intended patient population(s), and the market competition. The task of rationally designing a chemistry strategy for circumventing a limiting P-gp interaction can be daunting. The necessity of retaining biological potency and metabolic stability places restrictions on what can be done, and the factors for P-gp recognition of substrates are complicated and poorly understood. The parameters within the assays that affect overall pump efficiency or net efflux, such as passive diffusion, membrane partitioning, and molecular interaction between pump and substrate, should be understood when interpreting data sets associated with chemistry around a scaffold. No single, functional group alone is often the cause, but one group can accentuate the recognition points existing within a scaffold. This can be likened to a rheostat, rather than an on/off switch, where addition or removal of a key group can increase or decrease the pumping efficiency. The most practical approach to de-emphasize the limiting effects of P-gp on a particular scaffold is to increase passive diffusion. Efflux pumping efficiency may be overcome when passive diffusion is fast enough. Eliminating, or substituting with fewer, groups that solvate in water, or decreasing their hydrogen bonding capacity, and adding halogen groups can

  4. 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

  5. Fatal toxic leukoencephalopathy secondary to overdose of a new psychoactive designer drug 2C-E ("Europa").

    Science.gov (United States)

    Sacks, Justin; Ray, M Jordan; Williams, Sue; Opatowsky, Michael J

    2012-10-01

    We present a case of a fatal toxic leukoencephalopathy following ingestion of a new psychoactive designer drug known as 2C-E or "Europa." Recreational drugs, particularly hallucinogenic substances, appear to be growing in popularity, with increasing amounts of information available via the Internet to entice potential users. In addition, some newer "designer" psychoactive substances are available for purchase online without adverse legal consequences, therefore adding to their popularity. We describe magnetic resonance imaging (MRI) findings to include selective diffuse toxic injury of the cerebral white matter with sparing of the cortex and most of the deep gray nuclei. To our knowledge, this is the first reported description of cerebral findings on MRI that are likely related to a lethal ingestion of 2C-E.

  6. Design and syntheses of MMP inhibitors and photosensitive lipid nanoparticle formulations for drug delivery

    Science.gov (United States)

    Subramaniam, Rajesh

    Drug administration without any compromise to the quality of life and lifespan is the ideal goal for disease management. The molecular mechanisms of several pathologies have shown that site-specific delivery of target-specific drugs seems to be a promising avenue to achieve this goal. This thesis describes the initial steps that we have taken toward that goal. Matrix metalloproteinases (MMPs) are a family of about 23 isozymes in humans that were actively targeted for treating a multitude of pathologies. Clinical studies carried out on cancer patients have revealed the complexity of the working of this enzyme family and necessitated the development of isozyme-specific MMP inhibitors. Our studies toward the development of isozyme-specific inhibitors have resulted in the development of several inhibitors that seem to be selective toward some MMP isozymes. Our understanding on the molecular mechanism that confers this selectivity is documented in this thesis. Another aspect of discussion in the thesis is the development of photosensitive liposomes for drug delivery that could be triggered to release the drug by irradiation with light of appropriate wavelength. Development of such delivery vehicles, in principle, would confer external spatiotemporal control on drug delivery. This could potentially lead to better disease management by minimizing side effects and enhancing patient compatibility. The thesis discusses our attempts toward the development of photosensitive liposomes. These liposomes incorporated a photosensitive lipid (PSL) that would be cleaved upon irradiation with UV light, causing liposomal destabilization and release of the enclosed drug. The discussion includes: (i) the syntheses of the PSLs, (ii) formulation of the photosensitive liposomes that contained a model drug, (iii) light-mediated release of the drug and (iv) the mechanism of photocleavage of the PSL that leads to content release from liposomes. The thesis concludes with suggestions toward the

  7. Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design.

    Science.gov (United States)

    Tice, Colin M; Zhao, Wei; Xu, Zhenrong; Cacatian, Salvacion T; Simpson, Robert D; Ye, Yuan-Jie; Singh, Suresh B; McKeever, Brian M; Lindblom, Peter; Guo, Joan; Krosky, Paula M; Kruk, Barbara A; Berbaum, Jennifer; Harrison, Richard K; Johnson, Judith J; Bukhtiyarov, Yuri; Panemangalore, Reshma; Scott, Boyd B; Zhao, Yi; Bruno, Joseph G; Zhuang, Linghang; McGeehan, Gerard M; He, Wei; Claremon, David A

    2010-02-01

    Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  8. Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.

    Directory of Open Access Journals (Sweden)

    Juan Carlos Pizarro

    Full Text Available Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp, while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF. Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.

  9. Straightforward single-calibrant quantification of seized designer drugs by liquid chromatography-chemiluminescence nitrogen detection.

    Science.gov (United States)

    Rasanen, Ilpo; Kyber, Marianne; Szilvay, Ilmari; Rintatalo, Janne; Ojanperä, Ilkka

    2014-04-01

    Sixty-one different psychoactive substances were quantified by liquid chromatography-chemiluminescence nitrogen detection (LC-CLND) in 177 samples, using a single secondary standard (caffeine), in a trial concerning the quantitative purity assessment of drug-related material seized by the police in 2011-2012 and customs in 2011-2013 in Finland. The substances found were predominantly substituted phenethylamines, cathinones, tryptamines and synthetic cannabinoids, which were identified by appropriate methods prior to submitting the samples for quantification by LC-CLND. The equimolarity and expanded uncertainty of measurement by LC-CLND were on average 95% and 13%, respectively, based on 16 different substances. The median (mean) purity of stimulant/hallucinogenic drug samples seized at the border was 92.9% (87.6%) and in the street 82.0% (64.5%). The corresponding figures for powdery synthetic cannabinoid samples seized at the border and in the street were 99.0% (96.8%) and 90.0% (92.2%), respectively. There was generally only one active drug to be quantified in each sample. Seized herbal samples contained 0.15-9.2% of between one and three components. LC-CLND was found to be suitable for quantification of the nitrogen-containing drugs encountered in the study, showing sufficient N-equimolarity for both stimulant/hallucinogenic drugs and synthetic cannabinoids. The technique possesses great potential as a standard technique in forensic laboratories. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Applying the methodology of Design of Experiments to stability studies: a Partial Least Squares approach for evaluation of drug stability.

    Science.gov (United States)

    Jordan, Nika; Zakrajšek, Jure; Bohanec, Simona; Roškar, Robert; Grabnar, Iztok

    2018-05-01

    The aim of the present research is to show that the methodology of Design of Experiments can be applied to stability data evaluation, as they can be seen as multi-factor and multi-level experimental designs. Linear regression analysis is usually an approach for analyzing stability data, but multivariate statistical methods could also be used to assess drug stability during the development phase. Data from a stability study for a pharmaceutical product with hydrochlorothiazide (HCTZ) as an unstable drug substance was used as a case example in this paper. The design space of the stability study was modeled using Umetrics MODDE 10.1 software. We showed that a Partial Least Squares model could be used for a multi-dimensional presentation of all data generated in a stability study and for determination of the relationship among factors that influence drug stability. It might also be used for stability predictions and potentially for the optimization of the extent of stability testing needed to determine shelf life and storage conditions, which would be time and cost-effective for the pharmaceutical industry.

  11. In Situ Formation of Steroidal Supramolecular Gels Designed for Drug Release

    Directory of Open Access Journals (Sweden)

    Hana Bunzen

    2013-03-01

    Full Text Available In this work, a steroidal gelator containing an imine bond was synthesized, and its gelation behavior as well as a sensitivity of its gels towards acids was investigated. It was shown that the gels were acid-responsive, and that the gelator molecules could be prepared either by a conventional synthesis or directly in situ during the gel forming process. The gels prepared by both methods were studied and it was found that they had very similar macro- and microscopic properties. Furthermore, the possibility to use the gels as carriers for aromatic drugs such as 5-chloro-8-hydroxyquinoline, pyrazinecarboxamide, and antipyrine was investigated and the prepared two-component gels were studied with regard to their potential applications in drug delivery, particularly in a pH-controlled drug release.

  12. Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

    Directory of Open Access Journals (Sweden)

    Qing-Xi Wu

    2014-12-01

    Full Text Available Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail.

  13. Design of chitosan and its water soluble derivatives-based drug carriers with polyelectrolyte complexes.

    Science.gov (United States)

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-12-19

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail.

  14. Towards novel therapeutics for HIV through fragment-based screening and drug design.

    Science.gov (United States)

    Tiefendbrunn, Theresa; Stout, C David

    2014-01-01

    Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

  15. Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

    Science.gov (United States)

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-01-01

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail. PMID:25532565

  16. Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents.

    Science.gov (United States)

    Serra, Laura; Doménech, Josep; Peppas, Nicholas A

    2009-03-01

    The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications.

  17. Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee

    Science.gov (United States)

    Paller, Channing J.; Bradbury, Penelope A.; Ivy, S. Percy; Seymour, Lesley; LoRusso, Patricia M.; Baker, Laurence; Rubinstein, Larry; Huang, Erich; Collyar, Deborah; Groshen, Susan; Reeves, Steven; Ellis, Lee M.; Sargent, Daniel J.; Rosner, Gary L.; LeBlanc, Michael L.; Ratain, Mark J.

    2014-01-01

    Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistical and regulatory challenges. The phase 1 trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee developed a set of recommendations for the phase 1 development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biological or pharmacological rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase 1 clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamic (i.e., biomarker). PMID:25125258

  18. Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

    Science.gov (United States)

    Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

    2017-07-21

    In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

  19. Predictive routing for autonomous mobility-on-demand systems with ride-sharing

    NARCIS (Netherlands)

    Alonso Mora, J.; Wallar, Alex; Rus, Daniela; Bicchi, A.; Maciejewski, T.

    2017-01-01

    Ride-sharing, or carpooling, systems with autonomous vehicles will provide efficient and reliable urban mobility on demand. In this work we present a method for dynamic vehicle routing that leverages historical data to improve the performance of a network of self-driving taxis. In particular, we

  20. On-demand virtual optical network access using 100 Gb/s Ethernet.

    Science.gov (United States)

    Ishida, Osamu; Takamichi, Toru; Arai, Sachine; Kawate, Ryusuke; Toyoda, Hidehiro; Morita, Itsuro; Araki, Soichiro; Ichikawa, Toshiyuki; Hoshida, Takeshi; Murai, Hitoshi

    2011-12-12

    Our Terabit LAN initiatives attempt to enhance the scalability and utilization of lambda resources. This paper describes bandwidth-on-demand virtualized 100GE access to WDM networks on a field fiber test-bed using multi-domain optical-path provisioning. © 2011 Optical Society of America

  1. Optimization-based feedforward control for a drop-on-demand inkjet printer

    NARCIS (Netherlands)

    Khalate, A.; Bombois, X.; Babuska, R.; Wijshoff, H.M.A.; Waarsing, R.

    2010-01-01

    The printing quality delivered by a Drop-on-Demand (DoD) inkjet printhead is limited due to operational issues such as residual oscillations in the ink channel and the cross-talk between the ink channels. The maximal jetting frequency of a DoD inkjet printhead can be increased by quickly damping the

  2. Just add water: reproducible singly dispersed silver nanoparticle suspensions on-demand

    International Nuclear Information System (INIS)

    MacCuspie, Robert I.; Allen, Andrew J.; Martin, Matthew N.; Hackley, Vincent A.

    2013-01-01

    Silver nanoparticles (AgNPs) are of interest due to their antimicrobial attributes, which are derived from their inherent redox instability and subsequent release of silver ions. At the same time, this instability is a substantial challenge for achieving stable long-term storage for on-demand use of AgNPs. In this study, we describe and validate a “just add water” approach for achieving suspensions of principally singly dispersed AgNPs. By lyophilizing (freeze drying) the formulated AgNPs into a solid powder, or cake, water is removed thereby eliminating solution-based chemical changes. Storing under inert gas further reduces surface reactions such as oxidation. An example of how to optimize a lyophilization formulation is presented, as well as example formulations for three AgNP core sizes. This “just add water” approach enables ease of use for the researcher desiring on-demand singly dispersed AgNP suspensions from a single master batch. Implementation of this methodology will enable studies to be performed over long periods of time and across different laboratories using particles that are identical chemically and physically and available on-demand. In addition, the approach of freeze drying and on-demand reconstitution by adding water has enabled the development of AgNP reference materials with the required shelf-life stability, one of the principal objectives of this research

  3. 26 CFR 1.453-3 - Purchaser evidences of indebtedness payable on demand or readily tradable.

    Science.gov (United States)

    2010-04-01

    ... obligation (determined by taking into account all relevant factors, including proper discount to reflect the... demand or readily tradable. 1.453-3 Section 1.453-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Income Included § 1.453-3 Purchaser evidences of indebtedness payable on demand or readily tradable. (a...

  4. Scheduling jobs in the cloud using on-demand and reserved instances

    NARCIS (Netherlands)

    Shen, S.; Deng, K.; Iosup, A.; Epema, D.H.J.; Wolf, F.; Mohr, B.; Mey, an D.

    2013-01-01

    Deploying applications in leased cloud infrastructure is increasingly considered by a variety of business and service integrators. However, the challenge of selecting the leasing strategy — larger or faster instances? on-demand or reserved instances? etc.— and to configure the leasing strategy with

  5. Impact-driven ejection of micro metal droplets on-demand

    NARCIS (Netherlands)

    Luo, Jun; Qi, Lehua; Tao, Yuan; Ma, Qian; Visser, C.W.

    2016-01-01

    On-demand metal droplet deposition will be a cornerstone technology in 3D metal printing. However, suitable small nozzles are hardly available, limiting the resolution and surface finish of final products. Here, the ejection of record-small metal droplets with a diameter of only 0.55±0.07 times the

  6. Towards Hybrid Online On-Demand Querying of Realtime Data with Stateful Complex Event Processing

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Qunzhi; Simmhan, Yogesh; Prasanna, Viktor K.

    2013-10-09

    Emerging Big Data applications in areas like e-commerce and energy industry require both online and on-demand queries to be performed over vast and fast data arriving as streams. These present novel challenges to Big Data management systems. Complex Event Processing (CEP) is recognized as a high performance online query scheme which in particular deals with the velocity aspect of the 3-V’s of Big Data. However, traditional CEP systems do not consider data variety and lack the capability to embed ad hoc queries over the volume of data streams. In this paper, we propose H2O, a stateful complex event processing framework, to support hybrid online and on-demand queries over realtime data. We propose a semantically enriched event and query model to address data variety. A formal query algebra is developed to precisely capture the stateful and containment semantics of online and on-demand queries. We describe techniques to achieve the interactive query processing over realtime data featured by efficient online querying, dynamic stream data persistence and on-demand access. The system architecture is presented and the current implementation status reported.

  7. Design and evaluation of mPEG-PLA micelles functionalized with drug-interactive domains as improved drug carriers for docetaxel delivery.

    Science.gov (United States)

    Qi, Dingqing; Gong, Feirong; Teng, Xin; Ma, Mingming; Wen, Huijing; Yuan, Weihao; Cheng, Yi; Lu, Chong

    2017-10-01

    Polymeric micelles are very attractive drug delivery systems for hydrophobic agents, owing to their readily tailorable chemical structure and ease for scale-up preparation. However, the intrinsic poor stability of drug-loaded micelles presents one of the major challenges for most micellar systems in the translation to clinical applications. In this study, a simple, well-defined, and easy-to-scale up 9-Fluorenylmethoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) containing lysine dendronized mPEG-PLA (mPEG-PLA-Lys(FB) 2 ) micellar formulation was designed and prepared for docetaxel (DTX) delivery, in an effort to improve the stability of the micelles, and its physicochemical properties, pharmacokinetics, and anti-tumor efficacy against SKOV-3 ovarian cancer were evaluated. MPEG-PLA-Lys(FB) 2 was synthesized via a three-step synthetic route, and it actively interacted with DTX in aqueous media to form stable micelles with small particle sizes (~17-19 nm) and narrow size distribution (PI PLA-Lys(FB) 2 micelles achieved delayed and sustained release manner of DTX in comparison with mPEG-PLA micelles. Further in vivo xenograft tumor model in nude mice DTX/mPEG-PLA-Lys(FB) 2 micelles demonstrated significantly higher inhibitory effect on tumor growth than the marketed formulation Taxotere. Thus, our system may hold promise as a simple and effective delivery system for DTX with a potential for translation into clinical study.

  8. Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals.

    Science.gov (United States)

    Kitson, Philip J; Marie, Guillaume; Francoia, Jean-Patrick; Zalesskiy, Sergey S; Sigerson, Ralph C; Mathieson, Jennifer S; Cronin, Leroy

    2018-01-19

    Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  9. Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate.

    Science.gov (United States)

    Amrutkar, P P; Chaudhari, P D; Patil, S B

    2012-01-01

    Zolpidem tartarate is a non-benzodiazepine, sedative-hypnotic, which finds its major use in various types of insomnia. The present work relates to development of multiparticulate floating drug delivery system based on gas generation technique to prolong the gastric residence time and to increase the overall bioavailability. Modified release dosage form of zolpidem tartarate adapted to release over a predetermined time period, according to biphasic profile of dissolution, where the first phase is immediate release phase for inducing the sleep and the second phase is modified release phase for maintaining the sleep up to 10 h. The system consists of zolpidem tartarate layered pellets coated with effervescent layer and polymeric membrane. The floating ability and in vitro drug release of the system were dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the drug layered pellets, and coating level of the polymeric membrane (Eudragit(®) NE 30D). The system could float completely within 5 min and maintain the floating over a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate with rapid floating and modified drug release was obtained. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. A Copula Based Approach for Design of Multivariate Random Forests for Drug Sensitivity Prediction.

    Science.gov (United States)

    Haider, Saad; Rahman, Raziur; Ghosh, Souparno; Pal, Ranadip

    2015-01-01

    Modeling sensitivity to drugs based on genetic characterizations is a significant challenge in the area of systems medicine. Ensemble based approaches such as Random Forests have been shown to perform well in both individual sensitivity prediction studies and team science based prediction challenges. However, Random Forests generate a deterministic predictive model for each drug based on the genetic characterization of the cell lines and ignores the relationship between different drug sensitivities during model generation. This application motivates the need for generation of multivariate ensemble learning techniques that can increase prediction accuracy and improve variable importance ranking by incorporating the relationships between different output responses. In this article, we propose a novel cost criterion that captures the dissimilarity in the output response structure between the training data and node samples as the difference in the two empirical copulas. We illustrate that copulas are suitable for capturing the multivariate structure of output responses independent of the marginal distributions and the copula based multivariate random forest framework can provide higher accuracy prediction and improved variable selection. The proposed framework has been validated on genomics of drug sensitivity for cancer and cancer cell line encyclopedia database.

  11. A Relational Learning Approach to Structure-Activity Relationships in Drug Design Toxicity Studies

    Directory of Open Access Journals (Sweden)

    Camacho Rui

    2011-12-01

    Full Text Available It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current “target-rich, lead-poor” scenario.

  12. The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A; Schouw, Marieke L J; Klomp, Anne; Tamminga, Hyke G H; Schrantee, Anouk G M; Bouziane, Cheima; de Ruiter, Michiel B; Boer, Frits; Ruhé, Henricus G; Denys, D.; Rijsman, Roselyne; Lindauer, Ramon J L; Reitsma, Hans B; Geurts, Hilde M; Reneman, Liesbeth

    2014-01-01

    BACKGROUND: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  13. The effects of psychotropic drugs on developing brain (ePOD) study: methods and design

    NARCIS (Netherlands)

    Bottelier, M.A.; Schouw, M.L.J.; Klomp, A.; Tamminga, G.H.; Schrantee, A.G.M.; Bouziane, C.; de Ruiter, M.B.; Boer, F.; Ruhé, H.G.; Denys, D.; Rijsman, R.; Lindauer, R.J.L.; Reitsma, H.B.; Geurts, H.M.; Reneman, L.

    2014-01-01

    Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  14. The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhe, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

    2014-01-01

    Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of

  15. The effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhé, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

    2014-01-01

    Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different

  16. The multiple roles of computational chemistry in fragment-based drug design

    Science.gov (United States)

    Law, Richard; Barker, Oliver; Barker, John J.; Hesterkamp, Thomas; Godemann, Robert; Andersen, Ole; Fryatt, Tara; Courtney, Steve; Hallett, Dave; Whittaker, Mark

    2009-08-01

    Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.

  17. Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bálint Mészáros

    2011-07-01

    Full Text Available Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only.

  18. Cartel Next: How Army Design Methodology Offers Holistic and Dissimilar Approaches to the Mexican Drug Problem

    Science.gov (United States)

    2011-06-30

    which the source is limited to South American regions that grow abundant quantities of the cocoa plant, this cycle manifests in many forms based upon...coffee, bananas, or other legal commodities. In other words, American apathy towards cultural drug consumption often verges on the comical; we

  19. A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

    Science.gov (United States)

    Choi, Du Hyung; Lim, Jun Yeul; Shin, Sangmun; Choi, Won Jun; Jeong, Seong Hoon; Lee, Sangkil

    2014-10-01

    To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  20. Design of a surface plasmon resonance immunoassay for therapeutic drug monitoring of amikacin.

    Science.gov (United States)

    Losoya-Leal, Adrian; Estevez, M-Carmen; Martínez-Chapa, Sergio O; Lechuga, Laura M

    2015-08-15

    The therapeutic drug monitoring (TDM) of pharmaceutical drugs with narrow therapeutic ranges is of great importance in the clinical setting. It provides useful information towards the enhancement of drug therapies, aiding in dosage control and toxicity risk management. Amikacin is an aminoglycoside antibiotic commonly used in neonatal therapies that is indicated for TDM due to the toxicity risks inherent in its use. Current techniques for TDM such as high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) are costly, time consuming, and cannot be performed at the site of action. Over the last decades, surface plasmon resonance (SPR) biosensors have become increasingly popular in clinical diagnostics due to their ability to detect biomolecular interactions in real-time. We present an SPR-based competitive immunoassay for the detection of the antibiotic amikacin, suitable for TDM in both adults and neonates. We have obtained high specificity and sensitivity levels with an IC50 value of 1.4ng/mL and a limit of detection of 0.13ng/mL, which comfortably comply with the drug's therapeutic range. Simple dilution of serum can therefore be sufficient to analyze low-volume real samples from neonates, increasing the potential of the methodology for TDM. Compared to current TDM conventional methods, this SPR-based immunoassay can provide advantages such as simplicity, potential portability, and label-free measurements with the possibility of high throughput. This work is the foundation towards the development of an integrated, simple use, highly sensitive, fast, and point-of-care sensing platform for the opportune TDM of antibiotics and other drugs in a clinical setting. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. 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.

  2. G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

    Science.gov (United States)

    2016-01-01

    Abstract Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G‐LoSA. G‐LoSA aligns protein local structures in a sequence order independent way and provides a GA‐score, a chemical feature‐based and size‐independent structure similarity score. Our benchmark validation shows the robust performance of G‐LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure‐centric comparative biology studies. In particular, G‐LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of G‐LoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer‐aided drug design. We hope that G‐LoSA can be a useful computational method for exploring interesting biological problems through large‐scale comparison of protein local structures and facilitating drug discovery research and development. G‐LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/. PMID:26813336

  3. G-LoSA: An efficient computational tool for local structure-centric biological studies and drug design.

    Science.gov (United States)

    Lee, Hui Sun; Im, Wonpil

    2016-04-01

    Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G-LoSA. G-LoSA aligns protein local structures in a sequence order independent way and provides a GA-score, a chemical feature-based and size-independent structure similarity score. Our benchmark validation shows the robust performance of G-LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure-centric comparative biology studies. In particular, G-LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of G-LoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer-aided drug design. We hope that G-LoSA can be a useful computational method for exploring interesting biological problems through large-scale comparison of protein local structures and facilitating drug discovery research and development. G-LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/. © 2016 The Protein Society.

  4. Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

    OpenAIRE

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-01-01

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have...

  5. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development

    DEFF Research Database (Denmark)

    Imamovic, Lejla; Sommer, Morten

    2013-01-01

    collateral sensitivity and resistance profiles, revealing a complex collateral sensitivity network. On the basis of these data, we propose a new treatment framework-collateral sensitivity cycling-in which drugs with compatible collateral sensitivity profiles are used sequentially to treat infection...... pathogens. These results provide proof of principle for collateral sensitivity cycling as a sustainable treatment paradigm that may be generally applicable to infectious diseases and cancer....

  6. DESIGN AND DEVELOPMENT OF MUCOADHESIVE DRUG DELIVERY SYSTEM OF MONTELUKAST SODIUM

    OpenAIRE

    N. G. Raghavendra Rao; V. B. Suryakar

    2011-01-01

    The Montelukast sodium is a leukotrine receptor antagonist used for the maintenance treatment of asthma, chronic asthma attacks and to relieve symptoms of seasonal allergies. The biological half life of montelukast sodium is 2.5 to 5.5 hrs and poor bioavailability upto 64%. Because of poor bioavailability of montelukast sodium by oral route, there is a need to increase its bioavailability by formulating it into buccal dosage forms. Hence, montelukast sodium is a suitable drug for buccal dosa...

  7. Design and Characterization of Buccoadhesive Liquisolid System of an Antihypertensive Drug

    Directory of Open Access Journals (Sweden)

    Nilesh P. Kala

    2015-01-01

    Full Text Available Nifedipine is an antihypertensive BCS class II drug which has poor bioavailability when given orally. The objective of the present study was to increase the bioavailability of nifedipine, by formulation and evaluation of a buccoadhesive liquisolid system using magnesium aluminium silicate (Neusilin as both carrier and coating material and dissolution media were selected based on the solubility studies. A mixture of carboxymethylcellulose sodium and carbomer was used as mucoadhesive polymers. Buccoadhesive tablets were prepared by direct compression. FTIR studies confirmed no interaction between drug and excipients. XRD studies indicated change/reduction in crystallinity of drug. The powder characteristics were evaluated by different flow parameters to comply with pharmacopoeial specifications. The dissolution studies for liquisolid compacts and tablet formulations were carried out and it was found that nifedipine liquisolid tablets formulated from bioadhesive polymers containing 49% liquisolid system, 17.5% carbomer, and 7.5% carboxymethylcellulose sodium showed the best results in terms of dissolution properties. Prepared formulation batches were evaluated for swelling, bioadhesion strength, ex vivo residence time, and permeability studies. The optimized batch was showing promising features of the system. Formulating nifedipine as a buccoadhesive tablet allows reduction in dose and offers better control over the plasma levels.

  8. Design of the Anti-tuberculosis Drugs induced Adverse Reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS

    Directory of Open Access Journals (Sweden)

    He Ping

    2010-05-01

    Full Text Available Abstract Background More than 1 million tuberculosis (TB patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS in China every year. Adverse reactions (ADRs induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients. Methods/Design Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA. Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI, a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis. Discussion ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy.

  9. Design of the Anti-tuberculosis Drugs induced Adverse Reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS)

    Science.gov (United States)

    2010-01-01

    Background More than 1 million tuberculosis (TB) patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS) in China every year. Adverse reactions (ADRs) induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients. Methods/Design Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA). Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI), a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis. Discussion ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy. PMID:20492672

  10. On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing.

    Science.gov (United States)

    Okwuosa, Tochukwu C; Soares, Cindy; Gollwitzer, Verena; Habashy, Rober; Timmins, Peter; Alhnan, Mohamed A

    2018-06-15

    A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R 2  = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets.

    Science.gov (United States)

    Wasko, Michael J; Pellegrene, Kendy A; Madura, Jeffry D; Surratt, Christopher K

    2015-01-01

    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 pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), 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 FBDD 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 not only 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.

  12. Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.

    Science.gov (United States)

    Yu, Wenying; Xiao, Hui; Lin, Jiayuh; Li, Chenglong

    2013-06-13

    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

  13. On-demand Antimicrobial Treatment with Antibiotic-Loaded Porous Silicon Capped with a pH-Responsive Dual Plasma Polymer Barrier.

    Science.gov (United States)

    Vasani, Roshan B; Szili, Endre J; Rajeev, Gayathri; Voelcker, Nicolas H

    2017-07-04

    Chronic wounds are a major socio-economic problem. Bacterial infections in such wounds are a major contributor to lack of wound healing. An early indicator of wound infection is an increase in pH of the wound fluid. Herein, we describe the development of a pH-responsive drug delivery device that can potentially be used for wound decontamination in situ and on-demand in response to an increase in the pH of the wound environment. The device is based on a porous silicon film that provides a reservoir for encapsulation of an antibiotic within the pores. Loaded porous silicon is capped with dual plasma polymer layers of poly(1,7-octadiene) and poly(acrylic acid), which provide a pH-responsive barrier for on-demand release of the antibiotic. We demonstrate that release of the antibiotic is inhibited in aqueous buffer at pH 5, whereas the drug is released in a sustainable manner at pH 8. Importantly, the released drug was bacteriostatic against the Pseudomonas aeruginosa wound pathogen. In the future, incorporation of the delivery device into wound dressings could potentially be utilized for non-invasive decontamination of wounds. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Database on Demand: insight how to build your own DBaaS

    CERN Document Server

    Aparicio, Ruben Gaspar

    2015-01-01

    At CERN, a number of key database applications are running on user-managed MySQL, PostgreSQL and Oracle database services. The Database on Demand (DBoD) project was born out of an idea to provide CERN user community with an environment to develop and run database services as a complement to the central Oracle based database service. The Database on Demand empowers the user to perform certain actions that had been traditionally done by database administrators, providing an enterprise platform for database applications. It also allows the CERN user community to run different database engines, e.g. presently three major RDBMS (relational database management system) vendors are offered. In this article we show the actual status of the service after almost three years of operations, some insight of our new redesign software engineering and near future evolution.

  15. Exploring Concepts of Operations for On-Demand Passenger Air Transportation

    Science.gov (United States)

    Nneji, Victoria Chibuogu; Stimpson, Alexander; Cummings, Mary; Goodrich, Kenneth H.

    2017-01-01

    In recent years, a surge of interest in "flying cars" for city commutes has led to rapid development of new technologies to help make them and similar on-demand mobility platforms a reality. To this end, this paper provides analyses of the stakeholders involved, their proposed operational concepts, and the hazards and regulations that must be addressed. Three system architectures emerged from the analyses, ranging from conventional air taxi to revolutionary fully autonomous aircraft operations, each with vehicle safety functions allocated differently between humans and machines. Advancements for enabling technologies such as distributed electric propulsion and artificial intelligence have had major investments and initial experimental success, but may be some years away from being deployed for on-demand passenger air transportation at scale.

  16. Web-based nephropathology teaching modules and user satisfaction: the nephrology on-demand experience.

    Science.gov (United States)

    Desai, Tejas; Talento, Romualdo; Christiano, Cynthia; Ferris, Maria; Hewan-Lowe, Karlene

    2011-01-01

    Nephropathology is an integral component of nephrology education. Online teaching sites provide valuable educational materials to learners, but learner satisfaction has not been measured. We developed a nephropathology website and measured learners' satisfaction. The Nephrology On-Demand Histopathology website (http://blog.ecu.edu/sites/nephrologyondemand/?page_id=4502) provided nephropathologic specimens with explanations. Users were asked to complete a Likert-based survey (1-strongly agree . . . 5-strongly disagree) regarding four key areas of content quality: accuracy, currency, objectivity, and usefulness. Learners of all training levels perceived the content quality favorably. The mean (±SD) for accuracy was 1.70 (0.89), currency 1.62 (0.90), objectivity 1.80 (1.01), and usefulness 1.72 (0.95). Nephrology On-Demand Histopathology is a well-received teaching tool to learners of all training levels. Educators may consider using it, as well as other online nephropathology sites, as adjunctive teaching tools.

  17. Database on Demand: insight how to build your own DBaaS

    Science.gov (United States)

    Gaspar Aparicio, Ruben; Coterillo Coz, Ignacio

    2015-12-01

    At CERN, a number of key database applications are running on user-managed MySQL, PostgreSQL and Oracle database services. The Database on Demand (DBoD) project was born out of an idea to provide CERN user community with an environment to develop and run database services as a complement to the central Oracle based database service. The Database on Demand empowers the user to perform certain actions that had been traditionally done by database administrators, providing an enterprise platform for database applications. It also allows the CERN user community to run different database engines, e.g. presently three major RDBMS (relational database management system) vendors are offered. In this article we show the actual status of the service after almost three years of operations, some insight of our new redesign software engineering and near future evolution.

  18. Mobility-Assisted on-Demand Routing Algorithm for MANETs in the Presence of Location Errors

    Directory of Open Access Journals (Sweden)

    Trung Kien Vu

    2014-01-01

    Full Text Available We propose a mobility-assisted on-demand routing algorithm for mobile ad hoc networks in the presence of location errors. Location awareness enables mobile nodes to predict their mobility and enhances routing performance by estimating link duration and selecting reliable routes. However, measured locations intrinsically include errors in measurement. Such errors degrade mobility prediction and have been ignored in previous work. To mitigate the impact of location errors on routing, we propose an on-demand routing algorithm taking into account location errors. To that end, we adopt the Kalman filter to estimate accurate locations and consider route confidence in discovering routes. Via simulations, we compare our algorithm and previous algorithms in various environments. Our proposed mobility prediction is robust to the location errors.

  19. Computational approaches for the study of serotonin and its membrane transporter SERT: implications for drug design in neurological sciences.

    Science.gov (United States)

    Pratuangdejkul, J; Schneider, B; Launay, J-M; Kellermann, O; Manivet, P

    2008-01-01

    Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, "selective" serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.

  20. Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design.

    Science.gov (United States)

    Krajewski, Wojciech W; Collins, Ruairi; Holmberg-Schiavone, Lovisa; Jones, T Alwyn; Karlberg, Tobias; Mowbray, Sherry L

    2008-01-04

    Glutamine synthetase (GS) catalyzes the ligation of glutamate and ammonia to form glutamine, with concomitant hydrolysis of ATP. In mammals, the activity eliminates cytotoxic ammonia, at the same time converting neurotoxic glutamate to harmless glutamine; there are a number of links between changes in GS activity and neurodegenerative disorders, such as Alzheimer's disease. In plants, because of its importance in the assimilation and re-assimilation of ammonia, the enzyme is a target of some herbicides. GS is also a central component of bacterial nitrogen metabolism and a potential drug target. Previous studies had investigated the structures of bacterial and plant GSs. In the present publication, we report the first structures of mammalian GSs. The apo form of the canine enzyme was solved by molecular replacement and refined at a resolution of 3 A. Two structures of human glutamine synthetase represent complexes with: a) phosphate, ADP, and manganese, and b) a phosphorylated form of the inhibitor methionine sulfoximine, ADP and manganese; these structures were refined to resolutions of 2.05 A and 2.6 A, respectively. Loop movements near the active site generate more closed forms of the eukaryotic enzymes when substrates are bound; the largest changes are associated with the binding of the nucleotide. Comparisons with earlier structures provide a basis for the design of drugs that are specifically directed at either human or bacterial enzymes. The site of binding the amino acid substrate is highly conserved in bacterial and eukaryotic GSs, whereas the nucleotide binding site varies to a much larger degree. Thus, the latter site offers the best target for specific drug design. Differences between mammalian and plant enzymes are much more subtle, suggesting that herbicides targeting GS must be designed with caution.